Abstract
Reduced DNA repair might affect the risk of progression from infection with carcinogenic human papillomavirus (HPV), the etiologic agent for cervical cancer (CC), to persistent HPV infection, and hence to cervical pre-cancer and cancer. We assessed the variation in baseline expression of base excision repair gene XRCC1 and three nucleotide excision repair genes ERCC1, ERCC2, and ERCC4 and the risk of developing cervical cancer. A hospital-based case–control study was designed with 50 invasive cervical cancer patients, 40 squamous intraepithelial lesions (SIL) patients and 85 controls subjects. RT-qPCR and Western blotting was used to quantitate in vitro the mRNA and protein levels in fresh CC, SIL and normal cervix tissue. The levels of XRCC1, ERCC2, ERCC4, and ERCC1 transcripts and their respective proteins were lower in cervical cancer and SILs as compared to controls (p ≤ 0.001, 0.001, 0.001, and 0.025, respectively). In multivariate logistic regression analysis (adjusting for parity, age at first child birth, use of oral contraceptives, smoking status), low expression of XRCC1, ERCC2, ERCC4, and ERCC1 was associated with a significant increased risk for CC and SIL. Our results suggest that individuals whose expression of XRCC1, ERCC4, ERCC2, and ERCC1 are reduced may be at a higher risk of developing SIL which eventually leads to invasive cervical carcinoma. Moreover, independently also the reduced expression of these genes can directly lead to cervical cancer progression.
Similar content being viewed by others
References
Franceschi S (2005) The IACR commitment to cancer prevention: the example of papillomavirus and cervical cancer. Recent Results Cancer Res 166:277–297
Danaei G, Vander SH, Lopez AD, Murray CJ, Ezzati M (2005) Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. Lancet 366:1784–1793
Herrera LA, Benitez-Bribiesca L, Mohar A, Ostrosky-Wegman P (2005) Role of infectious diseases in humans carcinogenesis. Environ Mol Mutagen 45:284–303
Zur HH (2002) Papillomavirus and cancer: from basic studies to clinical application. Nat Rev Cancer 2:342–350
Zur HH (2000) Papillomaviruses causing cancer: evasion from host cell control in early events in carcinogenesis. J Natl Cancer Inst 92:690–698
Niwaet Y et al (2005) Association of XRCC1 Arg399Gln and OGG1 Ser326 Cys polymorphisms with the risk of cervical cancer in Japanese subjects. Gynecol Oncol 99:43–49
Roszak A et al (2011) Involvement of the XRCC1 Arg399Gln gene polymorphism in the development of cervical carcinoma. Int J Biol Markers 26:216–220
Settheetham-Ishida W et al (2011) Genetic risk of DNA repair gene polymorphisms (XRCC1 and XRCC3) for high risk human papillomavirus negative cervical cancer in Northeast Thailand. Asian Pac J Cancer Prev 12:963–966
Wang SS et al (2010) Common genetic variants and risk for HPV persistence and progression to cervical cancer. PLoS ONE 1:e8667
Zhang L et al (2012) Single nucleotide polymorphisms in DNA repair genes and risk of cervical cancer: a case–control study. Oncol Lett 3:351–362
Britten RA et al (2000) ERCC1 expression as a molecular marker of cisplatin resistance in human cervical tumor cells. Int J Cancer 89:453–457
Caldecott KW (2007) Mammalian single-strand break repair: mechanisms and links with chromatin. DNA Repair (Amst) 6:443–453
de Boe J, Hoeijmakers JH (2000) Nucleotide excision repair and human syndromes. Carcinogenesis 21:453–460
Helleday T, Lo J, van Gent DC et al (2007) DNA double-strand break repair: from mechanistic understanding to cancer treatment. DNA Repair (Amst) 6:923–935
Rajewsky MF, Engelbergs J, Thomale J et al (2000) DNA repair: counteragent in mutagenesis and carcinogenesis-accomplice in cancer therapy resistance. Mutat Res 462:101–105
