SOX9 expression decreases survival of patients with intrahepatic cholangiocarcinoma by conferring chemoresistance
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SOX9 expression decreases survival of patients with intrahepatic cholangiocarcinoma by conferring chemoresistance. / Yuan, Xiaodong; Li, Jun; Coulouarn, Cédric; Lin, Tao; Sulpice, Laurent; Bergeat, Damien; De La Torre, Carolina; Liebe, Roman; Gretz, Norbert; Ebert, Matthias P A; Dooley, Steven; Weng, Hong-Lei.
In: BRIT J CANCER, Vol. 119, No. 11, 11.2018, p. 1358-1366.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -