bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2022–08–21
47 papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. METTL3 promotes the growth and metastasis of pancreatic cancer by regulating the m6A modification and stability of E2F5.
  2. N6-methyladenosine demethylase ALKBH5 suppresses colorectal cancer progression potentially by decreasing PHF20 mRNA methylation.
  3. Growth factor receptor signaling induces mitophagy through epitranscriptomic regulation.
  4. The role, mechanism, and application of RNA methyltransferase METTL14 in gastrointestinal cancer.
  5. The m6A methyltransferase WTAP plays a key role in the development of diffuse large B-cell lymphoma via regulating the m6A modification of catenin beta 1.
  6. METTL3 promotes prostatic hyperplasia by regulating PTEN expression in an m6A-YTHDF2-dependent manner.
  7. m6A-related metabolism molecular classification with distinct prognosis and immunotherapy response in soft tissue sarcoma.
  8. m6A Modification-Mediated GRAP Regulates Vascular Remodeling in Hypoxic Pulmonary Hypertension.
  9. METTL3-induced DLGAP1-AS2 promotes non-small cell lung cancer tumorigenesis through m6A/c-Myc-dependent aerobic glycolysis.
  10. ELAVL1 promotes prostate cancer progression by interacting with other m6A regulators.
  11. RNA methylation regulators contribute to poor prognosis of hepatocellular carcinoma associated with the suppression of bile acid metabolism: a multi-omics analysis.
  12. m6A regulator-mediated methylation modification highlights immune infiltration patterns for predicting risk in hepatocellular carcinoma.
  13. The comprehensive expression and functional analysis of m6A modification "readers" in hepatocellular carcinoma.
  14. m6A mRNA methylation regulates the ERK/NF-κB/AKT signaling pathway through the PAPPA/IGFBP4 axis to promote proliferation and tumor formation in endometrial cancer.
  15. METTL14 Regulates Osteogenesis of Bone Marrow Mesenchymal Stem Cells via Inducing Autophagy Through m6A/IGF2BPs/Beclin-1 Signal Axis.
  16. m6A RNA methylation-mediated NDUFA4 promotes cell proliferation and metabolism in gastric cancer.
  17. RNA N6 -methyladenosine reader YTHDC1 is essential for TGF-beta-mediated metastasis of triple negative breast cancer.
  18. Microarray and bioinformatic analysis reveal the parental genes of m6A modified circRNAs as novel prognostic signatures in colorectal cancer.
  19. Targeting N7-Methylguanosine tRNA modification blocks hepatocellular carcinoma metastasis after insufficient radiofrequency ablation.
  20. Alteration of N6-methyladenosine epitranscriptome profiles in bilateral ureteral obstruction-induced obstructive nephropathy in juvenile rats.
  21. Mettl3 regulates hypertrophic differentiation of chondrocytes through modulating Dmp1 mRNA via Ythdf1-mediated m6A modification.
  22. Development and validation of prognostic m6A-related lncRNA and mRNA model in thyroid cancer.
  23. Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/β-catenin signaling to promote colorectal cancer progression by preventing m6A-mediated degradation of STEAP3 mRNA.
  24. Identification and Validation of METTL3-Related Molecules for Predicting Prognosis and Efficacy of Immunotherapy in Gastric Cancer Based on m6A Methylome and Transcriptome Sequencing Analysis.
  25. Prognostic Evaluation for Oral Squamous Cell Carcinoma: A Novel Method Based on m6A Methylation Regulators.
  26. The m6A-induced lncRNA CASC8 promotes proliferation and chemoresistance via upregulation of hnRNPL in esophageal squamous cell carcinoma.
  27. ALKBH5/MAP3K8 axis regulates PD-L1+ macrophage infiltration and promotes hepatocellular carcinoma progression.
  28. The LINC00623/NAT10 signaling axis promotes pancreatic cancer progression by remodeling ac4C modification of mRNA.
  29. FOXA1 prevents nutrients deprivation induced autophagic cell death through inducing loss of imprinting of IGF2 in lung adenocarcinoma.
  30. Delicaflavone Represses Lung Cancer Growth by Activating Antitumor Immune Response through N6-Methyladenosine Transferases and Oxidative Stress.
  31. A novel defined m7G regulator signature to investigate the association between molecular characterization and clinical significance in lung adenocarcinoma.
  32. Fusobacterium nucleatum induces excess METTL3-mediated miR-4717-3p maturation to promote colorectal cancer cell proliferation.
  33. Tumor-derived endomucin promotes colorectal cancer proliferation and metastasis.
  34. Multi-omics analysis of expression and prognostic value of NSUN members in prostate cancer.
  35. Poly(ADP-ribosyl)ation of acetyltransferase NAT10 by PARP1 is required for its nucleoplasmic translocation and function in response to DNA damage.
  36. APAF1-Binding Long Noncoding RNA Promotes Tumor Growth and Multidrug Resistance in Gastric Cancer by Blocking Apoptosome Assembly.
  37. A systemic pan-cancer analysis of MPZL3 as a potential prognostic biomarker and its correlation with immune infiltration and drug sensitivity in breast cancer.
  38. YTHDC1 is downregulated by the YY1/HDAC2 complex and controls the sensitivity of ccRCC to sunitinib by targeting the ANXA1-MAPK pathway.
  39. Tumor-associated macrophage-derived chemokine CCL5 facilitates the progression and immunosuppressive tumor microenvironment of clear cell renal cell carcinoma.
  40. RNA-Editing Enzyme ADAR1 p150 Isoform Is Critical for Germinal Center B Cell Response.
  41. KCNK3 inhibits proliferation and glucose metabolism of lung adenocarcinoma via activation of AMPK-TXNIP pathway.
  42. Nitidine chloride induces cardiac hypertrophy in mice by targeting autophagy-related 4B cysteine peptidase.
  43. NAT10 promotes cell proliferation by acetylating CEP170 mRNA to enhance translation efficiency in multiple myeloma.
  44. Hidden patterns of gene expression provide prognostic insight for colorectal cancer.
  45. Lysine demethylase KDM1A promotes cell growth via FKBP8-BCL2 axis in hepatocellular carcinoma.
  46. Chemoprotective Effect of Decalactone on Hepatic Cancer via Diminishing the Inflammatory Response and Oxidative Stress.
  47. SHMT2 promotes tumor growth through VEGF and MAPK signaling pathway in breast cancer.
  1. Cell Signal. 2022 Aug 16. pii: S0898-6568(22)00202-9. [Epub ahead of print] 110440
    METTL3 promotes the growth and metastasis of pancreatic cancer by regulating the m6A modification and stability of E2F5.
    Yan Tang, Guo Gao, Wen-Wen Xia, Jing-Bo Wang.
       BACKGROUND: Pancreatic cancer belongs to lethal cancer with limited efficient treatment currently, and its main cause of death is rapid tumor growth and early metastasis. N6-methyladenosine (m6A) modification is a new method of epigenetic gene regulation involved in tumor progression, in which methyltransferase-like 3(METTL3) is the sole catalytic subunit. However, the role of METTL3 in pancreatic cancer remains to be explored.
    METHODS: m6A level was measured using MeRIP assay, and RT-qPCR and western blot were applied to determine mRNA and protein expression, respectively. Cellular behaviors were detected using CCK-8, EdU, wound healing and transwell assays. Xenograft assays were conducted to further verify the roles of METTL3 in pancreatic cancer.
    RESULTS: METTL3 was highly expressed in pancreatic cancer. However, downregulation of METTL3 restrained the viability, migration and invasion of pancreatic cancer cells. Moreover, E2F5 was found to be positively regulated by METTL3. Intriguingly, the anti-tumor functions of METTL3 knockdown in the phenotype of pancreatic cancer cells were overturned by overexpression of E2F5. Silencing METTL3 resulted in the decreased stability of E2F5 by methylating E2F5.
    CONCLUSIONS: In conclusion, METTL3 can promote the malignant progression of pancreatic cancer by modifying E2F5 through m6A methylation to promote its stability.
    Keywords:  E2F5; METTL3; Metastasis; N6-methyladenosine; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.cellsig.2022.110440
  2. Clin Transl Med. 2022 Aug;12(8): e940
    N6-methyladenosine demethylase ALKBH5 suppresses colorectal cancer progression potentially by decreasing PHF20 mRNA methylation.
    Zhen Zhang, Ling Wang, Long Zhao, Quan Wang, Changjiang Yang, Mengmeng Zhang, Bo Wang, Kewei Jiang, Yingjiang Ye, Shan Wang, Zhanlong Shen.
       BACKGROUND: As the most widespread mRNAs modification, N6-methyladenosine (m6 A) is dynamically and reversibly modulated by methyltransferases and demethylases. ALKBH5 is a major demethylase, and plays vital roles in the progression of cancers. However, the role and mechanisms of ALKBH5 in colorectal cancer (CRC) is unclear.
    RESULTS: Herein, we discovered that in CRC, downregulated ALKBH5 was closely related to poor prognosis of CRC patients. Functionally, our results demonstrated that knockdown of ALKBH5 enhanced the proliferation, migration and invasion of LOVO and RKO in vitro, while overexpression of ALKBH5 inhibited the functions of these cells. The results also demonstrated that knockdown of ALKBH5 promoted subcutaneous tumorigenesis of LOVO in vivo, while overexpression of ALKBH5 suppressed this ability. Mechanistically, results from joint analyses of MeRIP-seq and RNA-seq indicated that PHF20 mRNA was a key molecule that was regulated by ALKBH5-mediated m6 A modification. Further experiments indicated that ALKBH5 may inhibit stability of PHF20 mRNA by removing the m6 A modification of PHF20 mRNA 3'UTR.
    CONCLUSIONS: ALKBH5 suppresses CRC progression by decreasing PHF20 mRNA methylation. ALKBH5-mediated m6 A modification of PHF20 mRNA can serve as a hopeful strategy for the intervention and treatment of CRC.
    Keywords:  ALKBH5; PHF20; colorectal cancer; m6A modification
    DOI:  https://doi.org/10.1002/ctm2.940
  3. Autophagy. 2022 Aug 18.
    Growth factor receptor signaling induces mitophagy through epitranscriptomic regulation.
    Deguan Lv, Kailin Yang, Jeremy N Rich.
      Aberrant growth factor receptor signaling is among the most common oncogenic drivers in cancer biology. Receptor signaling classically induces cancer growth through signaling cascades that mediate effects largely through transcriptional control. Recently, post-transcriptional RNA modifications, collectively designated as epitranscriptomics, have emerged as a critical layer of dysregulation in cancer biology. We recently reported that PDGFR (platelet derived growth factor receptor) activity in cancer stem cells (CSCs) derived from glioblastoma patients display increased post-transcriptional mRNA methylation (N6-methyladenosine [m6A]), which promotes CSC maintenance through regulation of mitophagy. Specifically, PDGF-PDGFRB signaling upregulates expression of the m6A methyltransferase METTL3, which then decorates the mitophagy regulator OPTN (optineurin) mRNA with m6A, thereby promoting OPTN mRNA degradation. Glioblastomas express lower levels of OPTN than normal brain, and forced expression of OPTN reduces tumor growth, supporting a tumor suppressive role for OPTN. Pharmacological targeting of METTL3 with PDGFR or activation of mitophagy demonstrate a combinatorial benefit. Collectively, our results suggest that upstream regulation of mitophagy in lethal cancers is mediated through growth factor receptor control of post-transcriptional RNA regulation, offering novel therapeutic paradigms.
    Keywords:  Cancer stem cell; METTL3; N6-methyladenosine (m6A); OPTN; PDGF; PDGFR; glioblastoma; mitophagy; optineurin
    DOI:  https://doi.org/10.1080/15548627.2022.2114765
  4. Mol Cancer. 2022 Aug 16. 21(1): 163
    The role, mechanism, and application of RNA methyltransferase METTL14 in gastrointestinal cancer.
    Bin Shi, Wei-Wei Liu, Ke Yang, Guan-Min Jiang, Hao Wang.
      Gastrointestinal cancer is the most common human malignancy characterized by high lethality and poor prognosis. Emerging evidences indicate that N6-methyladenosine (m6A), the most abundant post-transcriptional modification in eukaryotes, exerts important roles in regulating mRNA metabolism including stability, decay, splicing, transport, and translation. As the key component of the m6A methyltransferase complex, methyltransferase-like 14 (METTL14) catalyzes m6A methylation on mRNA or non-coding RNA to regulate gene expression and cell phenotypes. Dysregulation of METTL14 was deemed to be involved in various aspects of gastrointestinal cancer, such as tumorigenesis, progression, chemoresistance, and metastasis. Plenty of findings have opened up new avenues for exploring the therapeutic potential of gastrointestinal cancer targeting METTL14. In this review, we systematically summarize the recent advances regarding the biological functions of METTL14 in gastrointestinal cancer, discuss its potential clinical applications and propose the research forecast.
