Abstract
BackgroundSex-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.MethodsSOX9 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.ResultsiCCA 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.ConclusionsSOX9 governs the response of CCA cells to chemotherapy. SOX9 is a biomarker to select iCCA patients eligible for efficient chemotherapy.
Highlights
Cholangiocarcinoma (CCA) is the second most common primary liver cancer following hepatocellular carcinoma (HCC), and accounts for approximately 10–15% of all primary liver malignancies.[1]
The results suggest that SOX9 expression in cholangiocytes is unstable in chronic liver disease compared to cytokeratin 19 (CK19)
As in chronic liver disease, SOX9 expression was observed in the nuclei of intrahepatic cholangiocarcinoma (iCCA) tumour cells, while CK19 localised in the cytoplasm of cancer cells (Fig. 1b)
Summary
Cholangiocarcinoma (CCA) is the second most common primary liver cancer following hepatocellular carcinoma (HCC), and accounts for approximately 10–15% of all primary liver malignancies.[1]. METHODS: SOX9 expression in 59 iCCA patients was examined by immunohistochemistry. Gene signature and biological functions of SOX9 in iCCA were examined in vitro. Median survival time in patients with low and high levels of SOX9 were 62 and 22 months, respectively. 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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
