MiR-22 regulates HIF-1A pathway and tumor progression and represents a possible biomarker of sorafenib response in hepatocellular carcinoma

Introduction Hepatocellular carcinoma (HCC) represents the third leading cause of cancer mortality worldwide with approximately 40% of patients diagnosed at advanced stages. Immunotherapy and tyrosine-kinase inhibitors sorafenib and lenvatinib represent the first-line treatments in HCC. Despite immunotherapy has revolutionized HCC management, advanced stages are characterized by limited response and early onset of drug-resistance. The identification of biomarkers of treatment response or tumor escape is still an unmet clinical need. Aims The aims of this study are to investigate miR-22 contribution to HCC tumorigenesis and sorafenib response, and to analyze its role as a biomarker of drug response. Materials and Methods Serum and tissue miR-22 levels were analyzed by qPCR in HCC patients and DEN-HCC rats. Proliferation and apoptosis assays and live imaging analysis evaluated miR-22 influence on HCC phenotype in vitro. A xenograft mouse model was used to determine the role of miR-22 on HCC tumorigenesis. Functional analysis elucidated the regulation of HIF-1A pathway following miR-22 modulation in different settings. Results MiR-22 was downregulated in human and rat HCCs and associated with microvascular invasion, tumor grade, and a worse overall survival. In vitro assays revealed that miR-22 inhibits cell growth in normoxic and hypoxic conditions and blocked HIF-1A pathway in HCC cells. Regarding in vivo tumorigenesis, miR-22 silencing gave rise to bigger and more vascularized tumor masses in xenograft mice. Lower miR-22 tissue levels associated with sorafenib resistance and correlated with apoptotic markers in the rat model while serum levels showed the opposite. In sorafenib-treated patients, a positive correlation between circulating miR-22 levels and days of treatment was observed. In line, lower miR-22 basal levels were detected in non-responder HCCs. Conclusion Low miR-22 levels favor HCC tumorigenesis and associate with a poor prognosis. MiR-22 influences sorafenib sensitivity and deserves attention as a possible biomarker of treatment response.