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SOX9 enhances sorafenib resistance through upregulating ABCG2 expression in hepatocellular carcinoma

Mengchao Wang1, Zhiheng Wang1, Xiaosong Zhi2

  • 1The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, China.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
|June 20, 2020
PubMed

Insights

SOX9 promotes sorafenib resistance in hepatocellular carcinoma (HCC) by upregulating ABCG2. Lower SOX9 expression correlates with better survival in HCC patients treated with sorafenib, identifying SOX9 as a potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Resistance

Background:

  • Sorafenib is a key treatment for advanced hepatocellular carcinoma (HCC), but resistance limits its efficacy.
  • Cancer stem cells, implicated in HCC progression, express SOX9, which is linked to poor prognosis.
  • The role of SOX9 in sorafenib resistance in HCC remains largely unknown.

Purpose of the Study:

  • To investigate the role of SOX9 in sorafenib resistance in hepatocellular carcinoma (HCC).
  • To explore the underlying molecular mechanisms, including the involvement of ABCG2.
  • To evaluate SOX9 expression as a prognostic marker in HCC patients receiving sorafenib therapy.

Main Methods:

  • Sorafenib treatment was applied to HCC cell lines to assess changes in SOX9 expression.
  • SOX9 was overexpressed and knocked down using exogenous expression and RNA interference, respectively.
  • In vitro and in vivo assays were performed to evaluate sorafenib resistance.
  • The expression of downstream genes, including ABCG2, was analyzed.
  • Patient cohorts treated with sorafenib were analyzed for SOX9 expression and survival outcomes (OS and PFS).

Main Results:

  • Sorafenib treatment increased SOX9-positive cells in HCC lines.
  • SOX9 overexpression enhanced sorafenib resistance in vitro and in vivo, while SOX9 knockdown reduced resistance.
  • Knockdown of SOX9 led to decreased expression of ABCG2, and ABCG2 inhibition ameliorated SOX9-driven resistance.
  • Lower SOX9 expression in patients correlated with longer overall survival (OS) and progression-free survival (PFS).
  • SOX9 was identified as an independent risk factor for OS and PFS in HCC patients on sorafenib.

Conclusions:

  • SOX9 plays a significant role in promoting sorafenib resistance in HCC.
  • SOX9 appears to mediate sorafenib resistance, at least partly, through the modulation of ABCG2 expression.
  • SOX9 expression is a valuable prognostic biomarker for predicting treatment response and survival in HCC patients treated with sorafenib.
Keywords:
ABCG2HCCSOX9Sorafenib resistance

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