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Methylation of microRNA-338-5p by EED promotes METTL3-mediated translation of oncogene CDCP1 in gastric cancer.

ABSTRACT: Unmasking the complex regulatory pathways that mediate the malignant phenotypes of cancer cells can provide novel targets for therapies that could limit the recurrence and metastasis of gastric cancer (GC). Herein, we intended to clarify the role of embryonic ectoderm development protein (EED), microRNA-228-5p (miR-338-5p), methyltransferase like 3 (METTL3) and CUB domain containing protein 1 (CDCP1) in GC. Differentially expressed miRNAs and their target genes were extracted by in silico analysis. The studies revealed high expression of EED in GC tissues and cell lines and it high expression in GC patients was shown to be associated with poor prognosis. The chromatin immunoprecipitation assay identified that EED methylated miR-338-5p to inhibit its expression. EED knockdown could restrain the proliferative and invasive abilities of GC cells by inducing miR-338-5p. Furthermore, miR-338-5p targeted m6A methylase METTL3, while METTL3 amplified the translation of CDCP1 via m6A activity which led to accelerated proliferation and invasion of GC cells. Moreover, in vivo experiments validated that EED promoted the progression of GC through mediating the miR-338-5p/METTL3/CDCP1 axis. Collectively, EED downregulated miR-338-5p through histone methylation, which in turn impaired miR-338-5p-dependent METTL3 inhibition and enhanced CDCP1 translation, therefore contributing to the development of GC.

SUBMITTER: Zhang F

PROVIDER: S-EPMC8109089 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:MiRNAs have been widely reported to be involved in the occurrence and development of cancers. So far, some studies have revealed that miR-338-5p has the functions of tumorigenesis and tumor suppression. However, the role of miR-338-5p in the pathogenesis, progression and treatment of gastric cancer (GC) has not been reported. MiRNAs microarray analysis showed for the first time that miR-338-5p was significantly lower-expression in cisplin-resistant GC cells SGC7901/DDP, and cell viability assay and flow cytometry confirmed that overexpression of miR-338-5p could significantly increase cisplatin-sensitivity of SGC7901/DDP and BGC823 cells. Subsequently, we found that the expression of miR-338-5p in postoperative cancer tissues of GC patients was also significantly lower than the corresponding paracancer tissues. The expression of miR-338-5p in peripheral blood serum of GC patients is generally lower than that of healthy people. Moreover, the low expression of miR-338-5p in the cancer tissues and serum of GC patients was closely associated with larger tumor volume, lymph node metastasis, later stage, and even poorer survival, which was confirmed by close 5-year cases follow-up. ZEB2, as a predictive target of miR-338-5p, its expression was negatively regulated by miR-338-5p and can promote cisplatin-resistance in SGC7901/DDP and BGC823 cells. The expression of ZEB2 in cisplatin-resistant SGC7901/DDP cells and GC tissues were significantly higher than SGC7901 cells and paracancer tissues, respectively. Moreover, the expression of ZEB2 in tumor tissues was negatively correlated with miR-338-5p in tumor tissues and peripheral blood serum of GC patients, and the abnormally high expression of ZEB2 in prospective case studies is positively related with more serious clinical pathology and worse survival. More meaningfully, in a retrospective case study, we found that high ZEB2 expression predicts worse clinical efficacy of platinum chemotherapy. Thus, miR-338-5p-ZEB2 axis have novel diagnostic, therapeutic predictive, and prognostic value in GC patients.

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Methylation of microRNA-338-5p by EED promotes METTL3-mediated translation of oncogene CDCP1 in gastric cancer.

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