bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2023–11–12
fourteen papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. m6A modification of AC026356.1 facilitates hepatocellular carcinoma progression by regulating the IGF2BP1-IL11 axis.
  2. ZC3H13 Enhances the Malignancy of Cervical Cancer by Regulating m6A Modification of CKAP2.
  3. Advanced glycation end products impair bone marrow mesenchymal stem cells osteogenesis in periodontitis with diabetes via FTO-mediated N6-methyladenosine modification of sclerostin.
  4. An experimental workflow for identifying RNA m6A alterations in cellular senescence by methylated RNA immunoprecipitation sequencing.
  5. IGF2BP2 promotes head and neck squamous carcinoma cell proliferation and growth via the miR-98-5p/PI3K/Akt signaling pathway.
  6. SHMT2 regulates esophageal cancer cell progression and immune Escape by mediating m6A modification of c-myc.
  7. ALKBH5 promotes the development of lung adenocarcinoma by regulating the polarization of M2 macrophages through CDCA4.
  8. METTL14-m6A-FOXO3a axis regulates autophagy and inflammation in ankylosing spondylitis.
  9. Identification of M5c regulator-medicated methylation modification patterns for prognosis and immune microenvironment in glioma.
  10. WTAP enhances the instability of SYTL1 mRNA caused by YTHDF2 in bladder cancer.
  11. MePMe-seq: antibody-free simultaneous m6A and m5C mapping in mRNA by metabolic propargyl labeling and sequencing.
  12. DCLRE1B promotes tumor progression and predicts immunotherapy response through METTL3-mediated m6A modification in pancreatic cancer.
  13. METTL16 Inhibits the Malignant Progression of Epithelial Ovarian Cancer through the lncRNA MALAT1/β-Catenin Axis.
  14. METTL3-mediated m6A methylation regulates ovarian cancer progression by recruiting myeloid-derived suppressor cells.
  1. Sci Rep. 2023 11 05. 13(1): 19124
    m6A modification of AC026356.1 facilitates hepatocellular carcinoma progression by regulating the IGF2BP1-IL11 axis.
    Huamei Wei, Jinhun Yang, Rongzhou Lu, Yanyan Huang, Zheng Huang, Lizheng Huang, Min Zeng, Yunyu Wei, Zuoming Xu, Wenchuan Li, Jian Pu.
      N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic RNAs. Although the important roles of m6A in RNA fate have been revealed, the potential contribution of m6A to RNA function in various diseases, including hepatocellular carcinoma (HCC), is still unclear. In this study, we identified a novel m6A-modified RNA AC026356.1. We found that AC026356.1 was increased in HCC tissues and cell lines. High expression of AC026356.1 was correlated with poor survival of HCC patients. m6A modification level of AC026356.1 was also increased in HCC and more significantly correlated with poor survival of HCC patients. Functional assays showed that m6A-modified AC026356.1 promoted HCC cellular proliferation, migration, and liver metastasis. Gene set enrichment analysis showed that AC026356.1 activated IL11/STAT3 signaling. Mechanistic investigation showed that m6A-modified AC026356.1 bound to IGF2BP1. The interaction between m6A-modified AC026356.1 and IGF2BP1 promoted the binding of IL11 mRNA to IGF2BP1, leading to increased IL11 mRNA stability and IL11 secretion. Functional rescue assays showed that depletion of IL11 reversed the oncogenic roles of AC026356.1. These findings revealed the potential influences of m6A modification on RNA biological functions and suggested that targeting m6A modification may be a novel strategy for HCC treatment.
    DOI:  https://doi.org/10.1038/s41598-023-45449-w
  2. Crit Rev Immunol. 2023 ;43(6): 1-13
    ZC3H13 Enhances the Malignancy of Cervical Cancer by Regulating m6A Modification of CKAP2.
    Yuan Zhang, Xiaoqing Chen, Huiqun Chen, Ying Zhang.
