bims-rimeca 2021-12-26 papers

bims-rimeca

Biomed News

on RNA methylation in cancer

Issue of 2021–12–26
nine papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics

Long noncoding RNA UBA6-AS1 inhibits the malignancy of ovarian cancer cells via suppressing the decay of UBA6 mRNA.
MiR-155 regulates m6A level and cell progression by targeting FTO in clear cell renal cell carcinoma.
N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) mitigates the liver fibrosis via WTAP/m6A/Ptch1 axis through Hedgehog pathway.
N6-Methyladenosine Methyltransferase METTL3 Promotes Angiogenesis and Atherosclerosis by Upregulating the JAK2/STAT3 Pathway via m6A Reader IGF2BP1.
Analysis and validation of m6A regulatory network: a novel circBACH2/has-miR-944/HNRNPC axis in breast cancer progression.
N6-methyladenosine-modified long non-coding RNA AGAP2-AS1 promotes psoriasis pathogenesis via miR-424-5p/AKT3 axis.
METTL1-m7 G-EGFR/EFEMP1 axis promotes the bladder cancer development.
Zingiberensis Newsaponin Inhibits the Malignant Progression of Hepatocellular Carcinoma via Suppressing Autophagy Moderated by the AKR1C1-Mediated JAK2/STAT3 Pathway.
Multi-omics of the expression and clinical outcomes of TMPRSS2 in human various cancers: A potential therapeutic target for COVID-19.

Bioengineered. 2022 Jan;13(1): 178-189

Long noncoding RNA UBA6-AS1 inhibits the malignancy of ovarian cancer cells via suppressing the decay of UBA6 mRNA.

Yaogang Wang, Zhigao Chen.

  Ovarian cancer (OC) is one of the most common cancer in women worldwide. A recent study reported that long noncoding RNA (lncRNA) Ubiquitin like modifier activating enzyme 6 antisense RNA 1 (UBA6-AS1) is significantly correlated with the prognosis of patients with OC and also involved in N6-methyladenosine (m6A) regulation. However, its influence on OC progression and the underlying mechanism is still not well demonstrated. Here, we found that UBA6-AS1 directly associated with UBA6 mRNA and inhibited its decay. Further mechanism investigation revealed that UBA6-AS1 increased the m6A methylation of UBA6 mRNA via recruiting RNA binding motif protein 15 (RBM15). Insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) was identified as the m6A reader protein of UBA6-AS1-RBM15-mediated m6A modification of UBA6 mRNA, which enhanced the stability of UBA6 mRNA. Functionally, UBA6-AS1 suppressed the proliferation, migration and invasion of OC cells via UBA6. Moreover, UBA6-AS1 positively correlated with UBA6 expression in OC tissues. Downregulation of UBA6-AS1 or UBA6 expression indicated poor. Collectively, we have identified a tumor-suppressive lncRNA that regulates its target mRNA via a m6A mechanism, highlighting the role that lncRNAs can play in OC progression.

Keywords:  IGF2BP1; M6a modification; RBM15; RNA stability

DOI:  https://doi.org/10.1080/21655979.2021.2011640
Cell Signal. 2021 Dec 16. pii: S0898-6568(21)00306-5. [Epub ahead of print]91 110217

MiR-155 regulates m6A level and cell progression by targeting FTO in clear cell renal cell carcinoma.

Weifeng Yang, Lei Xie, Peng Wang, Changshui Zhuang.

  Although FTO, as an eraser of N6-methyladenosine (m6A), plays context-dependent tumor-suppressive and oncogenic roles in various cancer type, underlying molecular events of its aberrant expression in cancers is complex and still poorly understood. Here we show that miR-155 directly targets FTO to negatively regulate its expression and increased m6A level in ccRCC. Combining bioinformatics analysis and luciferase reporter assays, we identified that miR-155 directly bound to the 3'UTR of FTO mRNA and reduced FTO protein levels in ccRCC cells. Moreover, cell function assays, xenografts assays and m6A dot blot assays revealed that overexpression of miR-155 enhanced tumor cell proliferation and global mRNA m6A level, while decreasing apoptosis in a FTO-dependent manner. Collectively, our data demonstrates the functional importance of miR-155 in regulating FTO expression and global mRNA m6A level, and provides profound insights into ccRCC tumorigenesis.

