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

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.