      Sustained expression of zinc finger CCCH-type containing 13 (ZC3H13) in tumors is essential for cancer cell malignancy; however, our understanding of its clinical effects and mechanisms in cervical cancer (CC) is limited. In this study, we aimed to reveal the effect on CC progression of ZC3H13-mediated N6-methyladenosine (m6A) modification to stabilize cytoskeleton-associated protein 2 (CKAP2) expression. CC tissues and paired adjacent normal tissues were collected from 50 patients. qRT-PCR was used to clarify ZC3H13 and CKAP2 expression levels in the CC tissues. The functional roles of ZC3H13 and CKAP2 in CC were analyzed by detecting the changes in CC cell proliferation, migration, invasion, and tumor growth in vivo. The regulatory relationship between ZC3H13 and CKAP2 was investigated by confirming m6A modification levels and their expression correlation. ZC3H13 and CKAP2 were highly expressed in CC and linked with poor prognosis. We observed that ZC3H13 inhibition decreased CC cell proliferation, invasion, and migration, while its facilitation promoted CC cell malignancy. ZC3H13 mediated m6A modification of CKAP2 to enhance CKAP2 expression in CC cells. Furthermore, CKAP2 overexpression partially restored the malignant phenotypic promotion induced by ZC3H13 overexpression in CC cells. In summary, this study revealed that ZC3H13-mediating m6A modification of CKAP2 promotes CC development. This finding should be conducive to an understanding of the role of ZC3H13-m6A-CKAP2 in CC and should provide an effective therapeutic target for this cancer.
    DOI:  https://doi.org/10.1615/CritRevImmunol.2023049342
  3. J Transl Med. 2023 Nov 04. 21(1): 781
    Advanced glycation end products impair bone marrow mesenchymal stem cells osteogenesis in periodontitis with diabetes via FTO-mediated N6-methyladenosine modification of sclerostin.
    Jie Zhou, Yanlin Zhu, Dongqing Ai, Mengjiao Zhou, Han Li, Guangyue Li, Leilei Zheng, Jinlin Song.
       BACKGROUND: Diabetes mellitus (DM) and periodontitis are two prevalent diseases with mutual influence. Accumulation of advanced glycation end products (AGEs) in hyperglycemia may impair cell function and worsen periodontal conditions. N6-methyladenosine (m6A) is an important post-transcriptional modification in RNAs that regulates cell fate determinant and progression of diseases. However, whether m6A methylation participates in the process of periodontitis with diabetes is unclear. Thus, we aimed to investigate the effects of AGEs on bone marrow mesenchymal stem cells (BMSCs), elucidate the m6A modification mechanism in diabetes-associated periodontitis.
    METHODS: Periodontitis with diabetes were established by high-fat diet/streptozotocin injection and silk ligation. M6A modifications in alveolar bone were demonstrated by RNA immunoprecipitation sequence. BMSCs treated with AGEs, fat mass and obesity associated (FTO) protein knockdown and sclerostin (SOST) interference were evaluated by quantitative polymerase chain reaction, western blot, immunofluorescence, alkaline phosphatase and Alizarin red S staining.
    RESULTS: Diabetes damaged alveolar bone regeneration was validated in vivo. In vitro experiments showed AGEs inhibited BMSCs osteogenesis and influenced the FTO expression and m6A level in total RNA. FTO knockdown increased the m6A levels and reversed the AGE-induced inhibition of BMSCs differentiation. Mechanically, FTO regulated m6A modification on SOST transcripts, and AGEs affected the binding of FTO to SOST transcripts. FTO knockdown accelerated the degradation of SOST mRNA in presence of AGEs. Interference with SOST expression in AGE-treated BMSCs partially rescued the osteogenesis by activating Wnt Signaling.
    CONCLUSIONS: AGEs impaired BMSCs osteogenesis by regulating SOST in an m6A-dependent manner, presenting a promising method for bone regeneration treatment of periodontitis with diabetes.
    Keywords:  Advanced glycation end products; Bone marrow mesenchymal stem cells; Diabetes mellitus; N 6-methyladenosine; Osteogenesis; Periodontitis
    DOI:  https://doi.org/10.1186/s12967-023-04630-5
  4. J Biol Methods. 2023 ;10 e99010004
    An experimental workflow for identifying RNA m6A alterations in cellular senescence by methylated RNA immunoprecipitation sequencing.
    Yue Shi, Zeming Wu, Weiqi Zhang, Jing Qu, Weimin Ci, Guang-Hui Liu.
