Abstract
High-risk human papillomaviruses (HPV) have been associated with many human cancers in clinical studies. Integration of HPV into the human genome is a suspected etiological factor in the induction of some HPV-associated cancers. The characteristics of HPV integration in certain HPV-integrated cancer cells remain unclear. In this study, ten HPV-associated carcinoma cell lines were evaluated for the presence, genotype, and integration status of HPV by nested polymerase chain reaction. The HPV genome did not insert in the genome of a mammary cancer cell line (MCF7), adrenal neuroblastoma cell line (NH-6), or three esophageal carcinoma cell lines (KYSE150, KYSE450 and KYSE140). HPV type 18 DNA did infect cell lines of tongue cancer (Tca83), hepatocellular carcinoma (Hep G2), and lung carcinoma (A549), but the HPV type 18 genes were not transcribed into mRNA. However, HPV type 18 integrated into the genomes of the esophageal carcinoma cell lines EC9706 and EC109, and the integration sites for both cell lines were in loci 8q24, which is a gene desert area adjacent to fragile sites. We speculate that HPV transcripts are more likely to integrate near highly susceptible fragile sites. This study suggests that HPV integration is still a significant issue that needs to be fully examined and can possibly be used as individualized biomarkers for the early diagnosis of HPV-related cancers.
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References
Burk RD, ChenK Z, Van Doorslaer K. Human papillomaviruses: genetic basis of carcinogenicity. Public Health Genomics. 2009;12(5–6):281–90.
Zhai K, Ding J, Shi HZ. HPV and lung cancer risk: A meta-analysis. J Clin Virol. 2015;63C:84–90.
Chen CJ, Hsu WL, Yang HI, Lee MH, Chen HC, Chien YC, et al. Epidemiology of virus infection and human cancer. Recent Results Cancer Res. 2014;193:11–32.
Liu H, Li J, Diao M, Cai Z, YangY J, Zeng Y. Statistical analysis of human papillomavirus in a subset of upper aerodigestive tract tumors. J Med Virol. 2013;85(10):1775–85.
Jalilvand S, ShojaR Z. Hamkar. Human papillomavirus burden in different cancers in Iran: a systematic assessment. Asian Pac J Cancer Prev. 2014;15(17):7029–35.
Ragin C, Obikoya-Malomo M, Kim S, Chen Z, Flores-Obando R, Gibbs D, et al. HPV-associated lung cancers: an international pooled analysis. Carcinogenesis. 2014;35(6):1267–75.
Betiol J, Villa LL, Sichero L. Impact of HPV infection on the development of head and neck cancer. Braz J Med Biol Res. 2013;46(3):217–26.
Schiller JT, Lowy DR. Virus infection and human cancer: an overview. Recent Results Cancer Res. 2014;193:1–10.
Palefsky J. Biology of HPV in HIV infection. Adv Dent Res. 2006;19(1):99–105.
Daibata M, Taguchi T, Nemoto Y, Saito T, Machida H, Imai S, et al. Epstein-Barr virus (EBV)-positive pyothorax-associated lymphoma (PAL): chromosomal integration of EBV in a novel CD2-positive PAL B-cell line. Br J Haematol. 2002;117(3):546–57.
Vilkin A, Niv Y. Association between hMLH1 hypermethylation and JC virus (JCV) infection in human colorectal cancer (CRC). Clin Epigenetics. 2011;2(1):1–5.
Yilmaz K, Koptur B, Dede DS, Aksoy S, Altundag K. Nasopharyngeal carcinoma with synchronous breast cancer; possible role of Epstein-Barr virus infection in the carcinogenesis of both cancers. J BUON. 2012;17(3):600.
Thomas LK, Bermejo JL, Vinokurova S, Jensen K, Bierkens M, Steenbergen R, et al. Chromosomal gains and losses in human papillomavirus-associated neoplasia of the lower genital tract—a systematic review and meta-analysis. Eur J Cancer. 2014;50(1):85–98.
Bosch FX, de Sanjose S. The epidemiology of human papillomavirus infection and cervical cancer. Dis Markers. 2007;23(4):213–27.
Levrero M. Viral hepatitis and liver cancer: the case of hepatitis C. Oncogene. 2006;25(27):3834–47.
Fallot G, Neuveut C, Buendia MA. Diverse roles of hepatitis B virus in liver cancer. Curr Opin Virol. 2012;2(4):467–73.
Mazumder Indra D, Singh RK, Mitra S, Dutta S, Chakraborty C, Basu PS, et al. Genetic and epigenetic changes of HPV16 in cervical cancer differentially regulate E6/E7 expression and associate with disease progression. Gynecol Oncol. 2011;123(3):597–604.
