XRCC1 mediated the development of cervival cancer through a novel Sp1/Krox-20 swich
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Qingtao Meng1,*, Shizhi Wang1,*, Weiyan Tang2,*, Shenshen Wu1, Na Gao3, Chengcheng Zhang1, Xiaoli Cao4, Xiaobo Li1, Zhengdong Zhang5, Michael Aschner6, Hua Jin7,**, Yue Huang8,** and Rui Chen1,9,**
1Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
2Medical Oncology, Jiangsu Cancer Hospital, Nanjing, China
3Institute of Bioinformatics, Heinrich Heine University, Düsseldorf, Germany
4Clinical Lab, Nantong Tumor Hospital, Nantong, China
5Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China
6Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
7Core Laboratory, Nantong Tumor Hospital, Nantong, China
8Department of Pathology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
9State Key Laboratory of Respiratory Disease, Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou, China
*These authors have contributed equally to this work
**These authors co-supervised this work
Rui Chen, email: [email protected]
Yue Huang, email: [email protected]
Hua Jin, email: [email protected]
Keywords: base excision repair, XRCC1, cervical cancer, Krox-20, specificity protein 1
Received: June 29, 2017 Accepted: August 09, 2017 Published: September 16, 2017
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.
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