Transcriptional Factor Sox9 Contributes To Chemoresistance Of Colorectal Cancer Cells

Background and Objective:SRY(sex region determing region Y)-box 9(Sox9)belongs to a HMG domain-containing transcription factor family,which plays critical roles in intestinal development and tumorigenesis.In intestine,Sox9 is mainly expressed in intestinal stem cells and involved in maintaining tissue homeostasis and determining cellular differentiation.It has been reported that Sox9 is overexpressed in colorectal cancer tissues and positively correlated with poor prognosis.Chemoresistance is one of the main causes of colorectal cancer-related death.However,whether Sox9 contributes to chemoresistance of colorectal cancer cells is still unknown.The aim of this study is to explore the role of Sox9 in the acquirement of chemoresistance in colorectal cancer cells and address the mechanisms underlying Sox9-mediated regulation.Results: We initially compared the expression levels of the Sox genes in 5-Futreated SW480 xenografts with those in the control tumor tissues,and found that the levels of Sox9 mRNA and protein were significantly upregulated in the residual tumor tissues in the mice with 5-Fu treatment.The enriched expression of Sox9 in the tumor cells after chemotherapy indicates that this transcriptional factor may confer a survival advantage or chemoresistance to tumor cells.Indeed,Sox9 overexpression in HCT8 and SW480 cells significantly promoted the chemoresistance of these cells in vitro,whereas knockdown of Sox9 expression in HCT116 and SW620 cells by shRNA inhibited tumor growth and increased the sensitivity of the tumor cells to 5-Fu in vivo.Consistently,overexpression of Sox9 was also contributable to the ability of spheroid formation in the colorectal tumor cells and the increased expression of certain stemness-related genes.Mechanistically,we found that Sox9 was a positive regulator of DNMT1 in colon cancer cells,wherein the process mediated by Sox9 was largely dependant on the downregulation of hsa-miR-148 a.Clinically,a correlation between DNMT1 and Sox9 expression was observed in colorectal cancer tissues,and the patients with high expression of Sox9 and DNMT1 in the colorectal cancer tissues had a poor prognosis.Conclusion : Sox9 increases DNMT1 expression through downregulating hsa-miR-148,and Sox9 decreases the vulnerability of colorectal cancer cells to the chemo-drugs at least partially through modulating hsa-miR-148/DNMT1 expression.In clinic,Sox9 expression correlates with DNMT1 expression in colorectal cancer tissues,and the hyperexprssion of these two factors predicts a poor prognosis in patients with colorectal cancer.Therefore,Sox9 functions critically in the acquirement of chemoresistance in colorectal cancer.