      N6-methyladenosine (m6A), the most prevalent mRNA modification in eukaryotic cells, is known to play regulatory roles in a wide array of biological processes, including aging and cellular senescence. To investigate such roles, the m6A modification can be identified across the entire transcriptome by immunoprecipitation of methylated RNA with an anti-m6A antibody, followed by high-throughput sequencing (meRIP-seq or m6A-seq). Presented here is a protocol for employing meRIP-seq to profile the RNA m6A landscape in senescent human cells. We described, in detail, sample preparation, mRNA isolation, immunoprecipitation, library preparation, sequencing, bioinformatic analysis and validation. We also provided tips and considerations for the optimization and interpretation of the results. Our protocol serves as a methodological resource for investigating transcriptomic m6A alterations in cellular senescence as well as a valuable paradigm for the validation of genes of interest.
    Keywords:  bioinformatic analysis; cellular senescence; m6A; meRIP-seq; qPCR
    DOI:  https://doi.org/10.14440/jbm.2023.403
  5. Front Oncol. 2023 ;13 1252999
    IGF2BP2 promotes head and neck squamous carcinoma cell proliferation and growth via the miR-98-5p/PI3K/Akt signaling pathway.
    Dan Yu, Zhenlong Xiao, Zhefei Zou, Ling Lin, Jing Li, Jian Tan, Wei Chen.
       Introduction: As a N6-methyladenosine reader protein, Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is a critical player in tumor progression and metastasis. However, its specific function in head and neck squamous carcinoma (HNSCC) has yet to be determined. The present study aimed to determine the role of IGF2BP2 in HNSCC.
    Methods: The expression of IGF2BP2 in HNSCC was analyzed using The Cancer Genome Atlas (TCGA) dataset and detected in HNSCC tissues and cells, respectively. Gain- and loss- of function methods were employed to study the effects of IGF2BP2 on HNSCC cell proliferation and tumorigenesis in vitro and in vivo. MicroRNAs (miRNAs) regulating IGF2BP2 were predicted using online tools and confirmed experimentally.
    Results: We showed augmented IGF2BP2 expression in HNSCC, which correlated with poor clinical outcomes. Functional studies showed that IGF2BP2 promoted HNSCC cell proliferation by facilitating cell cycle progression while inhibiting apoptosis. We further demonstrated that IGF2BP2 could enhance HNSCC cell tumorigenesis in vivo. Mechanistically, our data revealed that miR-98-5p could directly target IGF2BP2. The interplay between IGF2BP2 and miR-98-5p is essential to drive the progression of HNSCC via the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-protein kinase B (Akt) pathway signaling pathway.
    Discussion: The current study revealed the oncogenic role of IGF2BP2 and provided insights into its potential mechanism in HNSCC tumorigenesis. Additionally, IGF2BP2 might represent a promising therapeutic target and serve as prognostic biomarker in patients with HNSCC.
    Keywords:  HNSCC; IGF2BP2; PI3K/AKT; miR-98-5p; tumorigenesis
    DOI:  https://doi.org/10.3389/fonc.2023.1252999
  6. Cell Biosci. 2023 Nov 06. 13(1): 203
    SHMT2 regulates esophageal cancer cell progression and immune Escape by mediating m6A modification of c-myc.
    Zhe Qiao, Yu Li, Yao Cheng, Shaomin Li, Shiyuan Liu.
       BACKGROUND: In recent years, the role of altered cellular metabolism in tumor progression has attracted widespread attention. Related metabolic enzymes have also been considered as potential cancer therapeutic targets. Serine hydroxymethyltransferase 2 (SHMT2) has been reported to be upregulated in several cancers and associated with poor prognosis. However, there are few studies of SHMT2 in esophageal cancer (EC), and the related functions and mechanisms also need to be further explored.
    METHODS: In this study, we first analyzed SHMT2 expression in EC by online database and clinical samples. Then, the biological functions of SHMT2 in EC were investigated by cell and animal experiments. The intracellular m6A methylation modification levels were also evaluated by MeRIP. Linked genes and mechanisms of SHMT2 were analyzed by bioinformatics and rescue experiments.
    RESULTS: We found that SHMT2 expression was abnormally upregulated in EC and associated with poor prognosis. Functionally, SHMT2 silencing suppressed c-myc expression in an m6A-dependent manner, thereby blocking the proliferation, migration, invasion and immune escape abilities of EC cells. Mechanistically, SHMT2 encouraged the accumulation of methyl donor SAM through a one-carbon metabolic network, thereby regulating the m6A modification and stability of c-myc mRNA in a METTL3/FTO/ALKBH5/IGF2BP2-dependent way. In vivo animal experiments also demonstrated that SHMT2 mediated MYC expression by m6A-methylation modification, thus boosting EC tumorigenesis.
