Androgen receptor (AR)/miR-520f-3p/SOX9 signaling is involved in altering hepatocellular carcinoma (HCC) cell sensitivity to the Sorafenib therapy under hypoxia via increasing cancer stem cells phenotype

Early studies indicated that the androgen receptor (AR) might play key roles to impact hepatocellular carcinoma (HCC) progression at different stages. Its linkage to hypoxia, a condition that occurs frequently during the HCC progression, however, remains unclear. Here we found that AR/miR-520f-3p/SOX9 signaling is involved in altering HCC cells sensitivity to the Sorafenib therapy under hypoxia via increasing the cancer stem cells (CSC) population. Mechanism dissection revealed that AR might alter the miR-520f-3p/SOX9 signaling through transcriptional regulation via binding to the androgen-response-elements (AREs) on the promoter region of miR-520f, which could then suppress SOX9 mRNA translation via targeting its 3′ untranslated region (3′UTR). The in vivo mouse model with orthotopic xenografts of HCC cells also validated the in vitro data, and a human HCC sample survey confirmed the positive linkage of AR/miR-520f-3p/SOX9 signaling to the CSC population during HCC progression. Together, these preclinical findings suggest that hypoxia may increase the HCC CSC population via altering the AR/miR-520f-3p/SOX9 signaling, and targeting this newly identified signaling with the small molecule, miR-520f-3p, may help in the development of the novel therapy to better suppress the HCC progression.