MiR-30e-3p Influences Tumor Phenotype through <i>MDM2</i> / <i>TP53</i> 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 <i>TP53/MDM2</i> pathway, in HCC tissues and preclinical models. MiR-30e-3p was downregulated in human and rat HCCs, and its downregulation associated with <i>TP53</i> mutations. <i>TP53</i> contributed to miR-30e-3p biogenesis, and <i>MDM2</i> was identified among its target genes, establishing an miR-30e-3p/<i>TP53</i>/<i>MDM2</i> feedforward loop and accounting for miR-30e-3p dual role based on <i>TP53</i> status. <i>EpCAM</i>, <i>PTEN</i>, and <i>p27</i> were demonstrated as miR-30e-3p additional targets mediating its contribution to stemness and malignant features. In a preliminary cohort of patients with HCC 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 plays a predominant tumor suppressor function in wild-type <i>TP53</i> contexts, whereas other targets such as <i>PTEN</i>, <i>p27</i>, and <i>EpCAM</i> gain relevance and mediate miR-30e-3p oncogenic role in nonfunctional <i>TP53</i> backgrounds. Increased circulating levels of miR-30e-3p predict the development of sorafenib resistance in a preliminary series of patients with HCC and deserve future investigations. SIGNIFICANCE: The dual role of miR-30e-3p in HCC clarifies how the molecular context dictates the tumor suppressor or oncogenic function played by miRNAs.