SOX9 in chemoresistance of intracellular cholangiocarcinoma (iCCA)

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In most patients of intrahepatic cholangiocarcinoma (iCCA), systemic chemotherapy such as receiving gemcitabine remains the only approach to render them eligible for surgery and palliative treatment, given that tumors are too advanced at the time of diagnosis. However, the response of iCCA to current treatments is very weak. Our recent study found that sex-determining region Y-box (SRY-box) containing gene 9 (SOX9), the master transcription factor of cholangiocytes, plays a crucial role in chemoresistance of CCA cells to gemcitabine therapy through impacting on cell cycle check points and downstream p53 signaling. We further observed that SOX9 expression in iCCA is regulated by the retinoic acid – retinoic acid receptor (RAR) axis. Retinoic acid is largely produced during activation of hepatic stellate cells, the key event leading to fibrogenesis and induced by inflammation. Based on these findings, we propose two hypotheses in this project: (I) During chemotherapy, iCCA cells undergo cell cycle arrest to avoid cell death through SOX9-dependent activation of cell cycle checkpoint proteins, and (II) chronic inflammation plays a crucial role in upregulating SOX9 expression in iCCA cells through activated HSC, which release retinoic acid. To prove the proposed hypotheses, we will address five key questions: (1) How does RA-RAR regulate expression of SOX9 in iCCA? (2) What are the mechanisms of the disease environment (inflammation and fibrosis) that modulate SOX9 expression? (3) Does SOX9 contribute to activation of CHK1 transcription through upstream modulation of ATR? (4) Whether, and if yes, how SOX9 influences the ATM-CHK2-p53 pathway? (5) How does SOX9 mediate chemoresistance of iCCA? These experiments will clarify detailed molecular mechanisms of how SOX9 contribute to chemoresistance in iCCA and provide a novel approach to overcome SOX9-dependent chemoresistance in clinical practice.