SOX9 expression decreases survival of patients with intrahepatic cholangiocarcinoma by conferring chemoresistance

TY - JOUR

T1 - SOX9 expression decreases survival of patients with intrahepatic cholangiocarcinoma by conferring chemoresistance

AU - Yuan, Xiaodong

AU - Li, Jun

AU - Coulouarn, Cédric

AU - Lin, Tao

AU - Sulpice, Laurent

AU - Bergeat, Damien

AU - De La Torre, Carolina

AU - Liebe, Roman

AU - Gretz, Norbert

AU - Ebert, Matthias P A

AU - Dooley, Steven

AU - Weng, Hong-Lei

PY - 2018/11

Y1 - 2018/11

N2 - BACKGROUND: Sex-determining region Y-box (SRY-box) containing gene 9 (SOX9) expression confers cancer stem cell features. However, SOX9 function in intrahepatic cholangiocarcinoma (iCCA) is unknown. This study investigated the effects and underlying mechanisms of SOX9 in iCCA.METHODS: SOX9 expression in 59 iCCA patients was examined by immunohistochemistry. The association between SOX9 expression and clinical outcome was evaluated. Gene signature and biological functions of SOX9 in iCCA were examined in vitro.RESULTS: iCCA patients with high SOX9 expression had shorter survival time than those with low SOX9. In patients receiving chemotherapy, median survival time in patients with low and high levels of SOX9 were 62 and 22 months, respectively. In vitro, gemcitabine increased SOX9 expression in iCCA cells. When SOX9 was knocked down, gemcitabine-induced apoptosis was markedly increased. Silencing SOX9 significantly inhibited gemcitabine-induced phosphorylation of checkpoint kinase 1, a key cell cycle checkpoint protein that coordinates the DNA damage response and inhibited the expression of multidrug resistance genes. Microarray analyses showed that SOX9 knockdown in CCA cells altered gene signatures associated with multidrug resistance and p53 signalling.CONCLUSIONS: SOX9 governs the response of CCA cells to chemotherapy. SOX9 is a biomarker to select iCCA patients eligible for efficient chemotherapy.

AB - BACKGROUND: Sex-determining region Y-box (SRY-box) containing gene 9 (SOX9) expression confers cancer stem cell features. However, SOX9 function in intrahepatic cholangiocarcinoma (iCCA) is unknown. This study investigated the effects and underlying mechanisms of SOX9 in iCCA.METHODS: SOX9 expression in 59 iCCA patients was examined by immunohistochemistry. The association between SOX9 expression and clinical outcome was evaluated. Gene signature and biological functions of SOX9 in iCCA were examined in vitro.RESULTS: iCCA patients with high SOX9 expression had shorter survival time than those with low SOX9. In patients receiving chemotherapy, median survival time in patients with low and high levels of SOX9 were 62 and 22 months, respectively. In vitro, gemcitabine increased SOX9 expression in iCCA cells. When SOX9 was knocked down, gemcitabine-induced apoptosis was markedly increased. Silencing SOX9 significantly inhibited gemcitabine-induced phosphorylation of checkpoint kinase 1, a key cell cycle checkpoint protein that coordinates the DNA damage response and inhibited the expression of multidrug resistance genes. Microarray analyses showed that SOX9 knockdown in CCA cells altered gene signatures associated with multidrug resistance and p53 signalling.CONCLUSIONS: SOX9 governs the response of CCA cells to chemotherapy. SOX9 is a biomarker to select iCCA patients eligible for efficient chemotherapy.

U2 - 10.1038/s41416-018-0338-9

DO - 10.1038/s41416-018-0338-9

M3 - SCORING: Journal article

C2 - 30420613

VL - 119

SP - 1358

EP - 1366

JO - BRIT J CANCER

JF - BRIT J CANCER

SN - 0007-0920

IS - 11

ER -