Upregulation of YPEL3 expression and induction of human breast cancer cell death by microRNAs.

MicroRNAs (miRNAs), molecules comprising 18-22 nucleotides, regulate expression of genes post-transcriptionally at the 3' untranslated region of target mRNAs. However, the biological roles and mechanisms of action of miRNAs in breast cancer remain unelucidated. Thus, in this study, we aimed to investigate the functions and possible mechanisms of action of miRNAs in breast cancer to suppress carcinogenesis. Using miRNA databases, we selected miR-34a and miR-605-5p to downregulate MDM4 and MDM2, respectively, because these ubiquitin E3 ligases degrade p53 and promote carcinogenesis. Results showed that miR-34a and miR-605-5p suppressed MDM4 and MDM2 expression, respectively. Moreover, they reduced the expression of yes‑associated protein 1 (YAP1), a well-known oncogene involved in Hippo signaling, but upregulated the mRNA and protein expression of yippee-like 3 (YPEL3). To elucidate whether these miRNAs promote cellular senescence and death through YPEL3 upregulation, we examined their effects on cellular proliferation, SA-β-gal activity, and mitochondrial activity in human breast cancer MCF-7 cells. Given their upregulating effect on YPEL3 expression, miR-34a and miR-605-5p increased the number of β-galactosidase-positive cells and depolarized live cells (by 10%-12%). These data suggest that miR-34a and miR-605-5p promote cellular senescence and cell death. Thus, they may act as tumor suppressors by inducing Hippo signaling and may serve as novel therapeutic agents in breast cancer treatment.

Supplementary information: The online version contains supplementary material available at 10.1007/s43188-024-00251-2.