Barsoum J, Prakash SS, Han P, Androphy EJ. Mechanism of action of the papillomavirus E2 repressor: repression in the absence of DNA binding. J Virol. 1992;66(6):3941–5.
Guzman-Olea E, Bermudez-Morales VH, Peralta-Zaragoza O, Torres-Poveda K, Madrid-Marina V. Molecular mechanism and potential targets for blocking HPV-induced lesion development. J Oncol. 2012;2012:278312.
Schiller JT, Day PM, Kines RC. Current understanding of the mechanism of HPV infection. Gynecol Oncol. 2010;118(1 Suppl):S12–7.
Zhang K, Li JT, Li SY, Zhu LH, Zhou L, Zeng Y. Integration of human papillomavirus 18 DNA in esophageal carcinoma 109 cells. World J Gastroenterol. 2011;17(37):4242–6.
Schmitz M, Driesch C, Jansen L, Runnebaum IB, Durst M. Non-random integration of the HPV genome in cervical cancer. PLoS One. 2012;7(6):e39632.
Ragin CC, Reshmi SC, Gollin SM. Mapping and analysis of HPV16 integration sites in a head and neck cancer cell line. Int J Cancer. 2004;110(5):701–9.
Jimenez-Wences H, Peralta-Zaragoza O, Fernandez-Tilapa G. Human papilloma virus, DNA methylation and microRNA expression in cervical cancer (Review). Oncol Rep. 2014;31(6):2467–76.
Jang MK, Shen K, McBride AA. Papillomavirus genomes associate with BRD4 to replicate at fragile sites in the host genome. PLoS Pathog. 2014;10(5):e1004117.
Jacobs MV, Snijders PJ, van den Brule AJ, Helmerhorst TJ, Meijer CJ, Walboomers JM. A general primer GP5+/GP6(+)-mediated PCR-enzyme immunoassay method for rapid detection of 14 high-risk and 6 low-risk human papillomavirus genotypes in cervical scrapings. J Clin Microbiol. 1997;35(3):791–5.
Klaes R, Woerner SM, Ridder R, Wentzensen N, Duerst M, Schneider A, et al. Detection of high-risk cervical intraepithelial neoplasia and cervical cancer by amplification of transcripts derived from integrated papillomavirus oncogenes. Cancer Res. 1999;59(24):6132–6.
Zhang QY, Zhang DH, Shen ZY, Xu LY, Li EM, Au WW. Infection and integration of human papillomavirus in esophageal carcinoma. Int J Hyg Environ Health. 2011;214(2):156–61.
Annunziata C, Buonaguro L, Buonaguro FM, Tornesello ML. Characterization of the human papillomavirus (HPV) integration sites into genital cancers. Pathol Oncol Res. 2012;18(4):803–8.
Kraus I, Driesch C, Vinokurova S, Hovig E, Schneider A, von Knebel Doeberitz M, et al. The majority of viral-cellular fusion transcripts in cervical carcinomas cotranscribe cellular sequences of known or predicted genes. Cancer Res. 2008;68(7):2514–22.
Dall KL, Scarpini CG, Roberts I, Winder DM, Stanley MA, Muralidhar B, et al. Characterization of naturally occurring HPV16 integration sites isolated from cervical keratinocytes under noncompetitive conditions. Cancer Res. 2008;68(20):8249–59.
Ziegert C, Wentzensen N, Vinokurova S, Kisseljov F, Einenkel J, Hoeckel M, et al. A comprehensive analysis of HPV integration loci in anogenital lesions combining transcript and genome-based amplification techniques. Oncogene. 2003;22(25):3977–84.
Cicek MS, Slager SL, Achenbach SJ, French AJ, Blair HE, Fink SR, et al. Functional and clinical significance of variants localized to 8q24 in colon cancer. Cancer Epidemiol Biomark Prev. 2009;18(9):2492–500.
Acknowledgments
This study was supported by National Natural Sciences Foundation of China (No. 21277001) and Beijing Municipal Education Commission Science and Technology Project (No. KZ201110005003), partially supported by The State Key Laboratories Development Program of China (2011SLKID103) and the National High Technology Research Program of China (863 program) (Grant No. 2012AA02A404).
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All the authors declare no competing financial interests.
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Liu, CY., Li, F., Zeng, Y. et al. Infection and integration of high-risk human papillomavirus in HPV-associated cancer cells. Med Oncol 32, 109 (2015). https://doi.org/10.1007/s12032-015-0560-8
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DOI: https://doi.org/10.1007/s12032-015-0560-8