    Keywords:  Gastrointestinal cancer; METTL14; RNA modification; m6A
    DOI:  https://doi.org/10.1186/s12943-022-01634-5
  5. Ann Transl Med. 2022 Jul;10(14): 779
    The m6A methyltransferase WTAP plays a key role in the development of diffuse large B-cell lymphoma via regulating the m6A modification of catenin beta 1.
    Shuangshuang Guo, Chunling Zhao, Liang Fang, Wenzhong Xu, Samir Dalia, Jon Glass, Naoto Shikama, Zhiye Zhang.
       Background: Diffuse large B-cell lymphoma (DLBCL) is the most frequently occurring subtype of lymphoma. Unfortunately, the fundamental processes underlying the pathogenesis of DLBCL remain little understood. N6-methyladenosine (m6A) methylation has been shown to be the most common internal alteration of mRNAs found in eukaryotes, and it is thought to play a key role in cancer pathogenesis. However, the precise relationship between m6A mRNA methylation and DLBCL pathogenesis remains to be fully elucidated.
    Methods: The mRNA and protein expression of Wilms tumor 1-associating protein (WTAP) were determined using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis in lymphoma cells lines. The effects of WTAP expression on human lymphoma cells lines were assessed using cell proliferation assays, colony formation assays, and CCK8 assays. The Gene Expression Profiling Interactive Analysis (GEPIA) database was used to screen candidate gene targets of WTAP. Finally, the regulatory mechanisms of WTAP in DLBCL were investigated using methylated RNA immunoprecipitation (MeRIP) assays.
    Results: This study investigated the precise function of WTAP in DLBCL formation. The results demonstrated that the levels of m6A RNA methylation and WTAP expression were both elevated in DLBCL cell lines and tissues. Downregulation of WTAP expression in DLBCL cells caused a reduction in cell growth in a functional sense. WTAP knockdown reduced catenin beta 1 (CTNNB1) m6A methylation and CTNNB1 total mRNA levels. Furthermore, CTNNB1 overexpression eliminated the WTAP-induced reduction of cell growth in DLBCL cells.
    Conclusions: In conclusion, these findings demonstrated that WTAP promotes DLBCL development via modulation of m6A methylation in CTNNB1.
    Keywords:  CTNNB1; N6-methyladenosine (m6A); Wilms tumor 1-associating protein (WTAP); diffuse large B-cell lymphoma (DLBCL); proliferation
    DOI:  https://doi.org/10.21037/atm-22-3027
  6. Cell Death Dis. 2022 Aug 19. 13(8): 723
    METTL3 promotes prostatic hyperplasia by regulating PTEN expression in an m6A-YTHDF2-dependent manner.
    Jiaren Li, Hanyu Yao, Jin Huang, Chao Li, Yichuan Zhang, Ran Xu, Zhenting Wang, Zhi Long, Jin Tang, Long Wang.
      Uncontrolled epithelial cell proliferation in the prostate transition zone and the hyper-accumulation of mesenchymal-like cells derived from the epithelial-mesenchymal transition (EMT) of prostatic epithelium are two key processes in benign prostatic hyperplasia (BPH). m6A RNA modification affects multiple cellular processes, including cell proliferation, apoptosis, and differentiation. In this study, the aberrant up-regulation of methylase METTL3 in BPH samples suggests its potential role in BPH development. Elevated m6A modification in the prostate of the BPH rat was partially reduced by METTL3 knockdown. METTL3 knockdown also partially reduced the prostatic epithelial thickness and prostate weight, significantly improved the histological features of the prostate, inhibited epithelial proliferation and EMT, and promoted apoptosis. In vitro, METTL3 knockdown decreased TGF-β-stimulated BPH-1 cell proliferation, m6A modification, and EMT, whereas promoted cell apoptosis. METTL3 increased the m6A modification of PTEN and inhibited its expression through the reading protein YTHDF2. PTEN knockdown aggravated the molecular, cellular, and pathological alterations in the prostate of BPH rats and amplified TGF-β-induced changes in BPH-1 cells. More importantly, PTEN knockdown partially abolished the improving effects of METTL3 knockdown both in vivo and in vitro. In conclusion, the level of m6A modification is elevated in BPH; the METTL3/YTHDF2/PTEN axis disturbs the balance between epithelial proliferation and apoptosis, promotes EMT, and accelerates BPH development in an m6A modification-related manner.
    DOI:  https://doi.org/10.1038/s41419-022-05162-4
  7. Front Immunol. 2022 ;13 895465
    m6A-related metabolism molecular classification with distinct prognosis and immunotherapy response in soft tissue sarcoma.
    Zhen-Dong Huang, Yong-Cheng Fu, Shu-Yan Liu, Ya-Juan Mao, Yan Zhang, Chao Hu, Ren-Xiong Wei.
      N6-methyladenosine (m6A) methylation, one of the most crucial RNA modifications, has been proven to play a key role that affect prognosis of soft tissue sarcoma (STS). However, m6A methylation potential role in STS metabolic processes remains unknown. We comprehensively estimated the m6A metabolic molecular subtypes and corresponding survival, immunity, genomic and stemness characteristics based on 568 STS samples and m6A related metabolic pathways. Then, to quantify the m6A metabolic subtypes, machine learning algorithms were used to develop the m6A-metabolic Scores of individual patients. Finally, two distinct m6A metabolic subtypes (Cluster A and Cluster B) among the STS patients were identified. Compared to Cluster B subtype, the Cluster A subtype was mainly characterized by better survival advantages, activated anti-tumor immune microenvironment, lower gene mutation frequency and higher anti-PD-1 immunotherapy response rates. We also found that the m6A-metabolic Scores could accurately predict the molecular subtype of STS, prognosis, the abundance of immune cell infiltration, tumor metastasis status, sensitivity to chemotherapeutics and immunotherapy response. In general, this study revealed that m6A-regulated tumor metabolism processes played a key role in terms of prognosis of STS, tumor progression, and immune microenvironment. The identification of metabolic molecular subtypes and the construction of m6A-metabolic Score will help to more effectively guide immunotherapy, metabolic therapy and chemotherapy in STS.
    Keywords:  cancer metabolism; immunotherapy; m6A modification; machine learning; molecular classification; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2022.895465
  8. Am J Respir Cell Mol Biol. 2022 Aug 16.
    m6A Modification-Mediated GRAP Regulates Vascular Remodeling in Hypoxic Pulmonary Hypertension.
    Pengfei Liu, Aikai Zhang, Zheng Ding, Dongpu Dai, Boyan Li, Shao-Fei Liu, Jingjing Xu, Zhe Cheng, Song Zhao, Xiaoyan Zhao, Jianzeng Dong.
      Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular resistance (PVR) induced by human pulmonary arterial smooth muscle cells (HPASMCs) proliferation, migration and apoptosis resistance. N6-methyladenosine (m6A) is the most prevalent RNA posttranscriptional modification in eukaryotic cells. However, its role in PAH remains elusive. We designed this study to investigate whether m6A modification and its effector proteins play a role in PVR. Lung samples were used to profile m6A levels in control and PAH patients. Bioinformatics analysis, real-time PCR, immunohistochemistry, and western blotting were used to determine the role of m6A effectors in PAH. The biological effects of GRAP modified by m6A were investigated using vitro and in vivo models. Furthermore, RIP-PCR was used to assess the writers and readers of GRAP. In this study, we revealed that m6A-modified GRAP mRNA was upregulated in PAH lung samples, cHx/Su-induced mouse models and hypoxia-stimulated HPASMCs; however, GRAP mRNA and protein were abnormally downregulated. Functionally, overexpression of GRAP drastically alleviated the proliferative and invasive ability of PAH HPASMCs through inhibition of the Ras/ERK signaling pathway in vitro and in vivo. In addition, methyltransferase-like 14 (METTL14) and the m6A binding protein YTHDF2 were significantly increased in PAH. Moreover, we found that m6A-modified GRAP mRNA was recognized by YTHDF2 to mediate the degradation. GRAP expression was consistently negatively correlated with METTL14 and YTHDF2. Taken together, for the first time, our findings highlight the function and therapeutic target value of GRAP and extend understanding of the importance of RNA epigenetics in PAH.
    Keywords:  GRAP, YTHDF2, METTL14, m6A modification, pulmonary arterial hypertension, pulmonary vascular remodeling
    DOI:  https://doi.org/10.1165/rcmb.2021-0429OC
  9. Cell Cycle. 2022 Aug 16. 1-13
    METTL3-induced DLGAP1-AS2 promotes non-small cell lung cancer tumorigenesis through m6A/c-Myc-dependent aerobic glycolysis.
    Qiang Zhang, Yu Zhang, Hui Chen, Lei-Na Sun, Bin Zhang, Dong-Sheng Yue, Chang-Li Wang, Zhen-Fa Zhang.
      The critical roles of N6-methyladenosine (m6A) modification have been demonstrated by more and more evidence. However, the cross talk of m6A and long noncoding RNAs (lncRNAs) in non-small cell lung cancer (NSCLC) tumorigenesis is still unclear. Here, this work focused on the functions and molecular mechanism of m6A-modified lncRNA DLGAP1 antisense RNA 2 (DLGAP1-AS2) in NSCLC. Microarray analysis found that lncRNA DLGAP1-AS2 is upregulated in NSCLC cells. Clinical data showed that DLGAP1-AS2 high-expression was correlated with advanced pathological stage and poor prognosis. Functionally, DLGAP1-AS2 overexpression promoted the aerobic glycolysis and DLGAP1-AS2 knockdown suppressed the tumor growth of NSCLC cells. Mechanistically, m6A methyltransferase METTL3 enhanced the stability of DLGAP1-AS2 via m6A site binding. Moreover, DLGAP1-AS2 interacted with YTHDF1 to enhance the stability of c-Myc mRNA through DLGAP1-AS2/YTHDF1/m6A/c-Myc mRNA. In conclusion, our work indicates the functions of m6A-modified DLGAP1-AS2 in the NSCLC aerobic glycolysis, disclosing a potential m6A-dependent manner for NSCLC treatment.
    Keywords:  DLGAP1-AS2; N6-methyladenosine; YTHDF1; aerobic glycolysis; non-small cell lung cancer
    DOI:  https://doi.org/10.1080/15384101.2022.2105885
  10. Front Oncol. 2022 ;12 939784
    ELAVL1 promotes prostate cancer progression by interacting with other m6A regulators.
    Zhonglin Cai, Huan Xu, Gang Bai, Hanjing Hu, Di Wang, Hongjun Li, Zhong Wang.
      N6-Methyladenosine (m6A) imbalance is an important factor in the occurrence and development of prostate cancer (PCa). Many m6A regulators have been found to be significantly dysregulated in PCa. ELAVL1 is an m6A binding protein that can promote the occurrence and development of tumors in an m6A-dependent manner. In this study, we found that most m6A regulators were significantly dysregulated in PCa, and some m6A regulators were associated with the progression-free interval. Mutations and copy number variations of these m6A regulators can alter their expression. However, ELAVL1 mutations were not found in PCa. Nevertheless, ELAVL1 upregulation was closely related to PCa proliferation. High ELAVL1 expression was also related to RNA metabolism. Further experiments showed that ELAVL1 interacted with other m6A regulators and that several m6A regulatory mRNAs have m6A sites that can be recognized by ELAVL1. Additionally, protein-protein interactions occur between ELAVL1 and other m6A regulators. Finally, we found that the dysregulation of ELAVL1 expression occurred in almost all tumors, and interactions between ELAVL1 and other m6A regulators also existed in almost all tumors. In summary, ELAVL1 is an important molecule in the development of PCa, and its interactions with other m6A regulators may play important roles in PCa progression.
    Keywords:  ELAVL1; interaction; m6A; m6A regulators; prostate cancer
    DOI:  https://doi.org/10.3389/fonc.2022.939784
  11. Am J Cancer Res. 2022 ;12(7): 2989-3013
    RNA methylation regulators contribute to poor prognosis of hepatocellular carcinoma associated with the suppression of bile acid metabolism: a multi-omics analysis.
    Tao Zhang, Jian Gu, Xinyi Wang, Jiajia Luo, Jing Yan, Kailin Cai, Huili Li, Yingli Nie, Xiangdong Chen, Jiliang Wang.
      RNA methylation has been known to promote the initiation and progression of many types of cancer, including hepatocellular carcinoma (HCC). To fully understand the importance of this post-transcriptional modification in HCC, a thorough investigation that combines different patterns of RNA methylation is urgently needed. In this study, we investigated the regulators of the three most common types of RNA methylation: m6A, N1-methyladenosine (m1A) and 5-methylcytosine (m5C). Based on the genomic and proteomic data, we constructed a classifier consisting of seven RNA methylation regulators. This classifier performed well and robustly predicted the prognosis of HCC patients. By analysis using this classifier, we found that the primary bile acid biosynthesis pathway was mostly downregulated in high-risk HCC patients. Furthermore, we found that the gene expression patterns regulated by several bile acids were similar to those regulated by some well-defined anti-tumor compounds, indicating that bile acid metabolism plays a crucial role in the progression of HCC, and the related metabolites can be used as the potential agents for HCC treatments. Moreover, our study revealed a crosstalk between RNA methylation and bile acid regulators, demonstrating a novel mechanism of the downregulation of bile acid metabolism in HCC and providing new insights into how RNA methylation regulators affect the oncogenesis of HCC.
