CtBP2 is an independent prognostic marker that promotes GLI1 induced epithelial-mesenchymal transition in hepatocellular carcinoma.

Xin Zheng,Yuli Jia,Changwei Dou,Qingguang Liu,Tao Song

doi:10.18632/oncotarget.2915

Abstract

C-terminal binding protein 2 (CtBP2) is a transcriptional co-repressor that promotes cancer cell migration and invasion by inhibiting multiple tumor suppressor genes that contribute to cell mobility and adhesion. In this investigation, we showed thatCtBP2 expression was increased significantly in HCC tissues when compared to matched normal adjacent liver tissues. We also showed that CtBP2 expression is associated with worse HCC patient prognosis after liver resection. CtBP2 over-expression induced epithelial-mesenchymal transition (EMT) in Huh7 cells and, correspondingly, silencing CtBP2 suppressed EMT in MHCC97H cells. ChIP assays revealed that GLI1 increased CtBP2 transcription by directly binding its promoter. Furthermore, interaction of CtBP2 and Snail Family Zinc Finger 1 (SNAI1), both of which were found to be positively regulated by GLI1, was confirmed by Co-IP assay. SNAI1 knockdown revealed that SNAI1 was essential for CtBP2 induction of the EMT phenotype of HCC cells, and CtBP2 knockdown reversed GLI1-SNAI1 driven EMT in Huh7 cells. Finally, in vivo experiments demonstrated that enhanced CtBP2expression promoted HCC xenograft growth and induced EMT. In conclusion, CtBP2 may serve as a prognostic marker for post liver resection HCC and may play a role during GLI1-driven EMT as a transcriptional co-repressor of SNAI1.

Highlights

Hepatocellular carcinoma (HCC) is the most common primary liver cancer subtype [1] and one of the major causes of mortality in developing countries [2]
We report that C-terminal binding protein 2 (CtBP2) expression was upregulated in the HCC tissues examined in this study, and that elevated CtBP2 expression was associated with elevated Glioma-associated oncogene 1 (GLI1) expression and poor overall postsurgical survival
Mann-Whitney U analysis demonstrated that CtBP2 expression was significantly higher in HCC tissues when compared to adjacent liver tissues ( p < 0.001, Figure 1B)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most common primary liver cancer subtype [1] and one of the major causes of mortality in developing countries [2]. HCC recurrence occurs because of both primary tumor metastatic dissemination prior to surgery and new neoplasm development in the remaining liver tissues after surgery. Because of the high rate of recurrence, the postsurgical prognosis of HCC patients is extremely poor. A growing body of evidence indicates that CtBP2 is aberrantly upregulated in a variety of cancers and that its expression promotes cancer progression. Zhang et al reported that CtBP2 was overexpressed in prostate cancer tissues and associated with poor outcome and several indicators of malignancy, including elevated serum PSA levels, advanced tumor stages and higher Gleason www.impactjournals.com/oncotarget scores. Zhang et al reported that CtBP2 expression promoted prostate cancer cell proliferation through c-Myc signaling [12]. Similar findings have been reported in breast cancer studies that examined CtBP2 expression [14, 15]. The mechanism governing CtBP2 overexpression in cancer remains unclear

Methods

Results

Conclusion