XRCC1 mediated the development of cervival cancer through a novel Sp1/Krox-20 swich

Qingtao Meng,Xiaobo Li,Weiyan Tang,Michael Aschner,Shenshen Wu,Rui Chen,Na Gao,Yue Huang,Shizhi Wang,Xiaoli Cao,Zhengdong Zhang,Chengcheng Zhang,Hua Jin

doi:10.18632/oncotarget.21040

Abstract

Cervical cancer is the second leading cause of mortality among women. Impairment of the base excision repair (BER) pathway is one of the major causes of the initiation and progression of cervical cancer. However, whether the polymorphisms of the BER pathway components (i.e., HOGG1, XRCC1, ADPRT, and APE1) can affect the risk of cervical cancer remains unknown. Herein, we applied a hospital-based case-control study covering two independent cohorts and a subsequent functional assay to determine the roles of the single nucleotide polymorphisms (SNPs) of the BER pathway genes in cervical cancer. Results indicated that the XRCC1 rs3213245 (-77TC) TT genotype was associated with an increased risk of cervical cancer. The immunohistochemistry assay showed that XRCC1 protein expression levels were upregulated in cervical cancer patients with the XRCC1 rs3213245 CC genotype compared with the CT or TT genotypes. Further, results from ChIP assay showed that Sp1 could bind to the −77 site and that the rs3213245 C genotype promoted the binding of Sp1 to the XRCC1 promoter. Moreover, ChIP/Re-ChIP assays revealed that transcription factor Krox-20 was recruited to the XRCC1 rs3213245 mutation region and regulated the transcription of the XRCC1 gene by interacting with Sp1, ultimately mediated cervical cancer development. In summary, the findings indicated that the functional XRCC1 SNP rs3213245 was associated with the risk of cervical cancer based on the Sp1/Krox-20 switch.

Highlights

Cervical cancer is the second most common malignant tumor found in women worldwide accounting for 7.5% of all female cancer deaths [1]
The results showed that the X-ray cross complementing group 1 (XRCC1) TT genotype increased the risk of cervical cancer
Few studies have focused on the association between the functional polymorphisms in the base excision repair (BER) pathway and cervical cancer susceptibility

Summary

Introduction

Cervical cancer is the second most common malignant tumor found in women worldwide accounting for 7.5% of all female cancer deaths [1]. Impaired BER pathways are considered the major cause of cervical cancer [2]. The association between APE1 rs1760944 (−656T>G) and rs1130409 (Asp148Glu) polymorphisms and the risk of renal cell carcinoma and breast cancer have been indicated in several casecontrol studies [3, 4]. The HOGG1 (rs1052133) Ser genotype has failed to repair broken DNA and has been demonstrated to increase cancer susceptibility in the gallbladder cancer [6] and renal cell carcinoma [7]. XRCC1 serves as the scaffold protein in the BER pathway, which recognizes DNA breaks and interacts with DNA polymerase β, DNA ligase III, and other components to repair Single-Strand Breaks (SSBs) [8]. Sp1, which is one of the bestcharacterized transcriptional activators [14], plays a prominent role in cell-cycle development and regulation [15,16,17,18]

Methods

Results

Conclusion