    Keywords:  5-methylcytosine; Hepatocellular carcinoma; N1-methyladenosine; N6-methyladenosine; bile acid; prognosis
  12. J Cancer Res Clin Oncol. 2022 Aug 16.
    m6A regulator-mediated methylation modification highlights immune infiltration patterns for predicting risk in hepatocellular carcinoma.
    Dongkai Zhou, Yizhi Wang, Wei Wei, Wei Zhou, Jin Gu, Yang Kong, Qifan Yang, Yingsheng Wu.
       BACKGROUND: Increasing studies have demonstrated the biological function of RNA N6-methyladenosine (m6A) modifications in tumorigenesis. However, the potential role of m6A modifications in the tumor immune microenvironment (TIME) of hepatocellular carcinoma (HCC) remains unclear.
    METHODS: Herein, 23 m6A regulators were fetched and introduced into consensus clustering to identify distinct m6A modification patterns and develop m6A-based molecular signatures. Then, a principal component analysis algorithm was employed to construct an m6A-based scoring system to further quantify m6A modification patterns in individual tumors. Immunophenoscore (IPS) was used to estimate the immunotherapeutic response of patients.
    RESULTS: Three different m6A modification patterns with distinct prognoses and biological signatures were identified among 611 HCC samples. The TIME characteristics of these three patterns were consistent with three known immune profiles: immune-oasis, immune-excluded, and immune-inflamed phenotypes. Identifying m6A modification patterns within individual tumors based on the m6Ascore, developed under the m6A-related signature genes, contributed to elaborating biological processes, clinical outcomes, immune cell infiltration, immunotherapeutic effects, and genetic variations. The low-m6Ascore subtype, characterized by immunosuppression, suggested an immune-suppressed phenotype and a low probability of benefiting from immunotherapy. Finally, the potential function of PRDM4 in HCC was explored.
    CONCLUSION: This study comprehensively elucidated the indispensable role of m6A modification patterns in the complexity of TIME. The quantitative identification of m6A modification patterns in individual tumors will contribute to optimizing precision immunotherapy.
    Keywords:  Hepatocellular carcinoma; Immunotherapy; PRDM4; Tumor immune microenvironment; Tumor mutation burden; m6A modification patterns
    DOI:  https://doi.org/10.1007/s00432-022-04255-z
  13. Aging (Albany NY). 2022 Aug 12. 14(undefined):
    The comprehensive expression and functional analysis of m6A modification "readers" in hepatocellular carcinoma.
    Sha Qin, Gaoming Liu, Haoer Jin, Xue Chen, Jiang He, Juxiong Xiao, Yan Qin, Yitao Mao, Luqing Zhao.
      N6-methyladenosine (m6A) modification regulators are essential for the diagnosis and treatment of various cancers. However, the comprehensive analysis about roles of m6A "readers" in hepatocellular carcinoma (HCC) remains unclear. UALCAN, GEPIA2, HPA, Kaplan Meier plotter, cBioPortal, STRING WebGestalt, Metascape and TIMER 2.0 database and Cytoscape software were used to comprehensively analyze the bioinformatic data. We found that m6A "readers" were upregulated at the mRNA level and protein level in HCC patients. Highly expressed YTHDF1, IGF2BP3 and NKAP were positively correlated with advanced HCC stage and had a poor prognosis in OS and PFS. The gene alterations of m6A "readers" happened frequently, and YTHDF3 had the highest mutation rate. The function of m6A "readers" on HCC may be closely correlated with splicing related proteins (including HNRNP family, SNRP family, and SR family), metabolic process, protein binding and RNA splicing related signaling pathways. Moreover, although the correlation of YTHDF3 and CD8+ T cell infiltration, and the correlation of IGF2BP3 and infiltration of mast cells and CAF are negative, most m6A "readers" had a positive correlation with immune cells (including CD8+ T cell, CD4+ T cell, Tregs, B cell, neutrophil, monocyte, macrophage, myeloid dendritic cell, nature killer cell, mast cell, and CAF). Macrophages, CD4+ T cell, Treg, B cell, monocyte, and myeloid dendritic cell had a positively strong correlation (Rho>0.4) with most m6A "readers" (such as YTHDC1, YTHDC2, YTHDF1, IGF2BP3, HNRNPA2B1 and HNRNPC). In conclusion, by comprehensive analysis of m6A "readers", we found that they were involved in the prognosis of HCC, and m6A "readers" might regulate the development and progression of HCC by participating in some metabolism-related and RNA splicing-related signaling pathways as well as immune cell infiltration.
    Keywords:  N6-methyladenosine (m6A) modification; expression profiles; functional analysis; hepatocellular carcinoma (HCC); immune cell infiltration
    DOI:  https://doi.org/10.18632/aging.204217
  14. Cell Biol Toxicol. 2022 Aug 15.
    m6A mRNA methylation regulates the ERK/NF-κB/AKT signaling pathway through the PAPPA/IGFBP4 axis to promote proliferation and tumor formation in endometrial cancer.
    Peng Ruan, Shujun Wang, Chaoyi Yang, Xiaohui Huang, Pengxing Sun, Aili Tan.
      N6-methyladenosine (m6A) mRNA methylation has been considered a gene modulatory mechanism involved in disease progression and carcinogenesis. Herein, we aimed to explore the specific mechanism of m6A mRNA methylation in endometrial cancer. RT-qPCR was implemented to test the clinical correlation between m6A methylation and endometrial cancer. Bioinformatics analysis was performed to screen the genes related to endometrial cancer, and SRAMP was utilized for the prediction of m6A targets. Western blot assay and MeRIP-qPCR experiments were conducted to verify the effect of m6A methylation on the candidate genes and the signaling pathways involved in the occurrence of endometrial cancer. m6A-seq, RT-qPCR, and polysome profiling were used to confirm the mechanisms of m6A methylation in modulating related genes and pathways. The levels of m6A methylation, METTL3, and IGFBP4 were reduced in tumor tissues of patients with endometrial cancer, and SRAMP analysis confirmed that IGFBP4 and PAPPA had m6A methylation sites. Reduced m6A methylation promoted endometrial cancer cell progression and tumor formation in vivo. m6A methylation of RNA in endometrial cancer cells directly modulated IGFBP4 and PAPPA expression. m6A methylation regulated the PAPPA/IGFBP4 axis, thereby influencing endometrial cancer through the NF-κB and ERK signaling pathways. Knockdown of PAPPA or overexpression of IGFBP4 in endometrial cancer cells partially reduced disease progression caused by reduced m6A methylation. This research suggests that m6A mRNA methylation modulates the ERK/NF-κB/AKT signaling pathway through the PAPPA/IGFBP4 axis to induce cell proliferation and tumor formation in endometrial cancer. 1. METTL3 expressed modestly and m6A methylation of IGFBP4 and PAPPA mRNAs decreased in endometrial cancer; 2. YTHDF1-mediated IGFBP4 translation was reduced in HEC-1-A and AN3CA cells, and YTHDF2-mediated PAPPA mRNA degradation was blunted but its protein expression increased; 3. Increased PAPPA and reduced IGFBP4 activated IGF1-induced ERK, AKT, and NF-κB pathways by binding IGFR, thereby promoting cancer cell malignancy.
    Keywords:  AKT; ERK; IGFBP4; N6-methyladenosine mRNA methylation; NF-κB; PAPPA
    DOI:  https://doi.org/10.1007/s10565-022-09751-z
  15. Stem Cells Transl Med. 2022 Aug 18. pii: szac049. [Epub ahead of print]
    METTL14 Regulates Osteogenesis of Bone Marrow Mesenchymal Stem Cells via Inducing Autophagy Through m6A/IGF2BPs/Beclin-1 Signal Axis.
    Mingyu He, Hong Lei, Xiaoqi He, Ying Liu, Ao Wang, Zijing Ren, Xiaoyan Liu, Gege Yan, Wenbo Wang, Yang Wang, Guanghui Li, Tong Wang, Jiaying Pu, Zhihua Shen, Yanquan Wang, Jiajie Xie, Weijie Du, Ye Yuan, Lei Yang.
      The development of osteoporosis is often accompanied by autophagy disturbance, which also causes new osteoblast defects from bone marrow mesenchymal stem cells (BMSCs). However, the underlying molecular mechanisms are still not fully understood. Methyltransferase-like 14 (METTL14) is the main enzyme for N6-methyladenosine (m6A), the most prevalent internal modification in mammalian mRNAs, and it has been implicated in many bioprocesses. Herein, we demonstrate that METTL14 plays a critical role in autophagy induction and hinders osteoporosis process whose expression is decreased both in human osteoporosis bone tissue and ovariectomy (OVX) mice. In vivo, METTL14+/- knockdown mice exhibit elevated bone loss and impaired autophagy similar to the OVX mice, while overexpression of METTL14 significantly promotes bone formation and inhibits the progression of osteoporosis caused by OVX surgery. In vitro, METTL14 overexpression significantly enhances the osteogenic differentiation ability of BMSCs through regulating the expression of beclin-1 depending on m6A modification and inducing autophagy; the opposite is true with METTL14 silencing. Subsequently, m6A-binding proteins IGF2BP1/2/3 recognize m6A-methylated beclin-1 mRNA and promote its translation via mediating RNA stabilization. Furthermore, METTL14 negatively regulates osteoclast differentiation. Collectively, our study reveals the METTL14/IGF2BPs/beclin-1 signal axis in BMSCs osteogenic differentiation and highlights the critical roles of METTL14-mediated m6A modification in osteoporosis.
    Keywords:  METTL14; autophagy; bone marrow mesenchymal stem cells; m6A RNA methylation; osteogenic differentiation
    DOI:  https://doi.org/10.1093/stcltm/szac049
  16. Cell Death Dis. 2022 Aug 17. 13(8): 715
    m6A RNA methylation-mediated NDUFA4 promotes cell proliferation and metabolism in gastric cancer.
    Weihong Xu, Yanan Lai, Yunqi Pan, Meiyu Tan, Yanyun Ma, Huiming Sheng, Jiucun Wang.
      Gastric cancer (GC) is a malignancy with poor prognosis. NDUFA4 is reported to correlate with the progression of GC. However, its underlying mechanism in GC is unknown. Our study was to reveal the pathogenic mechanism of NDUFA4 in GC. NDUFA4 expression was explored in single-cell and bulk RNA-seq data as well as GC tissue microarray. Mitochondrial respiration and glycolysis were estimated by oxygen consumption rate and extracellular acidification rate, respectively. The interaction between NDUFA4 and METTL3 was validated by RNA immunoprecipitation. Flow cytometry was used to estimate cell cycle, apoptosis and mitochondrial activities. NDUFA4 was highly expressed in GC and its high expression indicated a poor prognosis. The knockdown of NDUFA4 could reduce cell proliferation and inhibit tumor growth. Meanwhile, NDUFA4 could promote glycolytic and oxidative metabolism in GC cells, whereas the inhibition of glycolysis suppressed the proliferation and tumor growth of GC. Besides, NDUFA4 inhibited ROS level and promoted MMP level in GC cells, whereas the inhibition of mitochondrial fission could reverse NDUFA4-induced glycolytic and oxidative metabolism and tumor growth of GC. Additionally, METTL3 could increase the m6A level of NDUFA4 mRNA via the m6A reader IGF2BP1 to promote NDUFA4 expression in GC cells. Our study revealed that NDUFA4 was increased by m6A methylation and could promote GC development via enhancing cell glycolysis and mitochondrial fission. NDUFA4 was a potential target for GC treatment.
    DOI:  https://doi.org/10.1038/s41419-022-05132-w
  17. Theranostics. 2022 ;12(13): 5727-5743
    RNA N6 -methyladenosine reader YTHDC1 is essential for TGF-beta-mediated metastasis of triple negative breast cancer.
    Brandon Tan, Keren Zhou, Wei Liu, Emily Prince, Ying Qing, Yangchan Li, Li Han, Xi Qin, Rui Su, Sheela Pangeni Pokharel, Lu Yang, Zhicong Zhao, Chao Shen, Wei Li, Zhenhua Chen, Zheng Zhang, Xiaolan Deng, Andrew Small, Kitty Wang, Keith Leung, Chun-Wei Chen, Binghui Shen, Jianjun Chen.
      RNA N6 -methyladenosine (m6A) modification and its regulators fine tune gene expression and contribute to tumorigenesis. This study aims to uncover the essential role and the underlying molecular mechanism(s) of the m6A reader YTHDC1 in promoting triple negative breast cancer (TNBC) metastasis.