    CONCLUSION: In conclusion, our data illustrated that SHMT2 regulated malignant progression and immune escape of EC cell through c-myc m6A modification. These revealed mechanisms related to SHMT2 in EC and maybe offer promise for the development of new therapeutic approaches.
    Keywords:  EC; One carbon metabolism; SHMT2; c-myc; m6A modification
    DOI:  https://doi.org/10.1186/s13578-023-01148-7
  7. Gene. 2023 Nov 08. pii: S0378-1119(23)00816-8. [Epub ahead of print] 147975
    ALKBH5 promotes the development of lung adenocarcinoma by regulating the polarization of M2 macrophages through CDCA4.
    Jianlong Tan, Fengyu Chen, Jufen Wang, Jianmin Li, Bin Ouyang, Xiuying Li, Yun Li, Weidong Zhang, Yongliang Jiang.
       OBJECTIVE: Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer, with high morbidity and mortality. N6-methyladenosine (m6A) is an important regulator of LUAD progression. Here, we investigated the potential biological functions of ALKBH5 (a m6A demethylated enzyme) and cell division cycle associated protein 4 (CDCA4) in the progression of LUAD.
    METHODS: The expressions of CDCA4, METTL3, ALKBH5, FTO, YTHDC2 and YTHDC1 mRNA and proteins in LUAD and adjacent tissues, as well as NCI-H1299 and NCI-H157 cells were detected by RT-qPCR and western blot. Meanwhile, the role of ALKBH5 and CDCA4 in macrophage polarization was explored through tumor formation in Lewis lung carcinoma (LLC) mice and the co-culture system of NCI-H1299 and NCI-H157/THP-1 cells. Cell characterization was further analyzed. The expression of Ki-67 in tumor tissue was tested by immunohistochemistry. The scale of M1 and M2 macrophages was determined by flow cytometry.
    RESULTS: CDCA4 was significantly overexpressed in NCI-H1299 and NCI-H157 cell lines compared with BEAS-2B cells. The fold enrichment of CDCA4 m6A level in the overexpression (oe)-METTL3 or short hairpin (sh)-ALKBH5 cells was enhanced. Overexpression of CDCA4 promoted the cell viability, proliferation and migration, and inhibited apoptosis, which was reversed by sh-ALKBH5 intervention. Overexpression of YTHDC2 (not YTHDC1) inhibited the effect of CDCA4 on sh-ALKBH5 cells. sh-CDCA4 inhibited tumor growth and weight of LLC cells in mice, and promoted M1/M2 ratio in LLC mice and NCI-H1299/THP-1 and NCI-H157/THP-1 co-culture systems. Oe-CDCA4 promoted the volume and weight of tumor and inhibited the M1/M2 ratio of tumor tissue in LLC mice, but was reversed by sh-ALKBH5 intervention.
    CONCLUSION: m6A demethylase ALKBH5 promotes the development of LUAD through CDCA4 regulation of malignant characterization and M1/M2 macrophage polarization.
    Keywords:  ALKBH5; CDCA4; M2 macrophage; lung adenocarcinoma; m6A
    DOI:  https://doi.org/10.1016/j.gene.2023.147975
  8. Clin Immunol. 2023 Nov 05. pii: S1521-6616(23)00601-0. [Epub ahead of print]257 109838
    METTL14-m6A-FOXO3a axis regulates autophagy and inflammation in ankylosing spondylitis.
    Yuting Chen, Ye Wu, Lanlan Fang, Hui Zhao, Shenqian Xu, Zongwen Shuai, Haiyang Yu, Guoqi Cai, He-Qin Zhan, Faming Pan.
      The role of m6A in ankylosing spondylitis (AS) remains largely obscure. In this study, we found that m6A modification was decreased in T cells of AS, and the abnormal m6A modification was attributed to the downregulation of methyltransferase-like 14 (METTL14). METTL14 exerted a critical role in regulating autophagy activity and inflammation via targeting Forkhead box O3a (FOXO3a). Mechanistically, the loss of METTL14 decreased the expression of FOXO3a, leading to the damage of autophagic flux and the aggravation of inflammation. Inversely, the forced expression of METTL14 upregulated the expression of FOXO3a, thereby activating autophagy and alleviating inflammation. Furthermore, our results revealed that METTL14 targeted FOXO3a mRNA and regulated its expression and stability in a m6A-dependent manner. These findings uncovered the functional importance of m6A methylation mechanisms in the regulation of autophagy and inflammation, which expanded our understanding of this interaction and was critical for the development of therapeutic strategies for AS.
