Metabolic reprogramming refers to the transformation of the whole metabolic network including glycolysis and mitochondrial metabolism, mainly manifested in Warburg effect and mitochondrial metabolic reprogramming. The roles of miR-145 in glycolysis have been established in ovarian cancer cells. Howerer, its roles in mitochondrial metabolic reprogramming are still unclear. This study aims to identify whether miR-145 regulates mitochondrial metabolic reprogramming in ovarian cancer cells. First, functional experiment showed that overexpression of miR-145 inhibited mitochondrial function in ovarian cancer cells, evident by the decreased mtDNA copy numbers, ATP level, mitochondrial membrane potential, and the expression levels of mitochondrial markers. Mechanistically, miR-145 inhibited mitochondrial function by targeting ARL5B directly. Futhermore, miR-145 overexpression decreased ARL5B expression in ovarian cancer tissue subcutaneous tumors of nude mice. In conclusion, we have highlighted that miR-145 inhibits mitochondrial function and achieves this by targeting ARL5B directly for the first time. The results provides a more adequate theoretical basis for understanding the molecular pathology of ovarian cancer, and provides the necessary basic data for miR-145 as a potential diagnosis and treatment target for ovarian cancer.
RNA methylation can reverse the methylation modification at RNA level, which is a kind of extremely important epigenetic modification. YTHDF2, as a reader of m6A modification, the function and mechanisms of in epithelial ovarian cancer(EOC) have not been elucidated so far. In this study, we demonstrated that YTHDF2 was significantly upregulated in EOC tissues compared with normal ovarian tissues, further function studies confirmed that YTHDF2 significantly promoted the proliferation and migration of EOC cell lines, and reduced the global mRNA m6A levels. Next, we found that the expression levels of miR-145 and YTHDF2 were inversely correlated in ovarian cancer tissues and cells, and YTHDF2 is the direct target gene of miR-145. Interestingly, there was a crucial crosstalk between miR-145 and YTHDF2 via a double-negative feedback loop. Overexpression of YTHDF2 rescues miR-145-induced reduction of proliferation and migration in EOC cells. To conclude, YTHDF2 and miR-145, as two crucial m6A regulators, are involved in the progression of EOC by indirectly modulating m6A levels. In view of these promising results, YTHDF2 and miR-145 may provide new insights into the carcinogenesis and new potential therapeutic targets for EOC.
RNA methylation can reverse the methylation modification at the RNA level, which is an extremely important epigenetic modification. The function and mechanism of YTHDF2, as a reader of m6A modification, in epithelial ovarian cancer (EOC) have not been elucidated so far. This study aimed to investigate how YTHDF2 and miR-145 modulated EOC progression through m6A modification. It demonstrated that YTHDF2 was significantly upregulated in EOC tissues compared with normal ovarian tissues. Further functional studies confirmed that YTHDF2 significantly promoted the proliferation and migration of EOC cell lines and reduced the global 6-methyladenine (m6A) mRNA levels. Next, the expression levels of miR-145 and YTHDF2 were found to be inversely correlated in ovarian cancer tissues and cells, and YTHDF2 was the direct target gene of miR-145. A crucial crosstalk occurred between miR-145 and YTHDF2 via a double-negative feedback loop. The overexpression of YTHDF2 rescued miR-145-induced reduction of the proliferation and migration of EOC cells. Hence, YTHDF2 and miR-145, as two crucial m6A regulators, were involved in the progression of EOC by indirectly modulating m6A levels. The findings of this study on YTHDF2 and miR-145 might provide new insights into carcinogenesis and new potential therapeutic targets for EOC.
Front Cover: The cover image is based on the ORIGINAL RESEARCH ARTICLE miR‐145 promotes miR‐133b expression through c‐myc and DNMT3A‐mediated methylation in ovarian cancer cells by Jie Li et al., https://doi.org/10.1002/jcp.29306. Cover Credit: Cover image © Jie li Images.
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