    METHODS: In vitro and in vivo models were employed to determine the pathological function of YTHDC1 in TNBC metastasis. To identify bona fide YTHDC1 target RNAs, we conducted RNA-seq, m6A-seq, and RIP-seq, followed by integrative data analysis and validation assays.
    RESULTS: By analyzing The Cancer Genome Atlas (TCGA) dataset, we found that elevated expression of YTHDC1 is positively correlated with poor prognosis in breast cancer patients. Using a mammary fat pad mouse model of TNBC, YTHDC1 significantly promoted lung metastasis of TNBC cells. Through multiple transcriptome-wide sequencing and integrative data analysis, we revealed dysregulation of metastasis-related pathways following YTHDC1 depletion and identified SMAD3 as a bona fide YTHDC1 target RNA. Depletion of YTHDC1 caused nuclear retention of SMAD3 mRNA, leading to lower SMAD3 protein levels. Loss of YTHDC1 led to impaired TGF-β-induced gene expression, leading to inhibition of epithelial-mesenchymal transition (EMT) and suppressed TNBC cell migration and invasion. SMAD3 overexpression was able to restore the response to TGF-β in YTHDC1 depleted TNBC cells. Furthermore, we demonstrated that the oncogenic role of YTHDC1 is mediated through its recognition of m6A as m6A-binding defective mutants of YTHDC1 were unable to rescue the impaired cell migration and invasion of YTHDC1 knockout TNBC cells.
    CONCLUSIONS: We show that YTHDC1 plays a critical oncogenic role in TNBC metastasis through promoting the nuclear export and expression of SMAD3 to augment the TGF-β signaling cascade. Overall, our study demonstrates that YTHDC1 is vital for TNBC progression by enhancing TNBC cell survival and TGF-β-mediated EMT via SMAD3 to enable the formation of distant metastasis and highlights the therapeutic potential of targeting the YTHDC1/m6A/SMAD3 axis for TNBC treatment.
    Keywords:  N6-methyladenosine; SMAD3; TGF-β; YTHDC1; metastasis
    DOI:  https://doi.org/10.7150/thno.71872
  18. Front Oncol. 2022 ;12 939790
    Microarray and bioinformatic analysis reveal the parental genes of m6A modified circRNAs as novel prognostic signatures in colorectal cancer.
    Wenken Liang, Liyuan Deng, Chune Mo, Wei Chen, Yu Sha, Jianling Shi, Xianliang Hou, Yuping Zhang, Min Yang, Minglin Ou.
       Background: Accumulating evidences have revealed that the abnormal N6-methyladenosine (m6A) modification is closely associated with the occurrence, development, progression and prognosis of cancer. It is noteworthy that m6A modification is widely existed in circRNAs and found its key biological functions in regulating circRNAs metabolism. However, the role of m6A modified circRNAs in colorectal cancer (CRC) remains unknown. To better understand the role of circRNAs in the pathogenesis of CRC, we focus on the relationship between m6A-modified circRNAs and their parental genes.
    Methods: Arraystar m6A-circRNA epitranscriptomic microarray was used to identify differentially m6A modified circRNAs between CRC and the control group. In addition, TCGA-COAD and GSE106582 cohort were used to identify differentially expressed mRNAs. In this study, we screened the parental genes for which both circRNAs and mRNAs were down-regulated further to analyze, including gene expression, survival prognosis, enrichment analysis. Additionally, Western Blotting was used to further validate the role of the parental gene in CRC.
    Results: We found that 1405 significantly downregulated circRNAs in CRC by our microarray data. Moreover, we obtained 113 parental genes for which both circRNAs and mRNAs were down-regulated to analyze the relationship with the prognosis of CRC based on TCGA-COAD cohort. And we identified nine potential prognostic genes, including ABCD3, ABHD6, GAB1, MIER1, MYOCD, PDE8A, RPS6KA5, TPM1 and WDR78. And low expression of these genes was associated with poor survival prognosis of the patients with CRC. In addition, we found that TPM1 is downregulated in CRC by western blotting experiment. And the calcium-signaling pathway may involve the process of the CRC progression.
    Conclusions: We identified nine potential prognostic genes, after analyzed the relationship between the parental genes of m6A modified circRNAs and the progression of CRC. Above all, our study further validated TPM1 can serve as a potentail signature for CRC patients.
    Keywords:  CRC; TCGA; circRNAs; m6A; prognostic signature
    DOI:  https://doi.org/10.3389/fonc.2022.939790
  19. Mol Ther. 2022 Aug 13. pii: S1525-0016(22)00492-0. [Epub ahead of print]
    Targeting N7-Methylguanosine tRNA modification blocks hepatocellular carcinoma metastasis after insufficient radiofrequency ablation.
    Shenghua Zhu, Yifan Wu, Xinyue Zhang, Sui Peng, Han Xiao, Shuling Chen, Lixia Xu, Tianhong Su, Ming Kuang.
      Radiofrequency heat ablation is an ideal radical treatment for hepatocellular carcinoma (HCC). However, insufficient radiofrequency ablation (IRFA) could lead to high recurrence of HCC. N7-methylguanosine (m7G) on tRNAs, an evolutionally conservative modification in mammalian and yeast, modulates heat stress responses and tumor progression, while its function in HCC recurrence after IRFA remains unknown. Here, we found that IRFA significantly up-regulates the level of m7G tRNA modification and its methyltransferase complex components METTL1/WDR4 in multiple systems including HCC patient-derived xenograft (PDX) mouse, patients' HCC tissues, sublethal-heat-treated models of HCC cell lines and organoids. Functionally, gain-/loss-of function assays showed that METTL1 mediated m7G tRNA modification promotes HCC metastasis under sublethal heat exposure both in vitro and in vivo. Mechanistically, we found that METTL1 and m7G tRNA modification enhance the translation of SLUG/SNAIL in a codon frequency dependent manner under sublethal heat stress. Overexpression of SLUG/SNAIL rescued the malignant potency of METTL1 knockdown HCC cells after sublethal heat exposure. Our study uncovers the key functions of m7G tRNA modification in heat stress responses and HCC recurrence after IRFA, providing molecular basis for targeting METTL1-m7G-SLUG/SNAIL axis to prevent HCC metastasis after radiofrequency heat ablation treatment.
    DOI:  https://doi.org/10.1016/j.ymthe.2022.08.004
  20. Pediatr Res. 2022 Aug 19.
    Alteration of N6-methyladenosine epitranscriptome profiles in bilateral ureteral obstruction-induced obstructive nephropathy in juvenile rats.
    Jinjin Feng, Yanping Zhang, Jianguo Wen, Yan Chen, Jin Tao, Shuanbao Yu, Zhaowei Zhu, Biao Dong, Yunlong Liu, Yafeng Fan, Lei Lv, Xuepei Zhang.
       BACKGROUND: Urinary tract obstruction is a common cause of renal failure in children and infants, and the pathophysiological mechanisms of obstructive nephropathy are largely unclear. It has been reported that m6A modulation is involved in renal injury. However, whether m6A RNA modulation is associated with obstructive nephropathy has not yet been reported. The aim of this study was to investigate the m6A epitranscriptome profiles in the kidneys of bilateral ureteral obstruction (BUO) in young rats.
    METHODS: The total level of m6A in the kidneys was measured by liquid chromatography-tandem mass spectrometry. The mRNAs of related genes were detected by real-time PCR. Methylated RNA immunoprecipitation sequencing was performed to map the epitranscriptome-wide m6A profile.
    RESULTS: Global m6A levels were increased after BUO, and the mRNA expression levels of m6A methyltransferases and demethylases were significantly decreased in BUO group rat kidneys; the expression levels of EGFR and Brcal were significantly upregulated, while the mRNA expression levels of Notch1 were downregulated (P < 0.05). A total of 154 genes associated with 163 m6A peaks were identified.
    CONCLUSION: The m6A epitranscriptome was significantly altered in BUO rat kidneys, which is potentially implicated in the pathophysiological processes of obstructive nephropathy.
    IMPACT: The m6A RNA modification was associated with the process of renal injury in ureteral obstructive nephropathy by participating in multiple dimensions. The dysregulation of m6A methyltransferases and demethylases may be related to the pathophysiological changes of BUO-induced obstructive nephropathy. The m6A RNA modulation of the genes EGFR, Brca1, and Notch1 that were related to the regulation of aquaporin2 might be the potential mechanism for the polyuresis after ureteral obstruction.
    DOI:  https://doi.org/10.1038/s41390-022-02228-z
  21. Bone. 2022 Aug 15. pii: S8756-3282(22)00199-5. [Epub ahead of print] 116522
    Mettl3 regulates hypertrophic differentiation of chondrocytes through modulating Dmp1 mRNA via Ythdf1-mediated m6A modification.
    Ying He, Wei Wang, Ping Luo, Yan Wang, Zhenru He, Wei Dong, Meie Jia, Xijie Yu, Beining Yang, Jiawei Wang.
      As the main cells in endochondral osteogenesis, chondrocytes have limited self-repair ability due to weak proliferation activity, low density, and dedifferentiation tendency. Here, a thorough inquiry about the effect and underlying mechanisms of methyltransferase like-3 (Mettl3) on chondrocytes was made. Functionally, it was indicated that Mettl3 promoted the proliferation and hypertrophic differentiation of chondrocytes. Mechanically, Dmp1 (dentin matrix protein 1) was proved to be the downstream direct target of Mettl3 for m6A modification to regulate the differentiation of chondrocytes through bioinformatics analysis and correlated experiments. The Reader protein Ythdf1 mediated Dmp1 mRNA catalyzed by Mettl3. In vivo, the formation of subcutaneous ectopic cartilage-like tissue further supported the in vitro results. In conclusion, the gene regulation of Mettl3/m6A/Ythdf1/Dmp1 axis in hypertrophic differentiation of chondrocytes for the development of endochondral osteogenesis may supply a promising treatment strategy for the repair and regeneration of bone defects.
    Keywords:  Dentin matrix protein 1; Endochondral osteogenesis; Methyltransferase like-3; YTH N(6)-Methyladenosine RNA binding protein 1; m(6)A modification
    DOI:  https://doi.org/10.1016/j.bone.2022.116522
  22. Am J Cancer Res. 2022 ;12(7): 3259-3279
    Development and validation of prognostic m6A-related lncRNA and mRNA model in thyroid cancer.
    Yu Zhu, Tian Yu, Ju Huang, Xitao Ma, Tao Shen, Annuo Li, Rensong Yue.
      Although N6-methyladenosine (m6A) regulators and lncRNAs influence the carcinogenesis of thyroid cancer (THCA), the association between m6A-related lncRNAs and THCA remains unexplored. Therefore, we have developed and validated a prognostic model based on m6A-related lncRNAs and mRNAs in THCA. Data from the Cancer Genome Atlas were used to analyze the expression and prognostic characteristics of m6A-related lncRNAs and mRNAs in THCA. Univariate Cox regression analysis was used to screen out independent prognostic factors, while Lasso Cox regression was performed to construct m6A-related lncRNA and mRNA models. The correlation between the prognostic models and gene mutation, immune cell infiltration, tumor microenvironment score, tumor mutational burden, and microsatellite instability were assessed. The prognostic models showed excellent accuracy in predicting the prognosis of patients with THCA. Our study established an m6A-related nomogram capable of predicting the prognosis of patients with THCA. In addition, the hub lncRNAs and mRNAs provide insight into improving the prognosis of THCA. These findings can improve our understanding of m6A modifications in THCA and the prognosis and treatment strategies of THCA.
    Keywords:  N6-methyladenosine; cancer; endocrine; long non-coding RNA; nomogram; tumor
  23. Mol Cancer. 2022 Aug 19. 21(1): 168
    Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/β-catenin signaling to promote colorectal cancer progression by preventing m6A-mediated degradation of STEAP3 mRNA.
    Li Zhou, Jingwen Jiang, Zhao Huang, Ping Jin, Liyuan Peng, Maochao Luo, Zhe Zhang, Yan Chen, Na Xie, Wei Gao, Edouard C Nice, Jing-Quan Li, Hai-Ning Chen, Canhua Huang.
       BACKGROUND: Hypoxia, a typical hallmark of solid tumors, exhibits an essential role in the progression of colorectal cancer (CRC), in which the dysregulation of long non-coding RNAs (lncRNAs) is frequently observed. However, the underlying mechanisms are not clearly defined.
    METHODS: The TCGA database was analyzed to identify differential lncRNA expression involved in hypoxia-induced CRC progression. qRT-PCR was conducted to validate the upregulation of lncRNA STEAP3-AS1 in CRC cell lines and tumor-bearing mouse and zebrafish models under hypoxia. ChIP-qRT-PCR was used to detect the transcriptional activation of STEAP3-AS1 mediated by HIF-1α. RNA-seq, fluorescent in situ hybridization, RNA pulldown, RNA immunoprecipitation, co-immunoprecipitation, immunofluorescence and immunoblot experiments were used to ascertain the involved mechanisms. Functional assays were performed in both in vitro and in vivo models to investigate the regulatory role of STEAP3-AS1/STEAP3/Wnt/β-catenin axis in CRC proliferation and metastasis.