    Keywords:  Ankylosing spondylitis; Autophagy; FOXO3a; Inflammation; METTL14; m6A
    DOI:  https://doi.org/10.1016/j.clim.2023.109838
  9. Aging (Albany NY). 2023 Nov 06. 15
    Identification of M5c regulator-medicated methylation modification patterns for prognosis and immune microenvironment in glioma.
    Zhenyong Xiao, Jinwei Li, Cong Liang, Yamei Liu, Yuxiu Zhang, Yuxia Zhang, Quan Liu, Xianlei Yan.
      Glioma is a common intracranial tumor and is generally associated with poor prognosis. Recently, numerous studies illustrated the importance of 5-methylcytosine (m5C) RNA modification to tumorigenesis. However, the prognostic value and immune correlation of m5C in glioma remain unclear. We obtained RNA expression and clinical information from The Cancer Genome Atlas (TCGA) and The Chinese Glioma Genome Atlas (CGGA) datasets to analyze. Nonnegative matrix factorization (NMF) was used to classify patients into two subgroups and compare these patients in survival and clinicopathological characteristics. CIBERSORT and single-sample gene-set algorithm (ssGSEA) methods were used to investigate the relationship between m5C and the immune environment. The Weighted correlation network analysis (WGCNA) and univariate Cox proportional hazard model (CoxPH) were used to construct a m5C-related signature. Most of m5C RNA methylation regulators presented differential expression and prognostic values. There were obvious relationships between immune infiltration cells and m5C regulators, especially NSUN7. In the m5C-related module from WGCNA, we found SEPT3, CHI3L1, PLBD1, PHYHIPL, SAMD8, RAP1B, B3GNT5, RER1, PTPN7, SLC39A1, and MXI1 were prognostic factors for glioma, and they were used to construct the signature. The great significance of m5C-related signature in predicting the survival of patients with glioma was confirmed in the validation sets and CGGA cohort.
    Keywords:  RNA methylation; WGCNA; glioma; immune microenvironment; m5C
    DOI:  https://doi.org/10.18632/aging.205179
  10. Histol Histopathol. 2023 Oct 23. 18671
    WTAP enhances the instability of SYTL1 mRNA caused by YTHDF2 in bladder cancer.
    Jiansong Wang, Jianjun Luo, Xuecheng Wu, Zhuo Li.
       BACKGROUND: Bladder cancer (BCa) is the most frequent type of cancer in humans. The association between m6A modification and the anti-tumor effects of natural killer (NK) cells has been described in BCa. This study intended to investigate the implications of m6A regulators in modulating SYTL1 expression in BCa and the association with the anti-tumor effects of NK cells.
    METHODS: The prognostic role of SYTL1 in BCa was investigated using bioinformatics analysis, and the correlation between SYTL1 expression and NK cells was analyzed. The effects of SYTL1 on the anti-tumor response of NK-92 cells were examined by RT-qPCR, cytotoxicity, western blot, and ELISA assays. The relationships among WTAP, YTHDF2, and SYTL1 were investigated by RT-qPCR, RIP-qPCR, ELISA, and actinomycin D treatment. Finally, the effects of WTAP and SYTL1 on BCa tumor growth and the anti-tumor response of NK cells were verified in vivo.
    RESULTS: SYTL1 was reduced in BCa tissues and had a prognostic significance, which was related to NK cell-mediated anti-tumor responses. NK-92 cells produced toxicity to BCa cells, which was further enhanced by SYTL1 overexpression in BCa cells through prompting LDH, NKG2D, NKp30, and NKp44 and IFN-γ levels. WTAP enhanced the degradation of the SYTL1 mRNA by YTHDF2. WTAP and YTHDF2 impaired the anti-tumor response of NK cells in BCa. SYTL1 inhibited the BCa progression in mice while enhancing the anti-tumor response of NK cells.
    CONCLUSIONS: WTAP inhibited the anti-tumor response of NK cells to BCa cells by promoting the degradation of SYTL1 mRNA through YTHDF2-mediated m6A methylation.
    DOI:  https://doi.org/10.14670/HH-18-671
  11. Nat Commun. 2023 Nov 07. 14(1): 7154
    MePMe-seq: antibody-free simultaneous m6A and m5C mapping in mRNA by metabolic propargyl labeling and sequencing.