Keywords:  FTO; Renal cell carcinoma; m(6)A; miR-155

DOI:  https://doi.org/10.1016/j.cellsig.2021.110217
Gene. 2021 Dec 15. pii: S0378-1119(21)00720-4. [Epub ahead of print] 146125

N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) mitigates the liver fibrosis via WTAP/m6A/Ptch1 axis through Hedgehog pathway.

Anwei Wei, Fei Zhao, Aiping Hao, Bowei Liu, Zhenzhen Liu.

  N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous tetrapeptide with potential antifibrotic effect. However, the underlying mechanism in the anti-fibrosis is still unclear. Here, we try to investigate its biofunction and deeplying mechanism in liver fibrosis. Rats were administrated with carbon tetrachloride (CCl4) for liver fibrosis model. The roles of AcSDKP on hepatic stellate cells (HSCs) were detected in vitro using isolated cells treated by TGF-β1. The m6A profie of HSCs was screened by methylated RNA immunoprecipitation sequencing (MeRIP-Seq). Results demonstrated that AcSDKP inhibited apoptosis through Hedgehog pathway in the CCl4-induced rat HSCs. Moreover, the administration of AcSDKP decreased the N6-methyladenosine (m6A) methyltransferase WTAP (Wilms' tumour 1-associated protein) expression. Mechanistically, WTAP targeted the 3'-UTR of Ptch1 mRNA, and administration of AcSDKP reduced the stability of Ptch1 mRNA. Thus, these findings revealed an anti-fibrosis axis of AcSDKP/WTAP/m6A/Ptch1 in liver fibrosis. Our results identify a novel role of AcSDKP in liver fibrosis via m6A modification and Hedgehog pathway, which helps us to shed light on the molecular mechanism in liver fibrosis progression.

Keywords:  AcSDKP; Hedgehog pathway; WTAP; liver fibrosis; m(6)A

DOI:  https://doi.org/10.1016/j.gene.2021.146125
Front Cell Dev Biol. 2021 ;9 731810

N6-Methyladenosine Methyltransferase METTL3 Promotes Angiogenesis and Atherosclerosis by Upregulating the JAK2/STAT3 Pathway via m6A Reader IGF2BP1.

Guo Dong, Jiangbo Yu, Gaojun Shan, Lide Su, Nannan Yu, Shusen Yang.

  Atherosclerosis (AS) is a life-threatening vascular disease. RNA N6-methyladenosine (m6A) modification level is dysregulated in multiple pathophysiologic processes including AS. In this text, the roles and molecular mechanisms of m6A writer METTL3 in AS progression were explored in vitro and in vivo. In the present study, cell proliferative, migratory, and tube formation capacities were assessed through CCK-8, Transwell migration, and tube formation assays, respectively. RNA m6A level was examined through a commercial kit. RNA and protein levels of genes were measured through RT-qPCR and western blot assays, respectively. VEGF secretion level was tested through ELISA assay. JAK2 mRNA stability was detected through actinomycin D assay. The relationship of METTL3, IGF2BP1, and JAK2 was investigated through bioinformatics analysis, MeRIP, RIP, RNA pull-down, and luciferase reporter assays. An AS mouse model was established to examine the effect of METTL3 knockdown on AS development in vivo. The angiogenetic activity was examined through chick chorioallantoic membrane assay in vivo. The results showed that METTL3 was highly expressed in ox-LDL-induced dysregulated HUVECs. METTL3 knockdown inhibited cell proliferation, migration, tube formation, and VEGF expression/secretion in ox-LDL-treated HUVECs, hampered AS process in vivo, and prevented in vivo angiogenesis of developing embryos. METTL3 positively regulated JAK2 expression and JAK2/STAT3 pathway in an m6A dependent manner in HUVECs. IGF2BP1 positively regulated JAK2 expression through directly binding to an m6A site within JAK2 mRNA in HUVECs. METTL3 knockdown weakened the interaction of JAK2 and IGF2BP1. METTL3 exerted its functions through JAK2/STAT3 pathway. In conclusion, METTL3 knockdown prevented AS progression by inhibiting JAK2/STAT3 pathway via IGF2BP1.

Keywords:  IGF2BP1; JAK2; METTL3; STAT3; atherosclerosis

DOI:  https://doi.org/10.3389/fcell.2021.731810
J Transl Med. 2021 Dec 24. 19(1): 527

Analysis and validation of m6A regulatory network: a novel circBACH2/has-miR-944/HNRNPC axis in breast cancer progression.

Wenchang Lv, Yufang Tan, Mingchen Xiong, Chongru Zhao, Yichen Wang, Min Wu, Yiping Wu, Qi Zhang.

   BACKGROUND: N6-methyladenosine (m6A), the most abundant and reversible modification of mRNAs in eukaryotes, plays pivotal role in breast cancer (BC) tumorigenesis and progression. Circular RNAs (circRNAs) can act as tumor promoters or suppressors by microRNA (miRNA) sponges in BC. However, the underlying mechanism of circRNAs in BC progression via regulating m6A modulators remains unclear.
METHODS: Prognostic m6A RNA methylation regulators were identified in 1065 BC patients from The Cancer Genome Atlas (TCGA) project. Differentially expressed (DE) miRNAs and DE circRNAs were identified between BC and normal samples in TCGA and GSE101123, respectively. MiRNA-mRNA interactive pairs and circRNA-miRNA interactive pairs were verified by MiRDIP and Circular RNA Interactome. GSEA, KEGG, and ssGSEA were executed to explore the potential biological and immune functions between HNRNPC-high and HNRNPC-low expression groups. qRT-PCR and Western blot were used to quantify the expression of HNRNPC and circBACH2 in MCF-7 and MDA-MB-231 cells. The proliferation of BC cells was assessed by CCK-8 and EdU assay.
RESULTS: 2 m6A RNA methylation regulators with prognostic value, including HNRNPC and YTHDF3, were identified in BC patients. Then, the regulatory network of circRNA-miRNA-m6A modulators was constructed, which consisted of 2 DE m6A modulators (HNRNPC and YTHDF3), 12 DE miRNAs, and 11 DE circRNAs. Notably, BC patients with high expression of HNRNPC and low expression of hsa-miR-944 were correlated with late clinical stages and shorter survival times. Besides, the results from the KEGG inferred that the DE HNRNPC was associated with the MAPK signaling pathway in BC. Moreover, the circBACH2 (hsa_circ_0001625) was confirmed to act as hsa-miR-944 sponge to stimulate HNRNPC expression to promote BC cell proliferation via MAPK signaling pathway, thus constructing a circBACH2/hsa-miR-944/HNRNPC axis in BC.
CONCLUSIONS: Our findings decipher a novel circRNA-based m6A regulatory mechanism involved in BC progression, thus providing attractive diagnostic and therapeutic strategies for combating BC.

Keywords:  Breast cancer; circular RNA; m6A RNA methylation modulator; microRNA

DOI:  https://doi.org/10.1186/s12967-021-03196-4
J Dermatol Sci. 2021 Nov 18. pii: S0923-1811(21)00292-9. [Epub ahead of print]

N6-methyladenosine-modified long non-coding RNA AGAP2-AS1 promotes psoriasis pathogenesis via miR-424-5p/AKT3 axis.

Jiayi Xian, Mingwei Shang, Yu Dai, Qi Wang, Xinxin Long, Jiazheng Li, Yantao Cai, Chenglai Xia, Xuebiao Peng.