    RESULTS: Here, we identified a hypoxia-induced antisense lncRNA STEAP3-AS1 that was highly expressed in clinical CRC tissues and positively correlated with poor prognosis of CRC patients. Upregulation of lncRNA STEAP3-AS1, which was induced by HIF-1α-mediated transcriptional activation, facilitated the proliferation and metastasis of CRC cells both in vitro and in vivo. Mechanistically, STEAP3-AS1 interacted competitively with the YTH domain-containing family protein 2 (YTHDF2), a N6-methyladenosine (m6A) reader, leading to the disassociation of YTHDF2 with STEAP3 mRNA. This effect protected STEAP3 mRNA from m6A-mediated degradation, enabling the high expression of STEAP3 protein and subsequent production of cellular ferrous iron (Fe2+). Increased Fe2+ levels elevated Ser 9 phosphorylation of glycogen synthase kinase 3 beta (GSK3β) and inhibited its kinase activity, thus releasing β-catenin for nuclear translocation and subsequent activation of Wnt signaling to support CRC progression.
    CONCLUSIONS: Taken together, our study highlights the mechanisms of lncRNA STEAP3-AS1 in facilitating CRC progression involving the STEAP3-AS1/STEAP3/Wnt/β-catenin axis, which may provide novel diagnostic biomarkers or therapeutic targets to benefit CRC treatment. Hypoxia-induced HIF-1α transcriptionally upregulates the expression of lncRNA STEAP3-AS1, which interacts competitively with YTHDF2, thus upregulating mRNA stability of STEAP3 and consequent STEAP3 protein expression. The enhanced STEAP3 expression results in production of cellular ferrous iron (Fe2+), which induces the Ser 9 phosphorylation and inactivation of GSK3β, releasing β-catenin for nuclear translocation and contributing to subsequent activation of Wnt signaling to promote CRC progression.
    Keywords:  Colorectal cancer; Hypoxia; LncRNA STEAPS-AS1; STEAP3; Wnt/β-catenin; YTHDF2; m6A modification
    DOI:  https://doi.org/10.1186/s12943-022-01638-1
  24. Front Oncol. 2022 ;12 935239
    Identification and Validation of METTL3-Related Molecules for Predicting Prognosis and Efficacy of Immunotherapy in Gastric Cancer Based on m6A Methylome and Transcriptome Sequencing Analysis.
    Shuran Chen, Xu Su, Jing Wang, Ni Zheng, Yuan Tang, Guisen Peng, Rui Dong, Fei Lu, Mulin Liu, Yunli Zhao, Huazhang Wu.
      Abnormal N6-methyladenosine (m6A) modification levels caused by METTL3 have been identified to be a critical regulator in human cancers, and its roles in the immune microenvironment and the relationship between targeted therapy and immunotherapy sensitivity in gastric cancer (GC) remain poorly understood. In this study, we assessed the transcriptome-wide m6A methylation profile after METTL3 overexpression by m6A sequencing and RNA sequencing in BGC-823 cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to analyze the function of core targets of METTL3. Eighteen methylation core molecules were identified in GC patients by combining transcriptome and methylome sequencing. GC patients can be separated into two subtypes based on the expression of 18 methylation core molecules. Furthermore, subgroup analysis showed that patients with different subtypes had a different OS, PFS, stage, grade, and TMB. Gene set enrichment analysis (GSEA) showed that immune-related pathways were enriched among subtype A. The ESTIMATE analysis suggested that the extent of infiltration of immune cells was different in two subtypes of GC patients. Tumor Immune Dysfunction and Exclusion (TIDE) and The Cancer Immunome Atlas (TCIA) database also showed that there were significant differences in the efficacy of immunotherapy among different types of GC patients. Altogether, our results reveal that METTL3-mediated m6A methylation modification is associated with the immune microenvironment and the effects of immunotherapy in GC patients. Our findings provide novel insights for clinicians in the diagnosis and optimal treatment of GC patients.
    Keywords:  METTL3; gastric cancer; immune checkpoint; immune microenvironment; m6A modification
    DOI:  https://doi.org/10.3389/fonc.2022.935239
  25. Curr Med Sci. 2022 Aug;42(4): 841-846
    Prognostic Evaluation for Oral Squamous Cell Carcinoma: A Novel Method Based on m6A Methylation Regulators.
    Li Xu, Cheng Yu, Xi-Jin Du.
       OBJECTIVE: This study aimed to examine a novel method for prognostic evaluation of patients with oral squamous cell carcinoma (OSCC) based on the expression of heterogeneous nuclear ribonucleoprotein C (HNRNPC), YTH domain-binding protein 2 (YTHDF2), and methyltransferase 14 (METTL14).
    METHODS: We obtained the RNA sequence and clinical information of OSCC patients from The Cancer Genome Atlas database. An optical method was established by the least absolute shrinkage and selection operator Cox regression algorithm, which was used to calculate the risk score of every sample. In addition, all samples (n=239) were classified into high-risk (n=119) and low-risk (n=120) groups, and the overall survival (OS) time and clinical characteristics were compared between groups. Moreover, bioinformatics analysis was carried out. Gene set enrichment analysis was performed to investigate the signaling pathways of HNRNPC, YTHDF2, and METTL14.
    RESULTS: The two groups showed significantly different OS time, tumor grades, tumor stages, and pathologic T stages (P<0.05). The receiver operating characteristic analysis identified that our method was effective and it was more accurate than use of age, gender, tumor grade, tumor stage, pathologic T stage, and pathologic N stage in OSCC prognostic prediction. Gene set enrichment analysis revealed that HNRNPC, YTHDF2, and METTL14 were mainly associated with ubiquitin-mediated proteolysis, cell cycle, RNA degradation, and spliceosome signaling pathways.
    CONCLUSION: The method based on the expression of HNRNPC, YTHDF2, and METTL14 can predict the prognosis of patients with OSCC independently, and its prognostic value is better than that of clinicopathological characteristic indicators.
    Keywords:  RNA modification; The Cancer Genome Atlas; m6A methylation regulators; oral squamous cell carcinoma; prognostic prediction
    DOI:  https://doi.org/10.1007/s11596-022-2611-7
  26. Int J Biol Sci. 2022 ;18(13): 4824-4836
    The m6A-induced lncRNA CASC8 promotes proliferation and chemoresistance via upregulation of hnRNPL in esophageal squamous cell carcinoma.
    Qingnan Wu, Hongyue Zhang, Di Yang, Qingjie Min, Yan Wang, Weimin Zhang, Qimin Zhan.
      Long noncoding RNAs (lncRNAs) are dysregulated in many cancers. Here, we identified the molecular mechanisms of lncRNA Cancer Susceptibility Candidate 8 (CASC8) in promoting the malignancy of esophageal squamous cell carcinoma (ESCC). CASC8 was highly overexpressed in ESCC tissues and upregulation of CASC8 predicted poor prognosis in ESCC patients. Moreover, CASC8 decreased the cisplatin sensitivity of ESCC cells and promoted ESCC tumor growth in vivo. Mechanistically, CASC8 interacted with heterogeneous nuclear ribonucleoprotein L (hnRNPL) and inhibited its polyubiquitination and proteasomal degradation, thus stabilizing hnRNPL protein levels and activating the Bcl2/caspase3 pathway. Additionally, AlkB Homolog 5, RNA demethylase (ALKBH5)-mediated m6A demethylation stabilized the CASC8 transcript, resulting in CASC8 upregulation. Taken together, these findings identified an oncogenic function of CASC8 in the progression of ESCC, which suggest that CASC8 might become a potential prognostic biomarker in ESCC.
    Keywords:  CASC8; cell apoptosis; esophageal squamous cell carcinoma; lncRNA; m6A demethylation
    DOI:  https://doi.org/10.7150/ijbs.71234
  27. Int J Biol Sci. 2022 ;18(13): 5001-5018
    ALKBH5/MAP3K8 axis regulates PD-L1+ macrophage infiltration and promotes hepatocellular carcinoma progression.
    Yu You, Diguang Wen, Lu Zeng, Jiao Lu, Xiao Xiao, Yucheng Chen, Hua Song, Zuojin Liu.
      Hepatocellular carcinoma is one of the most common malignant tumors.M6A is a novel epigenetic modification that have been emerged as vital regulators for the progression of HCC. However, the regulatory role, clinical significance and the details of the modification, such as the impact on the local tumor environment, remain largely unclear. Our study showed that ALKBH5 was highly expressed in HCC and high ALKBH5 expression predicted a worse prognosis of HCC patients. Prediction of ALKBH5 function by tissue samples and single cell sequencing Gene Set Variation Analysis. Primary CD3 + T lymphocytes and bone marrow-derived macrophages were used to evaluate the effect of ALKBH5 on immune microenvironment. The results indicated that ALKBH5 promote HCC cell proliferation, metastasis and PD-L1+macrophage recruitment. Mechanistically the results showed that ALKBH5 regulates MAP3K8 expression in a m6A dependent manner which mediates the proliferation and metastasis of HCC cells. ALKBH5 also promotes the activation of JNK and ERK pathways through upregulating MAP3K8, thus regulating the expression of IL-8 and promoting macrophage recruitment. Taken together, these data show that ALKBH5 promotes HCC growth, metastasis and macrophage recruitment through ALKBH5/MAP3K8 axis and it may serve as a potential diagnostic marker and target for treatment of HCC patients.
    Keywords:  Hypoxia; Immune microenvironment; M6A; PD-L1; Tumor-associated macrophages
    DOI:  https://doi.org/10.7150/ijbs.70149
  28. J Hematol Oncol. 2022 Aug 17. 15(1): 112
    The LINC00623/NAT10 signaling axis promotes pancreatic cancer progression by remodeling ac4C modification of mRNA.
    Zengyu Feng, Kexian Li, Kai Qin, Juyong Liang, Minmin Shi, Yang Ma, Shiwei Zhao, Huaiyu Liang, Dongni Han, Baiyong Shen, Chenghong Peng, Hao Chen, Lingxi Jiang.
       BACKGROUND: Although a substantial increase in the survival of patients with other cancers has been observed in recent decades, pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest diseases. No effective screening approach exists.
    METHODS: Differential exosomal long noncoding RNAs (lncRNAs) isolated from the serum of patients with PDAC and healthy individuals were profiled to screen for potential markers in liquid biopsies. The functions of LINC00623 in PDAC cell proliferation, migration and invasion were confirmed through in vivo and in vitro assays. RNA pulldown, RNA immunoprecipitation (RIP) and coimmunoprecipitation (Co-IP) assays and rescue experiments were performed to explore the molecular mechanisms of the LINC00623/NAT10 signaling axis in PDAC progression.
    RESULTS: A novel lncRNA, LINC00623, was identified, and its diagnostic value was confirmed, as it could discriminate patients with PDAC from patients with benign pancreatic neoplasms and healthy individuals. Moreover, LINC00623 was shown to promote the tumorigenicity and migratory capacity of PDAC cells in vitro and in vivo. Mechanistically, LINC00623 bound to N-acetyltransferase 10 (NAT10) and blocked its ubiquitination-dependent degradation by recruiting the deubiquitinase USP39. As a key regulator of N4-acetylcytidine (ac4C) modification of mRNA, NAT10 was demonstrated to maintain the stability of oncogenic mRNAs and promote their translation efficiency through ac4C modification.
    CONCLUSIONS: Our data revealed the role of LINC00623/NAT10 signaling axis in PDAC progression, showing that it is a potential biomarker and therapeutic target for PDAC.
    DOI:  https://doi.org/10.1186/s13045-022-01338-9
  29. Cell Death Dis. 2022 Aug 16. 13(8): 711
    FOXA1 prevents nutrients deprivation induced autophagic cell death through inducing loss of imprinting of IGF2 in lung adenocarcinoma.
    Junjun Li, Yongchang Zhang, Li Wang, Min Li, Jianbo Yang, Pan Chen, Jie Zhu, Xiayu Li, Zhaoyang Zeng, Guiyuan Li, Wei Xiong, James B McCarthy, Bo Xiang, Mei Yi.