Vidal AE, Boiteux S, Hickson ID et al (2001) XRCC1 coordinates the initial and late stages of DNA abasic site repair through protein–protein interactions. EMBO J 20:6530–6539
Thompson LH, West MG (2000) XRCC1 keeps DNA from getting stranded. Mutat Res 459:1–18
Shen MR, Jones IM, Mohrenweiser H (1998) Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans. Cancer Res 58:604–608
Busch D, Greiner C, Lewis K et al (1989) Summary of complementation groups of UV-sensitive CHO cell mutants isolated by large-scale screening. Mutagenesis 4:349–354
Lee TI, Young RA (2007) Transcription of eukaryotic protein-coding genes. Annu Rev Genet 34:77–137
Cleaver JE (1968) Defective repair replication of DNA in xeroderma pigmentosum. Nature 218:652–656
Wei Q, Cheng L, Hong WK et al (1996) Reduced DNA repair capacity in lung cancer patients. Cancer Res 56:4103–4107
Cheng L, Eicher SA, Guo Z et al (1998) Reduced DNA repair capacity in head and neck cancer patients. Cancer Epidemiol Biomarkers Prev 7:465–468
Datta P, Bhatla N, Dar L et al (2010) Prevalence of human papillomavirus infection among young women in North India. Cancer Epidemiol 34:157–161
Kumar A, Pant MC, Singh HS et al (2012) Reduced expression of DNA repair genes (XRCC1, XPD, and OGG1) in squamous cell carcinoma of head and neck in North India. Tumor Biol 33:111–119
Pathak S, Sharma C, Jayaram HN, Singh N (2009) Apoptotic signaling induced by benzamide riboside: an in vitro study. Mol Cell Biochem 328:67–73
Wang SS, Bratti MC, Rodríguez AC et al (2009) Common variants in immune and DNA repair genes and risk for human papillomavirus persistence and progression to cervical cancer. J Infect Dis 199:20–30
Cheng L, Sturgis EM, Eicher SA et al (2002) Expression of nucleotide excision repair genes and the risk for squamous cell carcinoma of the head and neck. Cancer 94:393–397
Liu R, Yin LH, Pu YP (2007) Reduced expression of human DNA repair genes in esophageal squamous-cell carcinoma in china. J Toxicol Environ Health A 70:956–963
Morimoto H, Tsukada J, Kominato JY et al (2005) Reduced expression of human mismatch repair genes in adult T-cell leukemia. Am J Hematol 78:100–107
Wei QY, Eicher SA, Guan YL et al (1998) Reduced expression of hMLH1 and TBPH/hMSH6: a risk factor for head and neck cancer. Cancer Epidemiol Biomarkers Prev 7:309–314
Cherpillod P, Amstad PA (1995) Benzo[a]pyrene-induced mutagenesis and p53 hot-spot codons 248 and 249 in human hepatocytes. Mol Carcinog 13:15–20
Casse C, Hu YC, Ahrendt SA (2003) The XRCC1 codon 399 Gln allele is associated with adenine to guanine p53 mutations in non-small cell lung cancer. Mutat Res 528:19–27
Iftner T, Elbel M, Schopp B et al (2002) Interference of papillomavirus E6 protein with single-strand break repair by interaction with XRCC1. EMBO J 21:4741–4748
Kane MF, Loda M, Gaida GM et al (1997) Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 57:808–811
Qian X, von Wronski MA, Brent TP (1995) Localization of methylation sites in the human O6-methylguanine-DNA methyltransferase promoter: correlation with gene suppression. Carcinogenesis 16:1385–1390
Oesch F, Aulman W, Platt KL et al (1987) Individual differences in DNA repair capacities in man. Arch Toxicol Suppl 10:172–179
Wang P et al (2010) XRCC1 downregulated through promoter hypermethylation is involved in human gastric carcinogenesis. J Dig Dis 11:343–351
Chen HY et al (2010) Role of ERCC1 promoter hypermethylation in drug resistance to cisplatin in human gliomas. Int J Cancer 126:1944–1954
Lunn RuthM (2000) XPD polymorphisms: effects on DNA repair proficiency. Carcinogenesis 21:551–555
Lunn RuthM (1999) XRCC1 polymorphisms: effects on aflatoxin B1-DNA adducts and glycophorin a variant frequency. Cancer Res 59:2557