    Katja Hartstock, Nadine A Kueck, Petr Spacek, Anna Ovcharenko, Sabine Hüwel, Nicolas V Cornelissen, Amarnath Bollu, Christoph Dieterich, Andrea Rentmeister.
      Internal modifications of mRNA have emerged as widespread and versatile regulatory mechanism to control gene expression at the post-transcriptional level. Most of these modifications are methyl groups, making S-adenosyl-L-methionine (SAM) a central metabolic hub. Here we show that metabolic labeling with a clickable metabolic precursor of SAM, propargyl-selenohomocysteine (PSH), enables detection and identification of various methylation sites. Propargylated A, C, and G nucleosides form at detectable amounts via intracellular generation of the corresponding SAM analogue. Integration into next generation sequencing enables mapping of N6-methyladenosine (m6A) and 5-methylcytidine (m5C) sites in mRNA with single nucleotide precision (MePMe-seq). Analysis of the termination profiles can be used to distinguish m6A from 2'-O-methyladenosine (Am) and N1-methyladenosine (m1A) sites. MePMe-seq overcomes the problems of antibodies for enrichment and sequence-motifs for evaluation, which was limiting previous methodologies. Metabolic labeling via clickable SAM facilitates the joint evaluation of methylation sites in RNA and potentially DNA and proteins.
    DOI:  https://doi.org/10.1038/s41467-023-42832-z
  12. BMC Cancer. 2023 Nov 07. 23(1): 1073
    DCLRE1B promotes tumor progression and predicts immunotherapy response through METTL3-mediated m6A modification in pancreatic cancer.
    Lincheng Li, Fei Wang, Zhaoda Deng, Gong Zhang, Lin Zhu, Zhiming Zhao, Rong Liu.
       BACKGROUND: DCLRE1B is a 5'-to-3' exonuclease, which is involved in repairing ICL-related DNA damage. DCLRE1B has been reported to cause poor prognosis in a variety of cancers. Nonetheless, there is no research on DCLRE1B's biological role in pan-cancer datasets. Thus, ascertaining the processes via which DCLRE1B modulates tumorigenesis was the goal of the extensive bioinformatics investigation of pan-cancer datasets in the present research.
    METHODS: In our research, employing internet websites and databases including TIMER, GEPIA, TISIDB, Kaplan-Meier Plotter, SangerBox, cBioPortal, and LinkedOmics, DCLRE1B-related data in numerous tumors were extracted. To ascertain the association among DCLRE1B expression, prognosis, genetic changes, and tumor immunity, the pan-cancer datasets were examined. The DCLRE1B's biological roles in pancreatic cancer cells were ascertained by employing wound healing, in vitro CCK-8, and MeRIP-qPCR assays.
    RESULT: According to the pan-cancer analysis, in numerous solid tumors, DCLRE1B upregulation was observed. Expression of DCLRE1B was found to be substantially related to the cancer patients' prognoses. Similarly, expression of DCLRE1B exhibited substantial association with immune cells in several cancer types. DCLRE1B expression correlated with immune checkpoint (ICP) gene expression and impacted immunotherapy sensitivity. According to in vitro trials, DCLRE1B promoted PC cells' proliferation and migration capacities. Also, according to GSEA enrichment analysis, DCLRE1B might participate in the JAK-STAT signaling pathway, which was confirmed by western blotting. In addition, we also found that the downregulation of DCLRE1B may be regulated by METTL3-mediated m6A modification.
    CONCLUSIONS: In human cancer, the overexpression of DCLRE1B was generally observed, which aided cancer onset and advancement via a variety of processes comprising control of the immune cells' tumor infiltration. According to this study's findings, in a few malignant tumors, DCLRE1B is a candidate immunotherapeutic and prognostic biomarker.
    Keywords:  DCLRE1B; Immunotherapy; Pan-cancer; Pancreatic cancer; m6A
    DOI:  https://doi.org/10.1186/s12885-023-11524-8
  13. Anal Cell Pathol (Amst). 2023 ;2023 9952234
    METTL16 Inhibits the Malignant Progression of Epithelial Ovarian Cancer through the lncRNA MALAT1/β-Catenin Axis.
    Changshu Li, Ji Liu, Yuanyuan Lyu, Shizhang Ling, Yonghong Luo.