      Lung cancer remains one of the most common malignancies and the leading cause of cancer-related death worldwide. Forkhead box protein A1 (FOXA1) is a pioneer factor amplified in lung adenocarcinoma (LUAD). However, its role in LUAD remains elusive. In this study, we found that expression of FOXA1 enhanced LUAD cell survival in nutrients deprived conditions through inhibiting autophagic cell death (ACD). FOXA1 bound to the imprinting control region of insulin-like growth factor 2 (IGF2) and interacted with DNA methyltransferase 1 (DNMT1), leading to initiation of DNMT1-mediated loss of imprinting (LOI) of IGF2 and autocrine of IGF2. Blockage of IGF2 and its downstream insulin-like growth factor 1 receptor (IGF1R) abolished the protective effect of FOXA1 on LUAD cells in nutrients deprived conditions. Furthermore, FOXA1 suppressed the expression of the lysosomal enzyme glucocerebrosidase 1 (GBA1), a positive mediator of ACD, through ubiquitination of GBA1 enhanced by IGF2. Notably, FOXA1 expression in A549 cells reduced the efficacy of the anti-angiogenic drug nintedanib to inhibit xenograft tumor growth, whereas a combination of nintedanib with IGF1R inhibitor linsitinib or mTORC1 inhibitor rapamycin enhanced tumor control. Clinically, high expression level of FOXA1 protein was associated with unfavorable prognosis in LUAD patients of advanced stage who received bevacizumab treatment. Our findings uncovered a previously unrecognized role of FOXA1 in mediating loss of imprinting of IGF2, which confer LUAD cells enhanced survival ability against nutrients deprivation through suppressing autophagic cell death.
    DOI:  https://doi.org/10.1038/s41419-022-05150-8
  30. Oxid Med Cell Longev. 2022 ;2022 8619275
    Delicaflavone Represses Lung Cancer Growth by Activating Antitumor Immune Response through N6-Methyladenosine Transferases and Oxidative Stress.
    Xuewen Wang, Dafen Xu, Bing Chen, Dandan Huang, Zhijun Li, Yuxia Sui, Fei Lin, Hong Yao, Huang Yuan Li, Xinhua Lin.
      Our previous studies have shown that delicaflavone (DLL), a biocomponent extracted from Selaginella doederleinii Hieron, has antitumor activity. However, the role of DLL in the antitumor immune response is unknown. In this study, we tested the potential roles of DLL in antitumor immune response. An animal tumor model with Lewis lung cancer cell line (3LL) in C57BL/6 mice was established to determine whether DLL induced the tumor-bearing host's antitumor immune response. m6A-MeRIP-qPCR, western blot, and flow cytometry were performed to explore the underlying mechanisms. DLL inhibited the proliferation of 3LL lung cancer cells in vitro and in vivo and induced tumor cell oxidative stress. DLL significantly inhibited tumor growth in immunocompetent mice compared with nude mice. DLL treatment significantly increased Th1 cytokine production and CD8+ T cell infiltration into tumor tissues in tumor-bearing mice. DLL-mediated antitumor immune effects were reversed by overexpression of the N6-methyladenosine (m6A) transferase Mettl3/Mettl14. Mechanistically, DLL upregulated the expression of Stat1 and Irf1 and the secretion of cytokines by inhibiting Mettl3 and Mettl14 in lung cancer cells. In conclusion, DLL inhibited lung cancer cell growth by suppressing Mettl3/Mettl14 to activate antitumor immunity. These findings provided an opportunity to enhance lung cancer immunotherapy.
    DOI:  https://doi.org/10.1155/2022/8619275
  31. Front Oncol. 2022 ;12 897323
    A novel defined m7G regulator signature to investigate the association between molecular characterization and clinical significance in lung adenocarcinoma.
    Yi Dong, Yingge Li, Yi Yao, Qibin Song.
       Background: About170 chemical modifications to RNAs have been identified, which significantly affect gene expression. Dysregulation of RNA modifications induced by abnormal expression or mutations in RNA modifiers might result in cancer. The most frequent RNA modifications are N6-methyladenosine (m6A), 5-methylcytosine (m5C), and N7-methylguanosine (m7G). Lung cancer is the leading cause of cancer-related deaths globally. The present study aimed to investigate whether the expression of the m7G-related genes is linked to lung cancer cases with lung adenocarcinoma (LUAD), which accounts for about 40% of lung cancer cases.
    Methods: A total of 12 m7G-related differentially expressed genes (DEGs) were identified in LUAD patients by The Cancer Genome Atlas (TCGA). The least absolute shrinkage and selection operator (LASSO) Cox regression method was used to build a four-gene risk model. Then, LUAD patients in the TCGA cohort were divided into low- and high-risk groups based on their risk scores for subsequent molecular and clinical research.
    Results: Compared to the low-risk group, the high-risk group had a decreased overall survival (OS) (P=0.047). The risk score and stage were independent factors for predicting the OS of LUAD (P=0.0004 and P<0.0001, respectively). Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses based on the two groups showed that the DEGs were metabolically and hormonally related. The high-risk group showed a higher mutation rate and lesser immune cell infiltration, especially in TP53, KRAS, and MET. The expression level of PD-L1 and CTLA4 was high in the high-risk group (P<0.05). The high-risk group is more sensitive to anti-cancer therapy with lower IC50 and higher immunophenoscore (IPS).
    Conclusions: In this study, we developed a novel LUAD stratification model based on m7G-related genes that successfully predicts the prognosis of LUAD patients and serves as a guide for clinically personalized treatment.
    Keywords:  immunity; lung adenocarcinoma; m7G; mutation; prognosis
    DOI:  https://doi.org/10.3389/fonc.2022.897323
  32. Cancer Sci. 2022 Aug 19.
    Fusobacterium nucleatum induces excess METTL3-mediated miR-4717-3p maturation to promote colorectal cancer cell proliferation.
    Qiaolin Xu, Xiaoxue Lu, Jing Li, Yuyang Feng, Jie Tang, Tao Zhang, Yilan Mao, Yuanzhi Lan, Huaxing Luo, Linghai Zeng, Yuanyuan Xiang, Lv Hu, Yan Zhang, Qian Li, Ling Deng, Xiaoyi He, Bin Tang, Xuhu Mao, Dongzhu Zeng.
      Fusobacterium nucleatum (F. nucleatum) infection plays vital roles in colorectal cancer (CRC) progression. Over-expression of miR-4717-3p (miR-4717) has been previously up-regulated in F. nucleatum positive CRC tissues, however, the underlying mechanism is unknown. In this study, we found that miR-4717 promoted CRC cell proliferation in vitro and growth of CRC in vivo upon F. nucleatum infection. MiR-4717 suppressed the expression of mitogen-activated protein kinase kinase 4 (MAP2K4), a tumor suppressor, by directly targeting its 3'UTR. Furthermore, we confirmed that methyltransferase-like 3 (METTL3) -dependent m6 A methylation could methylate pri-miR-4717, which further promoted the maturation of pri-miR-4717, and METTL3 positively regulated CRC cell proliferation through miR-4717/MAP2K4 pathways. In conclusion, F. nucleatum-induced miR-4717 excessive maturation via METTL3-dependent m6 A modification promotes CRC cell proliferation, which provides a potential therapeutic target and diagnostic biomarker for CRC.
    Keywords:  Fusobacterium nucleatum; MAP2K4; METTL3; colorectal cancer; miR-4717-3p
    DOI:  https://doi.org/10.1111/cas.15536
  33. Cancer Med. 2022 Aug 15.
    Tumor-derived endomucin promotes colorectal cancer proliferation and metastasis.
    Qi Huang, Xue-Mei Li, Jing-Ping Sun, Yan Zhou.
       BACKGROUND: Endomucin (EMCN) is a type I transmembrane glycoprotein and a mucin-like component of the endothelial cell glycocalyx. The mechanism of EMCN action in colorectal cancer (CRC) remains unclear.
    AIMS: Our aim was to explore the role of EMCN in the progression of CRC.
    MATERIALS & METHODS: We examined EMCN expression in CRC tissues and normal para-carcinoma tissues. The function and mechanisms of EMCN were checked in CRC cell lines and in mouse xenograft. Additionally, we used co-immunoprecipitation and mass spectrometry to identify the potential EMCN-binding proteins. Functional annotation analysis showed where these genes were enriched.
    RESULTS: We found that EMCN was overexpressed in tumor tissues compared with that in normal para-carcinoma tissues. We also found that overexpression of EMCN induced CRC proliferation and metastasis both in vitro and in vivo. EMCN knockdown prevents epithelial-mesenchymal transition in vitro. We identified 178 potential EMCN-binding partners. Furthermore, functional annotation analysis indicated that these genes were considerably enriched in carcinogenic-related functions and pathways. Collectively, the identification of EMCN-binding partners enhanced our understanding of the mechanism of EMCN-mediated malignant phenotypes, and this research may provide valuable insights into the molecular mechanisms underlying CRC.
    CONCLUSION: Tumor-derived endomucin promotes colorectal cancer proliferation and metastasis. We identified 178 EMCN-binding proteins and initially screened three potential EMCN-interacting proteins: NALCN, and TPM2, ANKK1. Our study provides valuable insights into the molecular mechanisms underlying CRC development.
    Keywords:  colorectal cancer; endomucin; metastasis; proliferation
    DOI:  https://doi.org/10.1002/cam4.5055
  34. Front Oncol. 2022 ;12 965571
    Multi-omics analysis of expression and prognostic value of NSUN members in prostate cancer.
    Guangyu Sun, Shenfei Ma, Zhiwen Zheng, Xiaohua Wang, Shuaiqi Chen, Taihao Chang, Zhengxin Liang, Yuchen Jiang, Shengxian Xu, Ranlu Liu.
       Background: Prostate cancer is the most common tumor in men worldwide, seriously threatening the health of older men, and 5-methylcytosine (m5C) RNA modification has been shown to have a significant impact on the development and progression of various tumors. However, as the most critical methyltransferase for m5c RNA modification, the role of the NSUN members (NSUN1-7) in prostate cancer is unclear.
    Methods: We obtained sequencing data of genes and related clinical data of prostate cancer from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database and analyzed the correlation between NSUN members' expression and prognosis. we found that NSUN2 was closely implicated in the prognosis of prostate cancer, then verified the expression of NSUN2 in clinical samples, and obtained the correlation between NSUN2 and immune cell infiltration through CIBERSORT algorithm and ESTIMATE method. The relationship between NSUN2 copy number variation and immune cell infiltration was further analyzed in the TIMER database and identified signaling pathways associated with NSUN2 expression by GO, KEGG, and GSEA analysis. Finally, we verified the expression of NSUN2 in prostate cancer cell lines and confirmed the role of NSUN2 on the biological behavior of prostate cancer cells by proliferation and migration-related assays.
    Results: NOP2 and NSUN2 were upregulated in prostate tumor tissues. NSUN2 expression is closely associated with tumor prognosis. NSUN2 high expression implies poor clinical features, and the NSUN family is significantly associated with tumor stromal score and immune score. Besides, NSUN2 is associated with a variety of immune infiltrating cells (B cells memory, T cells CD4 memory resting, T cells CD4 memory activated, NK cells resting, and so on). High NSUN2 expression lowers the sensitivity of many chemotherapy drugs, such as docetaxel, doxorubicin, fluorouracil, cisplatin, and etoposide. In prostate cancer, the most common type of mutation in NSUN2 is amplification, and NSUN2 copy number variation is closely associated with NSUN2 expression and immune cell infiltration. GSEA analysis showed that the related genes were mainly enriched in ubiquitin-mediated protein hydrolysis, cell cycle, RNA degradation, endometrial cancer, prostate cancer, p53 signaling pathway, and NSUN2 potentiated the proliferation and migration of prostate cancer cells.
    Conclusions: NSUN2 is highly expressed in prostate cancer, which contributes to the progression of prostate cancer, and is closely implicated in immune cell infiltration and chemotherapy drugs. NSUN2 is expected to be a prospective marker and a new treatment target for prostate cancer.
    Keywords:  5-Methylcytosine (5mC); NSun2; immune cell infiltration; mutation; prostate cancer
    DOI:  https://doi.org/10.3389/fonc.2022.965571
  35. Cell Commun Signal. 2022 Aug 19. 20(1): 127
    Poly(ADP-ribosyl)ation of acetyltransferase NAT10 by PARP1 is required for its nucleoplasmic translocation and function in response to DNA damage.
    Hong-Yi Liu, Ying-Ying Liu, Yin-Ling Zhang, Yan Ning, Fang-Lin Zhang, Da-Qiang Li.
       BACKGROUND: N-acetyltransferase 10 (NAT10), an abundant nucleolar protein with both lysine and RNA cytidine acetyltransferase activities, has been implicated in Hutchinson-Gilford progeria syndrome and human cancer. We and others recently demonstrated that NAT10 is translocated from the nucleolus to the nucleoplasm after DNA damage, but the underlying mechanism remains unexplored.
    METHODS: The NAT10 and PARP1 knockout (KO) cell lines were generated using CRISPR-Cas9 technology. Knockdown of PARP1 was performed using specific small interfering RNAs targeting PARP1. Cells were irradiated with γ-rays using a 137Cs Gammacell-40 irradiator and subjected to clonogenic survival assays. Co-localization and interaction between NAT10 and MORC2 were examined by immunofluorescent staining and immunoprecipitation assays, respectively. PARylation of NAT10 and translocation of NAT10 were determined by in vitro PARylation assays and immunofluorescent staining, respectively.
