Z Gastroenterol 2018; 56(01): E2-E89
DOI: 10.1055/s-0037-1612795
Poster Visit Session IV Tumors, Liver Surgery and Transplantation – Saturday, January 27, 2018, 8:30am – 9:15am, Foyer area West Wing
Georg Thieme Verlag KG Stuttgart · New York

SOX9 is a crucial transcription factor determining intrahepatic cholangiocarcinoma resistance to chemotherapy

X Yuan
1   Medical Faculty Mannheim, Heidelberg University, Department of Medicine II,, Mannheim
,
J Li
2   University Medical Center Hamburg-Eppendorf, Department of Hepatobiliary Surgery and Visceral Transplantation, Hamburg
,
C Coulouarn
3   Liver Metabolisms and Cancer, University of Rennes, Rennes
,
S Dooley
1   Medical Faculty Mannheim, Heidelberg University, Department of Medicine II,, Mannheim
,
H Weng
1   Medical Faculty Mannheim, Heidelberg University, Department of Medicine II,, Mannheim
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2018 (online)

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Question:

Expression of sex-determining region Y (SRY)-box 9 (SOX9) in hepatocellular carcinoma suggests cancer stem cell features. However, how SOX9 functions in intrahepatic cholangiocarcinoma (iCCA) is unknown. This study investigated the effects and underlying mechanisms of SOX9 in iCCA.

Methods:

SOX9 expression was examined in 59 iCCA patients by immunohistochemistry. The association between SOX9 expression and clinical outcome was evaluated. The gene signature and biological functions of SOX9 in iCCA were examined further in vitro.

Results:

SOX9 expression was significantly associated with survival of iCCA patients. The patients with high SOX9 expression had shorter survival time than those with low SOX9. Impressively, iCCA patients with low levels of SOX9 had 62 months of median survival time following chemotherapy. In the contrary, the time was only 22 months in those with SOX9 high expression. In vitro, gemcitabine treatment in iCCA cells upregulated SOX9 expression. When SOX9 was knocked down, gemcitabine-induced cell apoptosis was markedly increased. Silence of SOX9 significantly inhibited gemcitabine-induced phosphorylation of Checkpoint kinase 1, a key cell cycle check point protein that coordinates the DNA damage response, and expression of multidrug resistance genes. Microarray analysis showed that SOX9 knockdown in CCA cells altered gene signature associated with adenosine triphosphate-binding cassette transporters, drug metabolism enzymes and with p53 signaling.

Conclusions:

SOX9 governs the response of CCA cells to chemotherapy through regulating activation of Chk1 and multidrug resistance genes. A validating clinical study is required to confirm the hypothesis: SOX9 is a hallmark determining whether iCCA patients need chemotherapy.