   BACKGROUND: Psoriasis is a chronic, complicated, and recurrent inflammatory skin disease. However, the precise molecular mechanisms remain largely elusive and the present treatment is unsatisfactory.
OBJECTIVE: This study aimed to unravel the functions of long noncoding RNA (lncRNA) AGAP2-AS1 and its biological mechanism in psoriasis pathogenesis, hinting for the new therapeutic targets in psoriasis.
METHODS: The expression of AGAP2-AS1 in the skin tissue of psoriasis patients and healthy controls were detected by qRT-PCR and RNAscope®. Cell Counting Kit‑8 (CCK8) and clone formation assays were utilized to assess proliferation. Methylated RNA immunoprecipitation (MeRIP) was performed to detect the N6-methyladenosine (m6A) modification. RNA immunoprecipitation (RIP) was used to detect the interaction of AGAP2-AS1 with YTH domain family 2(YTHDF2). The relationships among AGAP2-AS1, miR-424-5p and AKT3 were examined by dual-luciferase reporter assay and RIP assay.
RESULTS: We found that AGAP2-AS1 level was upregulated in the skin tissue of psoriasis patients than that of healthy controls and AGAP2-AS1 could promote proliferation and inhibit apoptosis of keratinocytes. Methyltransferase like 3(METTL3)-mediated m6A modification suppressed the expression of AGAP2-AS1 via YTHDF2-dependent AGAP2-AS1 stability. Thus, downregulation of METTL3 resulted in the upregulation of AGAP2-AS1 in psoriasis. AGAP2-AS1 functioned as a competitive endogenous RNA by sponging miR-424-5p to upregulate AKT3, activate AKT/mTOR pathway, as well as promote cell proliferation in keratinocytes.
CONCLUSION: AGAP2-AS1 is upregulated in the skin tissue of psoriasis patients and m6A methylation was involved in its upregulation. AGAP2-AS1 promotes keratinocyte proliferation through miR-424-5p/AKT/mTOR axis and may be a promising target for psoriasis therapy.

Keywords:  AGAP2-AS1; AKT3; M(6)A; MiR-424–5p; Psoriasis

DOI:  https://doi.org/10.1016/j.jdermsci.2021.11.007
Clin Transl Med. 2021 Dec;11(12): e675

METTL1-m7 G-EGFR/EFEMP1 axis promotes the bladder cancer development.

Xiaoling Ying, Bixia Liu, Zusen Yuan, Yapeng Huang, Cong Chen, Xu Jiang, Haiqing Zhang, Defeng Qi, Shulan Yang, Shuibin Lin, Junhang Luo, Weidong Ji.

   BACKGROUND: The posttranscriptional modifications of transfer RNA (tRNA) are critical for all aspects of the tRNA function and have been implicated in the tumourigenesis and progression of many human cancers. By contrast, the biological functions of methyltransferase-like 1 (METTL1)-regulated m7 G tRNA modification in bladder cancer (BC) remain obscure.
RESULTS: In this research, we show that METTL1 was highly expressed in BC, and its level was correlated with poor patient prognosis. Silencing METTL1 suppresses the proliferation, migration and invasion of BC cells in vitro and in vivo. Multi-omics analysis reveals that METTL1-mediated m7 G tRNA modification altered expression of certain target genes, including EGFR/EFEMP1. Mechanistically, METTL1 regulates the translation of EGFR/EFEMP1 via modifying certain tRNAs. Furthermore, forced expression of EGFR/EFEMP1 partially rescues the effect of METTL1 deletion on BC cells.
CONCLUSIONS: Our findings demonstrate the oncogenic role of METTL1 and the pathological significance of the METTL1-m7 G-EGFR/EFEMP1 axis in the BC development, thus providing potential therapeutic targets for the BC treatment.

Keywords:  EFEMP1; EGFR; METTL1; N7-methylguanosine (m7G); bladder cancer

DOI:  https://doi.org/10.1002/ctm2.675
Evid Based Complement Alternat Med. 2021 ;2021 4055209

Zingiberensis Newsaponin Inhibits the Malignant Progression of Hepatocellular Carcinoma via Suppressing Autophagy Moderated by the AKR1C1-Mediated JAK2/STAT3 Pathway.

