HMGA2 enhances 5-fluorouracil chemoresistance in colorectal cancer via the Dvl2/Wnt pathway

Xi Xu,Jingjing Wu,Maode Lai,Chungang Liu,Hong Deng,Yunfeng Wang

doi:10.18632/oncotarget.24133

Abstract

Drug resistance is one of the main hurdles to overcome for the improvement of cancer patient survival. However, the underlying mechanisms remain largely unknown, and therapeutic options are limited. Here, we demonstrate a strong correlation between HMGA2 expression and chemosensitivity to 5-fluorouracil (5-FU), a widely used first-line systemic chemotherapy regimen for colorectal cancer (CRC) patients. Overexpression of HMGA2 enhances chemoresistance to 5-FU of CRC both in vitro and in vivo. Further experiments indicate that HMGA2 directly binds to the promoter of Dvl2 and induces its transcription, which leads to increased activation of the Wnt/β-catenin pathway. Taken together, our data suggest that HMGA2 enhances the chemoresistance to 5-FU in CRC via activating the Dvl2/Wnt pathway. Therefore, HMGA2 may serve as a predictive biomarker and a potential therapeutic target in CRC.

Highlights

Colorectal cancer is the third most common type of tumor worldwide
A heat map indicated that HMGA2 belonged to a set of genes that were upregulated in the non-responder group compared with the responder group (Figure 1A and 1B)
High levels of HMGA2 mRNA expression were seen in the nonresponder group compared with that in the responder group (P < 0.05). These observations indicated that HMGA2 may be associated with 5-FU chemoresistance in colorectal cancer (CRC)

Summary

Introduction

Colorectal cancer is the third most common type of tumor worldwide. In the USA, more than 1.3 million new cases of CRC are diagnosed every year [1]. 5-FU-based chemotherapy has improved response rates to greater 50% and achieves a median survival rate of up to 2 years [3, 4], failure of this treatment in > 90% of patients is due to drug resistance. Human HMGA2 consists of five exons and four introns. The first three exons encode three DNAbinding domains responsible for preferential binding of HMGA2 to adenine-thymine (AT)-rich minor grooves of nuclear B-form DNA via its “AT hooks” [5]. HMGA2 is commonly overexpressed in numerous malignant cancers and is associated with increased invasiveness, stemness and a poor prognosis due to mediating downstream pathways, such as the TGFβ [9] and Akt [10] pathways

Methods

Results

Conclusion