Wang S, Wu X, Chen Y et al (2012) Prognostic and predictive role of JWA and XRCC1 expressions in gastric cancer. Clin Cancer Res 18:2987–2996
Cheng XD, Lu WG, Ye F et al (2009) The association of XRCC1 gene single nucleotide polymorphisms with response to neoadjuvant chemotherapy in locally advanced cervical carcinoma. J Experim Clin Cancer Res 28:91
Vodicka P, Stetina R, Polakova V et al (2007) Association of DNA repair polymorphisms with DNA repair functional outcomes in healthy human subjects. Carcinogenesis 28:657–664
Chang JS, Wrensch MR, Hansen HM et al (2009) Base excision repair genes and risk of lung cancer among San Francisco bay area latinos and African Americans. Carcinogenesis 78:78–87
Rodriguez M, Yu X, Chen J et al (2003) Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains. J Biol Chem 278:52914–52918
Qiao Y, Spitz MR, Guo Z et al (2002) Rapid assessment of repair of ultraviolet dna damage with a modified host-cell reactivation assay using a luciferase reporter gene and correlation with polymorphisms of DNA repair genes in normal human lymphocytes. Mutat Res 509:165–174
Sliwinski T, Przybylowska K, Markiewicz L et al (2010) MUTYH Tyr165Cys, OGG1 Ser326Cys and XPD Lys751Gln polymorphisms and head neck cancer susceptibility: a case control study. Mol Biol Rep 38:1251–1261
Goode EL, Ulrich CM, Potter JD (2002) Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomarkers Prev 11:1513–1530
Zhou W, Gurubhagavatula S, Liu G et al (2004) Excision repair cross-complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res 10:939–4943
Olaussen KA, Dunant A, Fouret P, IALT Bio Investigators et al (2006) DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 355:983–991
Welsh C, Day R, McGurk C et al (2004) Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines. IntJ Cancer 110:352–361
Ferry KV, Hamilton TC, Johnson SW (2000) Increased nucleotide excision repair in cisplatin-resistant ovarian cancer cells: role of ERCC1-XPF. Biochem Pharmacol 60:1305–1313
Konno R et al (2011) Prevalence and type distribution of human papillomavirus in healthy Japanese women aged 20 to 25 years enrolled in a clinical study. Cancer Sci 102:877–882
Suthipintawong C et al (2011) Human papilloma virus prevalence, genotype distribution, and pattern of infection in Thai women. Asian Pac J Cancer Prev 12:853–856
Zamora P et al (2009) Genotype distribution of human papillomavirus (HPV) and co-infections in cervical cytologic specimens from two outpatient gynecological clinics in a region of southeast Spain. BMC Infect Dis 9:24
Pathak S et al (2012) Cervical cancer pathogenesis is associated with one-carbon metabolism. Mol Cell Biochem 369:1–2
Villa LL (1997) Human papillomaviruses and cervical cancer. Adv Cancer Res 71:321–341
Chatterjee K et al (2010) CCR2-V64I polymorphism is associated with increased risk of cervical cancer but not with HPV infection or pre-cancerous lesions in African women. BMC Cancer 10:278
Acknowledgments
The authors thank Dr. Guresh Kumar (Department of Biostastics, AIIMS) for helping in statistical analysis. We are also grateful to the participants of the study. D. Bajpai is thankful to ICMR, New Delhi for providing Senior Research Fellowship.
Conflict of interest
The authors declare that they have no competing interests.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Bajpai, D., Banerjee, A., Pathak, S. et al. Decreased expression of DNA repair genes (XRCC1, ERCC1, ERCC2, and ERCC4) in squamous intraepithelial lesion and invasive squamous cell carcinoma of the cervix. Mol Cell Biochem 377, 45–53 (2013). https://doi.org/10.1007/s11010-013-1569-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-013-1569-y