    RESULTS: Here, we provide the first evidence that NAT10 underwent covalent PARylation modification following DNA damage, and poly (ADP-ribose) polymerase 1 (PARP1) catalyzed PARylation of NAT10 on three conserved lysine (K) residues (K1016, K1017, and K1020) within its C-terminal nucleolar localization signal motif (residues 983-1025). Notably, mutation of those three PARylation residues on NAT10, pharmacological inhibition of PARP1 activity, or depletion of PARP1 impaired NAT10 nucleoplasmic translocation after DNA damage. Knockdown or inhibition of PARP1 or expression of a PARylation-deficient mutant NAT10 (K3A) attenuated the co-localization and interaction of NAT10 with MORC family CW-type zinc finger 2 (MORC2), a newly identified chromatin-remodeling enzyme involved in DNA damage response, resulting in a decrease in DNA damage-induced MORC2 acetylation at lysine 767. Consequently, expression of a PARylation-defective mutant NAT10 resulted in enhanced cellular sensitivity to DNA damage agents.
    CONCLUSION: Collectively, these findings indicate that PARP1-mediated PARylation of NAT10 is key for controlling its nucleoplasmic translocation and function in response to DNA damage. Moreover, our findings provide novel mechanistic insights into the sophisticated paradigm of the posttranslational modification-driven cellular response to DNA damage. Video Abstract.
    Keywords:  DNA damage response; Nucleolar localization signal; Nucleoplasmic translocation; PARylation; Posttranslational modification
    DOI:  https://doi.org/10.1186/s12964-022-00932-1
  36. Adv Sci (Weinh). 2022 Aug 17. e2201889
    APAF1-Binding Long Noncoding RNA Promotes Tumor Growth and Multidrug Resistance in Gastric Cancer by Blocking Apoptosome Assembly.
    Qiang Wang, Chen Chen, Xiao Xu, Chuanjun Shu, Changchang Cao, Zhangding Wang, Yao Fu, Lei Xu, Kaiyue Xu, Jiawen Xu, Anliang Xia, Bo Wang, Guifang Xu, Xiaoping Zou, Ruibao Su, Wei Kang, Yuanchao Xue, Ran Mo, Beicheng Sun, Shouyu Wang.
      Chemotherapeutics remain the first choice for advanced gastric cancers (GCs). However, drug resistance and unavoidable severe toxicity lead to chemotherapy failure and poor prognosis. Long noncoding RNAs (lncRNAs) play critical roles in tumor progression in many cancers, including GC. Here, through RNA screening, an apoptotic protease-activating factor 1 (APAF1)-binding lncRNA (ABL) that is significantly elevated in cancerous GC tissues and an independent prognostic factor for GC patients is identified. Moreover, ABL overexpression inhibits GC cell apoptosis and promotes GC cell survival and multidrug resistance in GC xenograft and organoid models. Mechanistically, ABL directly binds to the RNA-binding protein IGF2BP1 via its KH1/2 domain, and then IGF2BP1 further recognizes the METTL3-mediated m6A modification on ABL, which maintains ABL stability. In addition, ABL can bind to the WD1/WD2 domain of APAF1, which competitively prevent cytochrome c from interacting with APAF1, blocking apoptosome assembly and caspase-9/3 activation; these events lead to resistance to cell death in GC cells. Intriguingly, targeting ABL using encapsulated liposomal siRNA can significantly enhance the sensitivity of GC cells to chemotherapy. Collectively, the results suggest that ABL can be a potential prognostic biomarker and therapeutic target in GC.
    Keywords:  ABL; IGF2BP1; apoptosis; apoptotic protease-activating factor 1 (APAF1); drug resistance; gastric cancer; m6A
    DOI:  https://doi.org/10.1002/advs.202201889
  37. Front Oncol. 2022 ;12 901728
    A systemic pan-cancer analysis of MPZL3 as a potential prognostic biomarker and its correlation with immune infiltration and drug sensitivity in breast cancer.
    Renhong Huang, Liangqiang Li, Zheng Wang, Kunwei Shen.
       Background: This study aimed to analyze the role of myelin protein zero-like 3 (MPZL3), a single membrane glycoprotein, in prognosis, tumor immune infiltration, and drug susceptibility in human cancers.
    Methods: Data regarding MPZL3 were extracted from the TCGA, GTEx, CellMiner, CCLE, TIMER, GSEA, and USCS Xena databases. The expression difference, survival outcomes, DNA methylation, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), tumor microenvironment (TME), immune cell infiltration, and drug sensitivity of MPZL3 were analyzed by R language software. Cell proliferation and drug sensitivity tests were applied to analyze the biological role of MPZL3 and drug sensitivities in breast cancer.
    Results: MPZL3 was highly expressed in most cancer types and correlated with unfavorable survival outcomes in several cancers. TMB, MSI, MMR, DNA methylation, and RNA modification played a significant role in mediating MPZL3 dysregulation in cancers, and MPZL3 was closely linked to CD8+ T cells and CD4+ T immune infiltration. The MPML3 mRNA level was associated with protein secretion, the Notch signaling pathway, and heme metabolism. In addition, drug sensitivity analysis and validation also indicated that MPZL3 expression influenced the sensitivity of therapeutics targeting EGFR, ABL, FGFR, etc. Additionally, MPZL3 overexpression contributed to proliferation and drug sensitivity in different subtypes of breast cancer.
    Conclusions: This study provides a comprehensive analysis and understanding of the oncogenic roles of the pan-cancer gene MPZL3 across different tumors, including breast cancer. MPZL3 could be a potential prognostic biomarker and therapeutic target for breast cancer.
    Keywords:  MPZL3; biomarker; breast cancer; drug susceptibility; immune infiltration; prognosis
    DOI:  https://doi.org/10.3389/fonc.2022.901728
  38. J Exp Clin Cancer Res. 2022 Aug 17. 41(1): 250
    YTHDC1 is downregulated by the YY1/HDAC2 complex and controls the sensitivity of ccRCC to sunitinib by targeting the ANXA1-MAPK pathway.
    Wei Li, Kun Ye, Xurui Li, Xinlin Liu, Mou Peng, Fang Chen, Wei Xiong, Yinhuai Wang, Liang Zhu.
       BACKGROUND: Tyrosine kinase inhibitors (TKIs) such as sunitinib are multitarget antiangiogenic agents in clear cell renal cell carcinoma (ccRCC). They are widely used in the treatment of advanced/metastatic renal cancer. However, resistance to TKIs is common in the clinic, particularly after long-term treatment. YTHDC1 is the main nuclear reader protein that binds with m6A to regulate the splicing, export and stability of mRNA. However, the specific role and corresponding mechanism of YTHDC1 in renal cancer cells are still unclear.
    METHODS: The Cancer Genome Atlas (TCGA) dataset was used to study the expression of YTHDC1 in ccRCC. Cell counting kit-8 (CCK-8), wound healing, Transwell and xenograft assays were applied to explore the biological function of YTHDC1 in ccRCC. Western blot, quantitative real time PCR (RT‒qPCR), RNA immunoprecipitation PCR (RIP-qPCR), methylated RIP-qPCR (MeRIP-qPCR) and RNA sequencing (RNA-seq) analyses were applied to study the YY1/HDAC2/YTHDC1/ANXA1 axis in renal cancer cells. The CCK-8 assay and xenograft assay were used to study the role of YTHDC1 in determining the sensitivity of ccRCC to sunitinib.
    RESULTS: Our results demonstrated that YTHDC1 is downregulated in ccRCC tissues compared with normal tissues. Low expression of YTHDC1 is associated with a poor prognosis in patients with ccRCC. Subsequently, we showed that YTHDC1 inhibits the progression of renal cancer cells via downregulation of the ANXA1/MAPK pathways. Moreover, we also showed that the YTHDC1/ANXA1 axis modulates the sensitivity of tyrosine kinase inhibitors. We then revealed that HDAC2 inhibitors resensitize ccRCC to tyrosine kinase inhibitors through the YY1/HDAC2 complex. We have identified a novel YY1/HDAC2/YTHDC1/ANXA1 axis modulating the progression and chemosensitivity of ccRCC.
    CONCLUSION: We identified a novel YY1/HDAC2/YTHDC1/ANXA1 axis modulating the progression and chemosensitivity of ccRCC.
    Keywords:  ANXA1; Clear cell renal cell carcinoma; HDAC2/YY1; Sunitinib; YTHDC1
    DOI:  https://doi.org/10.1186/s13046-022-02460-9
  39. Int J Biol Sci. 2022 ;18(13): 4884-4900
    Tumor-associated macrophage-derived chemokine CCL5 facilitates the progression and immunosuppressive tumor microenvironment of clear cell renal cell carcinoma.
    Wenhao Xu, Yuhao Wu, Wangrui Liu, Aihetaimujiang Anwaier, Xi Tian, Jiaqi Su, Haineng Huang, Gaomeng Wei, Yuanyuan Qu, Hailiang Zhang, Dingwei Ye.
      Background: Tumor-associated macrophages (TAMs) dominate the malignancy of cancers by perturbing the tumor microenvironment (TME). However, the clinical implications of heterogeneous subpopulations of TAMs in clear cell renal cell carcinoma (ccRCC) remain to be elucidated. Methods: We comprehensively evaluated the prognostic implications, biological behaviors, and immunogenomics features of the C-C Motif Chemokine Ligand 5 (CCL5) expression and CCL5+ TME in vitro and in 932 real-world ccRCC patients from testing and public validation cohorts. Flow cytometry was used to examine the functional patterns of CCL5+ TAMs with TME cell-infiltrating characterizations. Results: Our results identified distinct prognostic clusters with gradual changes in clinicopathological indicators based on CCL5 expression. Knockdown of CCL5 significantly restrained cell viability, migration capabilities of ccRCC cells, and the inhibits the proliferation and chemotaxis of THP1-derived TAMs. Mechanically, down-regulation of CCL5 arrested epithelial-mesenchymal transition by modulating the PI3K/AKT pathway in ccRCC cells. In ccRCC samples with CCL5 upregulation, the proportion of CCL5+ TAMs and PD-L1+ CD68+ TAMs were prominently increased, showing a typical suppressive tumor immune microenvironment (TIME). Besides, intra-tumoral CCL5+ TAMs showed distinct pro-tumorigenic TME features characterized by exhausted CD8+ T cells and increased expression of immune checkpoints. Furthermore, elevated CCL5+ TAMs infiltration was prominently associated with a dismal prognosis for patients with ccRCC. Conclusion: In conclusion, this study first revealed the predictive value of the chemokine CCL5 on the progression and TME of ccRCC. The intra-tumoral CCL5+ TAMs could be applied to comprehensively evaluate the prognostic patterns as well as unique TME characteristics among individuals, allowing for the identification of immunophenotypes and promotion of treatment efficiency for ccRCC.
    Keywords:  C-C Motif Chemokine Ligand 5 (CCL5); clear cell renal cell carcinoma (ccRCC); epithelial-mesenchymal transition (EMT); tumor microenvironment (TME); tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.7150/ijbs.74647
  40. J Immunol. 2022 Aug 17. pii: ji2200149. [Epub ahead of print]
    RNA-Editing Enzyme ADAR1 p150 Isoform Is Critical for Germinal Center B Cell Response.
    Yuxing Li, Gui-Xin Ruan, Wenjing Chen, Hengjun Huang, Rui Zhang, Jing Wang, Yan Li, Shengli Xu, Xijun Ou.
      Adenosine deaminase acting on RNA (ADAR)1 is the principal enzyme for adenosine-to-inosine editing, an RNA modification-avoiding cytosolic nucleic acid sensor's activation triggered by endogenous dsRNAs. Two ADAR1 isoforms exist in mammals, a longer IFN-inducible and mainly cytoplasm-localized p150 isoform and a shorter constitutively expressed and primarily nucleus-localized p110 isoform. Studies of ADAR1 mutant mice have demonstrated that ADAR1 is essential for multiple physiological processes, including embryonic development, innate immune response, and B and T lymphocyte development. However, it remained unknown whether ADAR1 plays a role in the humoral immune response. In this study, we conditionally delete Adar1 in activated B cells and show that ADAR1-deficient mice have a defective T cell-dependent Ab response and diminished germinal center (GC) B cells. Using various double mutant mice concurrently deficient in ADAR1 and different downstream dsRNA sensors, we demonstrate that ADAR1 regulates the GC response by preventing hyperactivation of the melanoma differentiation-associated protein 5 (MDA5) but not the protein kinase R or RNase L pathway. We also show that p150 is exclusively responsible for ADAR1's function in the GC response, and the p110 isoform cannot substitute for the p150's role, even when p110 is constitutively expressed in the cytoplasm. We further demonstrated that the dsRNA-binding but not the RNA-editing activity is required for ADAR1's function in the GC response. Thus, our data suggest that the ADAR1 p150 isoform plays a crucial role in regulating the GC B cell response.
