MiR-30e-3p Influences Tumor Phenotype through MDM2/TP53 Axis and Predicts Sorafenib Resistance in Hepatocellular Carcinoma

Abstract

The molecular background of hepatocellular carcinoma (HCC) is highly heterogeneous and biomarkers predicting response to treatments are an unmet clinical need. We investigated miR-30e-3p contribution to HCC phenotype and response to sorafenib, as well as the mutual modulation of TP53/MDM2 pathway, in HCC tissues and preclinical models. MiR-30e-3p was downregulated in human and rat HCCs and its downregulation associated with TP53 mutations. TP53 contributed to miR-30e-3p biogenesis and MDM2 was identified among its target genes, establishing a miR-30e-3p/TP53/MDM2 feedforward loop and accounting for miR-30e-3p dual role based on TP53 status. EpCAM, PTEN and p27 were demonstrated as miR-30e-3p additional targets mediating its contribution to stemness and malignant features. In a preliminary cohort of HCC patients treated with sorafenib, increased miR-30e-3p circulating levels predicted the development of resistance. In conclusion, molecular background dictates miR-30e-3p dual behavior in HCC. Mdm2 targeting/p53 axis plays a predominant tumor-suppressor function in wild type TP53 contexts, whereas other targets such as PTEN, p27 and EpCAM gain relevance and mediate miR-30e-3p oncogenic role in non-functional TP53 backgrounds. Increased circulating levels of miR-30e-3p predict the development of sorafenib resistance in a preliminary series of HCC patients and deserve future investigations.