Keqing He, Xing Liu, Shiping Cheng, Pingsheng Zhou.

Objective: Saponins are a group of compounds from various plants, which exhibit an anticancer activity. This study aimed to explore the anticancer effect of zingiberensis newsaponin (ZnS) against hepatocellular carcinoma (HCC) and the underlying mechanism involving autophagy.
Methods: HCC cells (Huh7 and SMMC7721) were treated with ZnS and/or 3-MA. The cell viability, migration, and apoptosis were determined using CCK-8 assay, transwell assay, and flow cytometry, respectively. The levels of oxidative stress markers (ROS, SOD, and MDA) were measured by ELISA assay. Autophagy was monitored using MDC assay, immunofluorescence staining, and transmission electron microscopy. The relative protein expression of LC3II/LC3I, P62, AKR1C1, p-JAK2, p-STAT3, JAK2, and STAT3 was determined using Western blot.
Results: ZnS or 3-MA inhibited the cell viability and migration, and it promoted cell apoptosis and oxidative stress in HCC. MDC-positive cells and autophagosomes were reduced by ZnS or 3-MA treatment. The expression of autophagy-related proteins LC3 (LC3II/LC3I) and P62 was, respectively, downregulated and upregulated after ZnS or 3-MA treatment. In addition, ZnS or 3-MA suppressed the protein expression of AKR1C1, p-JAK2, and p-STAT3 in HCC cells. Furthermore, the above phenomena were evidently enhanced by ZnS combined 3-MA treatment. AKR1C1 overexpression weakened the effect of ZnS on inhibiting the expression of AKR1C1, p-JAK2, and p-STAT3.
Conclusion: ZnS exerts an anticancer effect on HCC via inhibiting autophagy moderated by the AKR1C1-mediated JAK2/STAT3 pathway. ZnS and 3-MA exert a synergistic effect on inhibiting HCC.

DOI: https://doi.org/10.1155/2021/4055209
J Cell Mol Med. 2021 Dec 24.

Multi-omics of the expression and clinical outcomes of TMPRSS2 in human various cancers: A potential therapeutic target for COVID-19.

Li Liu, Ju-Fang Qin, Man-Zhen Zuo, Quan Zhou.

  Growing evidence has shown that Transmembrane Serine Protease 2 (TMPRSS2) not only contributes to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but is also closely associated with the incidence and progression of tumours. However, the correlation of coronavirus disease (COVID-19) and cancers, and the prognostic value and molecular function of TMPRSS2 in various cancers have not been fully understood. In this study, the expression, genetic variations, correlated genes, immune infiltration and prognostic value of TMPRSS2 were analysed in many cancers using different bioinformatics platforms. The observed findings revealed that the expression of TMPRSS2 was considerably decreased in many tumour tissues. In the prognostic analysis, the expression of TMPRSS2 was considerably linked with the clinical consequences of the brain, blood, colorectal, breast, ovarian, lung and soft tissue cancer. In protein network analysis, we determined 27 proteins as protein partners of TMPRSS2, which can regulate the progression and prognosis of cancer mediated by TMPRSS2. Besides, a high level of TMPRSS2 was linked with immune cell infiltration in various cancers. Furthermore, according to the pathway analysis of differently expressed genes (DEGs) with TMPRSS2 in lung, breast, ovarian and colorectal cancer, 160 DEGs genes were found and were significantly enriched in respiratory system infection and tumour progression pathways. In conclusion, the findings of this study demonstrate that TMPRSS2 may be an effective biomarker and therapeutic target in various cancers in humans, and may also provide new directions for specific tumour patients to prevent SARS-CoV-2 infection during the COVID-19 outbreak.

Keywords:   TMPRSS2 ; bioinformatics; cancer progression; multi-omics analysis; prognostic analysis; prognostic biomarkers

DOI:  https://doi.org/10.1111/jcmm.17090