Despite extensive investigation into the role of let-7 miRNAs in pathological tumor processes, their involvement in the DNA damage response remains unclear. Here we show that most let-7 family members down-regulate MDM4 expression via binding to MDM4 mRNA at a conserved DNA sequence. Expression of exogenous let-7 miRNA mimics decreased MDM4 protein but not mRNA levels. Several DNA damage reagents increased let-7 expression, thereby decreasing MDM4 protein levels in glioma cells. Inhibition of endogenous let-7 with antisense RNAs rescued MDM4 protein levels with or without MG132, a proteasome-dependent degradation inhibitor. An MDM4 mutation identified in a glioma patient was associated with loss of the putative MDM4 target site. Therefore, let-7 binding to MDM4 is implicated in the DNA damage response.
MicroRNAs, one type of non-coding RNA, and Icariin have attracted tremendous attention concerning various diseases, especially cancers. Also, the function of Icariin on malignant behaviors by targeting miR-875-5p/MDM4 axis in cervical cancer remains unknown. MiR-875-5p analogs combined
with MDM4 or Icariin were used to explore autophagy and epithelial-mesenchymal transition in cancer cells. Xenograft mice were highlighted to elucidate the influences of Icariin and miR-875-5p in vivo. As a result, miR-875-5p was cut down in cervical cancer cells, which promoted malignant
phenotype, autophagy, and limited apoptosis in cervical cancer cells. Contrarily,miR-875-5p overexpression had a contrary performance in cervical cancer cells. miR-875-5p was validated as a sponge of MDM4. Enhanced expression of MDM4 weakened the performance of miR-875-5p mimic on autophagy
and epithelial-mesenchymal transition. Moreover, Icariin reversed the stimulative action of the inhibitor on autophagy and xenograft tumor growth. Generally, These findings imply that Icariin could be identified as a curative avenue for cervical cancer via miR-875-5p/MDM4 axis.
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