Sox9 Enhances Sorafenib Resistance Through Upregulating ABCG2 Expression in Hepatocellular Carcinoma

Abstract

Sorafenib is a multikinase blocker and the only suggested drug treatment for aggressive hepatocellular carcinoma (HCC) patients. However, drug resistance to sorafenib often occurs after a period of time and cause further tumor aggression. Cancer stem cells are recently found in HCC and regarded to be involved in this process. Sox9 is highly expressed in HCC cancer stem cells and promotes cell proliferation and self-renewal. Meanwhile, HCC patients with higher Sox9 expression show poorer prognosis. Whether Sox9 is involved in sorafenib resistance in HCC is still unclear. Here, we found that sorafenib treatment increased Sox9 expression in HCC cell lines. Overexpression of exogenous Sox9 in HCC increased sorafenib resistance both in vitro and in vivo, and such phenomenon could be inhibited when Sox9 was down-regulated. We checked the down-stream gene expression profile through Sox9 RNA interference and found ATP binding cassette subfamily G member 2 (ABCG2) expression was closely affected by Sox9. Furthermore, we overexpressed Sox9 in combination with ABCG2 inhibition in HCC cell lines, and confirmed that the drug resistance to sorafenib could be ameliorated. In the cohort of patients who took sorafenib, we found those with lower Sox9 expression had longer OS and PFS. Cox analysis shows that Sox9 expression is an independent risk factor of HCC and logistic regression analysis reveals that Sox9 expression, tumor capsule deficiency, tumor diameters and microvascular invasion are risk factors of prognosis of HCC patients. Conclusion: These findings demonstrate that Sox9 enhances sorafenib resistance of HCC and meanwhile Sox9 may regulate such process through modulating ABCG2 expression. Funding: Natural Science Foundation of China. Declaration of Interest: We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled ”Sox9 enhances sorafenib resistance through upregulating ABCG2 expression in hepatocellular carcinoma”. Ethical Approval: The animal experiments in this study conformed to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines and were approved by the Institutional Animal Care and Use Committee of Second Military Medical University (Shanghai,China).