    DOI:  https://doi.org/10.4049/jimmunol.2200149
  41. Cell Death Discov. 2022 Aug 13. 8(1): 360
    KCNK3 inhibits proliferation and glucose metabolism of lung adenocarcinoma via activation of AMPK-TXNIP pathway.
    Guofu Lin, Lanlan Lin, Hai Lin, Wenhan Chen, Luyang Chen, Xiaohui Chen, Shaohua Chen, Qinhui Lin, Yuan Xu, Yiming Zeng.
      Non-small cell lung cancer (NSCLC) is a primary histological subtype of lung cancer with increased morbidity and mortality. K+ channels have been revealed to be involved in carcinogenesis in various malignant tumors. However, TWIK-related acid-sensitive potassium channel 1 (TASK-1, also called KCNK3), a genetic member of K2P channels, remains an enigma in lung adenocarcinoma (LUAD). Herein, we investigated the pathological process of KCNK3 in proliferation and glucose metabolism of LUAD. The expressions of KCNK3 in LUAD tissues and corresponding adjacent tissues were identified by RNA sequencing, quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry. Gain and loss-of-function assays were performed to estimate the role of KCNK3 in proliferation and glucose metabolism of LUAD. Additionally, energy metabolites of LUAD cells were identified by targeted metabolomics analysis. The expressions of metabolic molecules and active biomarkers associated with AMPK-TXNIP signaling pathway were detected via western blot and immunofluorescence. KCNK3 was significantly downregulated in LUAD tissues and correlated with patients' poor prognosis. Overexpression of KCNK3 largely regulated the process of oncogenesis and glycometabolism in LUAD in vitro and in vivo. Mechanistic studies found that KCNK3-mediated differential metabolites were mainly enriched in AMPK signaling pathway. Furthermore, rescue experiments demonstrated that KCNK3 suppressed proliferation and glucose metabolism via activation of the AMPK-TXNIP pathway in LUAD cells. In summary, our research highlighted an emerging role of KCNK3 in the proliferative activity and glycometabolism of LUAD, suggesting that KCNK3 may be an optimal predictor for prognosis and a potential therapeutic target of LUAD.
    DOI:  https://doi.org/10.1038/s41420-022-01152-9
  42. Acta Pharmacol Sin. 2022 Aug 19.
    Nitidine chloride induces cardiac hypertrophy in mice by targeting autophagy-related 4B cysteine peptidase.
    Yang Hong, Wan-Qing Xu, Jing Feng, Han Lou, Heng Liu, Lei Wang, Hao Cui, Lin-Tong Jiang, Ran-Chen Xu, Heng-Hui Xu, Min-Zhen Xie, Yang Li, Philipp Kopylov, Qi Wang, Yong Zhang.
      Nitidine chloride (NC) is a standard active component from the traditional Chinese medicine Zanthoxylum nitidum (Roxb.) DC. (ZN). NC has shown a variety of pharmacological activities including anti-tumor activity. As a number of anti-tumor drugs cause cardiotoxicity, herein we investigated whether NC exerted a cardiotoxic effect and the underlying mechanism. Aqueous extract of ZN (ZNE) was intraperitoneally injected into rats, while NC was injected into beagles and mice once daily for 4 weeks. Cardiac function was assessed using echocardiography. We showed that both ZNE administered in rats and NC administered in mice induced dose-dependent cardiac hypertrophy and dysfunction, whereas administration of NC at the middle and high dose caused death in Beagles. Consistently, we observed a reduction of cardiac autophagy levels in NC-treated mice and neonatal mouse cardiomyocytes. Furthermore, we demonstrated that autophagy-related 4B cysteine peptidase (ATG4B) may be a potential target of NC, since overexpression of ATG4B reversed the cardiac hypertrophy and reduced autophagy levels observed in NC-treated mice. We conclude that NC induces cardiac hypertrophy via ATG4B-mediated downregulation of autophagy in mice. Thus, this study provides guidance for the safe clinical application of ZN and the use of NC as an anti-tumor drug.
    Keywords:  Zanthoxylum nitidum (Roxb.) DC; autophagy; autophagy-related 4B cysteine peptidase; cardiac hypertrophy; nitidine chloride; species-based differences
    DOI:  https://doi.org/10.1038/s41401-022-00968-6
  43. Acta Pharm Sin B. 2022 Aug;12(8): 3313-3325
    NAT10 promotes cell proliferation by acetylating CEP170 mRNA to enhance translation efficiency in multiple myeloma.
    Rongfang Wei, Xing Cui, Jie Min, Zigen Lin, Yanyan Zhou, Mengjie Guo, Xiaojuan An, Hao Liu, Siegfried Janz, Chunyan Gu, Hongbo Wang, Ye Yang.
      Multiple myeloma (MM) is still an incurable hematologic malignancy, which is eagerly to the discovery of novel therapeutic targets and methods. N-acetyltransferase 10 (NAT10) is the first reported regulator of mRNA acetylation that is activated in many cancers. However, the function of NAT10 in MM remains unclear. We found significant upregulation of NAT10 in MM patients compared to normal plasma cells, which was also highly correlated with MM poor outcome. Further enforced NAT10 expression promoted MM growth in vitro and in vivo, while knockdown of NAT10 reversed those effects. The correlation analysis of acetylated RNA immunoprecipitation sequencing (acRIP-seq) and ribosome profiling sequencing (Ribo-seq) combined with RIP-PCR tests identified centrosomal protein 170 (CEP170) as an important downstream target of NAT10. Interfering CEP170 expression in NAT10-OE cells attenuated the acceleration of cellular growth caused by elevated NAT10. Moreover, CEP170 overexpression promoted cellular proliferation and chromosomal instability (CIN) in MM. Intriguingly, remodelin, a selective NAT10 inhibitor, suppressed MM cellular growth, induced cellular apoptosis in vitro and prolonged the survival of 5TMM3VT mice in vivo. Collectively, our data indicate that NAT10 acetylates CEP1 70 mRNA to enhance CEP170 translation efficiency, which suggests that NAT10 may serve as a promising therapeutic target in MM.
    Keywords:  Acetylation; CEP170; Chromosomal instability; Multiple myeloma; NAT10; Remodelin; Target; Translation
    DOI:  https://doi.org/10.1016/j.apsb.2022.01.015
  44. Cancer Gene Ther. 2022 Aug 18.
    Hidden patterns of gene expression provide prognostic insight for colorectal cancer.
    Dongsan Kim, Kwang-Hyun Cho.
      Cancer tissue samples contain cancer cells and non-cancer cells with each biopsied site containing distinct proportions of these populations. Consequently, assigning useful tumor subtypes based on gene expression measurements from clinical samples is challenging. We applied a blind source separation approach to extract cancer cell-intrinsic gene expression patterns within clinical tumor samples of colorectal cancer. After a blind source separation, we found that a cancer cell-intrinsic gene expression program unique to each patient exists in the "residual" expression profile remaining after separation of the gene expression data. We performed a consensus clustering analysis of the extracted gene expression profiles to identify novel and robust cancer cell-intrinsic subtypes. We validated the identified subtypes using an independent clinical gene expression dataset. The cancer cell-intrinsic subtypes are independent of biopsy site and provided prognostic information in addition to currently available clinical and molecular variables. After validating this approach in colorectal cancer, we further identified novel tumor subtypes with unique clinical information across multiple types of cancer. These cancer cell-intrinsic molecular subtypes provide novel prognostic value for clinical assessment of cancer.
    DOI:  https://doi.org/10.1038/s41417-022-00520-y
  45. J Biol Chem. 2022 Aug 12. pii: S0021-9258(22)00817-1. [Epub ahead of print] 102374
    Lysine demethylase KDM1A promotes cell growth via FKBP8-BCL2 axis in hepatocellular carcinoma.
    Suli Lv, Xuefeng Zhao, Erlei Zhang, Yingying Yan, Xianyun Ma, Neng Li, Qingli Zou, Lidong Sun, Tanjing Song.
      Advanced hepatocellular carcinoma (HCC) has a dismal prognosis. KDM1A, overexpressed in multiple cancer types, is a lysine demethylase that targets both histone and non-histone proteins. However, it is unclear how KDM1A expression affects HCC etiology. Here, we show KDM1A can interact with and demethylate FKBP8, a cytoplasmic protein which regulates cell survival through the anti-apoptotic protein BCL2. We show demethylation of FKBP8 enhances its ability to stabilize BCL2. Consistently, we observed positive correlation between KDM1A and BCL2 protein levels in liver cancer patients. Functionally, we reveal FKBP8 demethylation by KDM1A is critical for liver cancer cell growth in vitro and in vivo. We went on to explore the mechanisms that might regulate KDM1A cytoplasmic localization. We found the cytoplasmic localization and protein stability of KDM1A was promoted by acetylation at Lysine-117 by the acetyl transferase KAT8. In agreement with this, we show KDM1A-K117 acetylation promotes demethylation of FKBP8 and level of BCL2. Finally, it has been shown that the efficacy of Sorafenib, a first-line treatment for advanced hepatocellular carcinoma, is limited by clinical resistance. We show KDM1A and BCL2 protein levels are increased during acquired sorafenib-resistance, while inhibiting KDM1A can antagonize sorafenib-resistance. Collectively, these results define a functional KDM1A-FKBP8-BCL2 axis in hepatocellular carcinoma.
    DOI:  https://doi.org/10.1016/j.jbc.2022.102374
  46. J Oleo Sci. 2022 Aug 15.
    Chemoprotective Effect of Decalactone on Hepatic Cancer via Diminishing the Inflammatory Response and Oxidative Stress.
    Haiyang Shen, Qian Li, Youtao Yu.
      Hepatocellular Carcinoma (HCC) is the 5th most common type of cancer in all types of cancers, globally. It is well known that the frequency of inflammatory reaction and oxidative stress increases during the HCC. The goal of this study was to see if decalactone could prevent rats against HCC caused by diethylnitrosamine (DEN). Single intraperitoneal administration of DEN (200 mg/kg) used as inducer and weekly intraperitoneal injection of phenobarbital (8 mg/kg) was used as promotor for induction the HCC in rats. Serum alpha fetoprotein (AFP) was used for the confirmation of HCC. Different doses of decalactone (5, 10 and 15 mg/kg) were orally administered to the rats. The body weight was determined at regular time. The hepatic, non-hepatic, antioxidant markers and inflammatory mediators were scrutinized. All groups of animals were scarified and macroscopically examination of the liver tissue was performed and the weight of organ (hepatic tissue) were estimated. Decalactone increased body weight while also suppressing hepatic nodules and tissue weight. Decalactone treatment reduced AFP, total bilirubin, and direct bilirubin levels while increasing albumin and total protein levels in a dose-dependent manner. Decalactone reduced lipid peroxidation (LPO) and increased catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), and superoxide dismutase (SOD) levels significantly (p < 0.001) (SOD). Decalactone lowered the levels of significantly (p < 0.001) inflammatory cytokines and inflammatory markers in the liver. Based on the findings, we may conclude that decalactone inhibited HCC in DEN-induced HCC animals via reducing oxidative stress and inflammatory mediators.
    Keywords:  chemoprevention; decalactone; diethyl nitrosamine; inflammation
    DOI:  https://doi.org/10.5650/jos.ess22033
  47. Am J Cancer Res. 2022 ;12(7): 3405-3421
    SHMT2 promotes tumor growth through VEGF and MAPK signaling pathway in breast cancer.
    Shuang-Yan Xie, Ding-Bo Shi, Yi Ouyang, Fei Lin, Xiao-Yu Chen, Tong-Chao Jiang, Wen Xia, Ling Guo, Huan-Xin Lin.
      Cancer cells modulate their metabolic activities to adapt to their growth and proliferation. Despite advances in breast cancer biology having led to the widespread use of molecular targeted therapy and hormonal drugs, the molecular mechanisms in metabolism related to the regulation of breast cancer cell proliferation are still poorly understood. Here, we investigate the possible role of SHMT2, a key enzyme in serine metabolism, in breast cancer. Firstly, SHMT2 is found highly expressed in both breast cancer cells and tissues, and patients with high expression of SHMT2 have a worse prognosis. Moreover, the intervention of SHMT2 by either knockdown or over-expression in vitro induces the effect on breast cancer proliferation. Mechanistically, RNA-seq shows that over-expression of SHMT2 affect multiple signaling pathways and biological process in breast cancer cells. Furthermore, we confirm that SHMT2 promotes breast cancer cell growth through MAPK and VEGF signaling pathways. Finally, we verify the role of SHMT2 in promoting breast cancer growth in the xenograft tumor model. Our results indicate that SHMT2 plays a critical role in regulating breast cancer growth through MAPK, and VEGF signaling pathways, and maybe serve as a therapeutic target for breast cancer therapy.
    Keywords:  MAPK; SHMT2; VEGF; breast cancer; serine/glycine metabolism
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