      Epithelial ovarian cancer (EOC) ranks third in the incidence of gynecological malignancies. m6A methylation as RNA modification plays a crucial role in the evolution, migration, and invasion of various tumors. However, the role of m6A methylation in ovarian cancer (OC) only recently has begun to be appreciated. Therefore, we used various bioinformatic methods to screen the public GEO datasets of epithelial ovarian cancer (EOC) for m6A methylation-related regulators. We identified methyltransferase 16 (METTL16) that was dramatically downregulated in EOC as such a regulator. We also identified metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a known target lncRNA of METTL16, in these five GEO datasets. RT-qPCR and immunohistochemical staining confirmed that compared with the normal ovarian tissues and cells, METTL16 was significantly downregulated, while lncRNA MALAT1 was significantly upregulated, in 30 EOC tissues of our own validation cohorts and EOC cell lines, revealing a negative correlation between METTL16 and lncRNA MALAT1. Moreover, our analysis unveiled a correlation between downregulated METTL16 and the known adverse prognostic factors of EOC patients in our own cohorts. The CCK-8, EdU, scratch wound healing, and transwell invasion assays revealed that METTL16 significantly suppressed the proliferating, migrating, and invading abilities of OC cells. The inhibitory effects of METTL16 on the in vivo tumor growth of EOC cells were measured by subcutaneous tumor formation assay in mice. Furthermore, the RIP, RNA stability assay, western blotting, and cytoimmunofluorescence staining showed that METTL16 hindered the growth of EOC cells through promoting the degradation of MALAT1 by binding that, in turn, upregulates β-catenin protein and promotes nuclear transport of β-catenin protein in EOC cells. This study suggests that METTL16 acts as a tumor suppressor gene of EOC by achieving its inhibitory function on the malignant progression of EOC through the METTL16/MALAT1/β-catenin axis that are new targets for EOC diagnosis and therapy.
    DOI:  https://doi.org/10.1155/2023/9952234
  14. Cell Biosci. 2023 Nov 06. 13(1): 202
    METTL3-mediated m6A methylation regulates ovarian cancer progression by recruiting myeloid-derived suppressor cells.
    Jinyong Wang, Dakai Ling, Lulin Shi, Huayun Li, Minhua Peng, Huihong Wen, Tao Liu, Ruifang Liang, Yongjian Lin, Laiyou Wei, Guangzhi Zhang, Shanze Chen.
       BACKGROUND: Ovarian cancer (OC) typically develops an immunosuppressive microenvironment by funtional changes of host immune cells. Dysregulated m6A level is associated with cancer progression via the intrinsic oncogenic pathways. However, the role of m6A in regulating host immune cell function during anti-tumor immunity needs comprehensive analysis. This study aimed to investigate the role of METTL3, a catalytic subunit of the methyltransferase complex, in regulating host immune cell response against OC.
    METHODS: In this study, myeloid-specific Mettl3 gene knockout (Mettl3-cKO) mice were bred using the Cre-LoxP system. Intraperitoneally injection of ID8 cells was used as a syngeneic OC model. Furthermore, the compositions of immune cell populations were analyzed by flow cytometry and single-cell sequencing. Moreover, chemokines and cytokines secretion were assessed using ELISA. Lastly, the role of METTL3 in regulating IL-1β secretion and inflammasome activation in bone marrow-derived macrophages cocultured with ID8 cells was specified by ELISA and immunoblotting.
    RESULTS: It was revealed that OC cell growth was enhanced in Mettl3-cKO mice. Furthermore, a shift of decreased M1 to increased M2 macrophage polarization was observed during OC progression. Moreover, Mettl3 depletion in myeloid lineage cells increased secretion of CCL2 and CXCL2 in peritoneal lavage fluild. Interestingly, Mettl3 deficiency enhanced IL-1β secretion induced by viable ID8 cells independent of inflammasome activation and cell death. Therefore, OC cells in tumor-bearing mice trigger a slight inflammatory response with a low-to-moderate secretion of pro-inflammatory cytokines and chemokines.
    CONCLUSION: This study provides new insights into METTL3-mediated m6A methylation, which regulates host immune response against OC.
    Keywords:  Inflammatory responses; METTL3; Myeloid-derived suppressive cells; Ovarian cancer; Tumor microenvironment; m6A
    DOI:  https://doi.org/10.1186/s13578-023-01149-6
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