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Sox9 regulates self‐renewal and tumorigenicity by promoting symmetrical cell division of cancer stem cells in hepatocellular carcinoma
Author(s) -
Liu Chungang,
Liu Limei,
Chen Xuejiao,
Cheng Jiamin,
Zhang Heng,
Shen Junjie,
Shan Juanjuan,
Xu Yanmin,
Yang Zhi,
Lai Maode,
Qian Cheng
Publication year - 2016
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28509
Subject(s) - numb , sox9 , cancer research , liver cancer , cancer stem cell , hepatocellular carcinoma , notch signaling pathway , stem cell , biology , transcription factor , medicine , signal transduction , microbiology and biotechnology , genetics , gene
Hepatocellular carcinoma (HCC) is a highly aggressive liver tumor containing cancer stem cells (CSCs) that participate in tumor propagation, resistance to conventional therapy, and promotion of tumor recurrence, causing poor patient outcomes. The protein SRY (sex determining region Y)‐box 9 (Sox9) is a transcription factor expressed in some solid tumors, including HCC. However, the molecular mechanisms underlying Sox9 function in liver CSCs remain unclear. Here, we show that Sox9 is highly expressed in liver CSCs and that high levels of Sox9 predict a decreased probability of survival in HCC patients. We demonstrate that Sox9 is required for maintaining proliferation, self‐renewal, and tumorigenicity in liver CSCs. Overexpression of exogenous Sox9 in liver non‐CSCs restored self‐renewal capacity. Additionally, a reduction in the asymmetrical cell division of spheroid‐cultured liver CSCs was observed when compared with differentiated cancer cells or liver CSCs with inhibited Notch signaling. Furthermore, we demonstrate that Sox9 is responsible for the asymmetrical‐to‐symmetrical cell division switch in liver CSCs. Sox9 also negatively regulates Numb expression, contributing to a feedback circuit that maintains Notch activity and directs symmetrical cell division. Clinical analyses revealed that the Sox9 High Numb Low profile is associated with poor prognosis in human HCC patients. Conclusion: We demonstrate that Sox9 plays a critical role in self‐renewal and tumor propagation of liver CSCs and identify the molecular mechanisms regulated by Sox9 that link tumor initiation and cell division . (H epatology 2016;64:117–129)