Sox9 confers stemness properties in hepatocellular carcinoma through Frizzled-7 mediated Wnt/β-catenin signaling
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Carmen Oi-Ning Leung1, Wing-Nga Mak1, Alan Ka-Lun Kai1, Kwan-Shuen Chan1, Terence Kin-Wah Lee1,2, Irene Oi-Lin Ng1,2, Regina Cheuk-Lam Lo1,2
1Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
2State Key Laboratory for Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong
Regina Cheuk-Lam Lo, email: [email protected]
Irene Oi-Lin Ng, email: [email protected]
Keywords: Sox9, liver cancer, tumor-initiating cells
Received: October 05, 2015 Accepted: March 29, 2016 Published: April 19, 2016
Sox9, an SRY-related HMG box transcription factor, is a progenitor/precursor cell marker of the liver expressed during embryogenesis and following liver injury. In this study, we investigated the role of Sox9 and its molecular mechanism with reference to stemness properties in hepatocellular carcinoma (HCC). Here, we observed upregulation of Sox9 in human HCC tissues compared with the non-tumorous liver counterparts (p < 0.001). Upregulation of Sox9 transcript level was associated with poorer tumor cell differentiation (p = 0.003), venous invasion (p = 0.026), advanced tumor stage (p = 0.044) and shorter overall survival (p = 0.042). Transcript levels of Sox9 and CD24 were positively correlated. Silencing of Sox9 in HCC cells inhibited in vitro cell proliferation and tumorsphere formation, sensitized HCC cells to chemotherapeutic agents, and suppressed in vivo tumorigenicity. In addition, knockdown of Sox9 suppressed HCC cell migration, invasion, and in vivo lung metastasis. Further studies showed that Sox9 endowed stemness features through activation of Wnt/β-catenin signaling, which was confirmed by the partial rescue effect on tumorigenicity and self-renewal upon transfection of active β-catenin in Sox9 knockdown cells. By ChIP and luciferase promoter assays, Frizzled-7 was identified to be the direct transcriptional target of Sox9. In conclusion, Sox9 confers stemness properties of HCC through Frizzled-7 mediated Wnt/β-catenin pathway.
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