Relationship among human papillomavirus infection, p16INK4a, p53 and NF-κB activation in penile cancer from northern Thailand

Senba,Masachika; Mori,Naoki; Fujita,Shuichi; Jutavijittum,Prapan; Yousukh,Amnat; Toriyama,Kan; Wada,Akihiro

doi:10.3892/ol_00000106

Relationship among human papillomavirus infection, p16INK4a, p53 and NF-κB activation in penile cancer from northern Thailand

Authors:
- Masachika Senba
- Naoki Mori
- Shuichi Fujita
- Prapan Jutavijittum
- Amnat Yousukh
- Kan Toriyama
- Akihiro Wada
View Affiliations

Affiliations: Department of Pathology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan. mikiyo@net.nagasaki-u.ac.jp
Published online on: July 1, 2010 https://doi.org/10.3892/ol_00000106
Pages: 599-603

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Human papillomavirus (HPV) E6 and E7 onco-proteins are essential factors for HPV oncogenesis. These E6 and E7 gene products play a central role in the induction of malignant transformation by interacting with several cellular regulatory proteins such as p16INK4a, p53 and nuclear factor κB (NF-κB). In the present study, conducted in northern Thailand, HPV-DNA was detected in penile cancer cases using an in situ hybridization procedure and p16INK4a, p53 and NF-κB were detected by immunohistochemistry. Using the cell cycle regulatory proteins p16INK4a (61.5%) and p53 (71.8%), it was found that of the 51 cases, 39 (76.5%) were HPV-DNA-positive in penile cancer. On the other hand, 25% p16INK4a and 75% p53, respectively, were found in HPV-negative cases. Prevalence of HPV infection (76.5%) was shown in penile cancer cases in northern Thailand. No difference was found between HPV-positive and HPV-negative cases with respect to the presence of the cell cycle regulatory protein p53. On the other hand, p16INK4a was found to be different between HPV-positive and HPV-negative cases. Inactivation of tumor suppressor genes, such as p16INK4a and p53, to genetic instability, cell immortalization, accumulation of mutations and cancer formation, with or without HPV and irrespective of HPV infection, is therefore suggested. Of the 39 HPV-positive cases, 35 (89.7%) were NF-κB-positive in the nucleus, 29 (74.4%) in the cytoplasm and 37 (94.9%) in the nucleus and/or cytoplasm. NF-κB was detected in 4 (33.3%) of the 12 HPV-negative cases. Therefore, we propose that penile cancer cases with HPV infection are more likely to activate NF-κB than those without HPV infection.

View Figures

View References

1	Tornesello ML, Duraturo ML, Losito S, et al: Human papillomavirus genotypes and HPV 16 variants in penile carcinoma. Int J Cancer. 122:132–137. 2008. View Article : Google Scholar : PubMed/NCBI
2	Gross G and Pfister H: Role of human papillomavirus in penile cancer, penile intraepithelial squamous cell neoplasias and in genital warts. Med Microbiol Immunol. 193:35–44. 2004. View Article : Google Scholar : PubMed/NCBI
3	Senba M, Mori N and Wada A: Oncogenesis and the link between inflammation and cancer due to human papillomavirus (HPV) infection, and the development of vaccine control strategies. Cancer Res J. 2:307–338. 2009.
4	Munger K, Baldwin A, Edwards KM, et al: Mechanisms of human papillomavirus-induced oncogenesis. J Virol. 78:11451–11460. 2004. View Article : Google Scholar : PubMed/NCBI
5	Zhang HS, Postigo AA and Dean DC: Active transcriptional repression by the Rb-E2F complex mediates G1 arrest triggered by p16^INK4a, TGFb, and contact inhibition. Cell. 97:53–61. 1999. View Article : Google Scholar : PubMed/NCBI
6	Sano T, Oyama T, Kashiwabara K, Fukuda T and Nakajima T: Expression status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. Am J Pathol. 153:1741–1748. 1998. View Article : Google Scholar : PubMed/NCBI
7	Klaes R, Friedrich T, Spitkovsky D, et al: Overexpression of p16^INK4a as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer. 92:276–284. 2001.
8	Humbey O, Cairey-Remonnay S, Guerrini JS, et al: Detection of the human papillomavirus and analysis of the TP53 polymorphism of exon 4 at codon 72 in penile squamous cell carcinoma. Eur J Cancer. 39:684–690. 2003. View Article : Google Scholar : PubMed/NCBI
9	Ferreux E, Lont AP, Horenblas S, et al: Evidence for at least three alternative mechanisms targeting the p16^INK4a/cyclin D/Rb pathway in penile carcinoma, one of which is mediated by high-risk human papillomavirus. J Pathol. 201:109–118. 2003.PubMed/NCBI
10	Prowse DM, Ktori EN, Chandrasekaran D, Prapa A and Baithun S: Human papillomavirus-associated increase in p16^INK4a expression in penile lichen sclerosus and squamous cell carcinoma. Br J Dermatol. 158:261–265. 2008.PubMed/NCBI
11	Sen R and Baltimore D: Inducibility of kappa immunoglobulin enhancer-binding protein NF-kappa B by a posttranslational mechanism. Cell. 47:921–928. 1986. View Article : Google Scholar : PubMed/NCBI
12	Rothwarf DM, Zandi E, Natoli G and Karin M: IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature. 395:297–300. 1998. View Article : Google Scholar : PubMed/NCBI
13	Karin M and Greten FR: NF-κB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 5:749–759. 2005.
14	Karin M: Nuclear factor-κB in cancer development and progression. Nature. 441:431–436. 2006.
15	Kiriakidis S, Andreakos E, Monaco C, Foxwell B, Feldmann M and Paleolog E: VEGF expression in human macrophages is NF-κB-dependent: studies using adenoviruses expressing the endogenous NF-κB inhibitor IkkappaBalpha and a kinase-defective form of the IkkappaB kinase 2. J Cell Sci. 116:665–674. 2003.
16	Senba M, Buziba N, Mori N, Wada A, Irie S and Toriyama K: Detection of human papillomavirus and cellular regulators p16^INK4A, p53, and NF-κB in penile cancer cases in Kenya. Acta Virol. 53:43–48. 2009. View Article : Google Scholar : PubMed/NCBI
17	Senba M, Mori N, Wada A, et al: Human papillomavirus genotypes in penile cancers from Japanese patients and HPV-induced NF-κB activation. Oncol Lett. 1:267–272. 2010.PubMed/NCBI
18	Senba M, Kumatori A, Fujita S, et al: The prevalence of human papillomavirus genotypes in penile cancers from northern Thailand. J Med Virol. 78:1341–1346. 2006. View Article : Google Scholar : PubMed/NCBI
19	Picconi MA, Eijan AM, Distefano AL, et al: Human papillomavirus (HPV) DNA in penile carcinomas in Argentina: analysis of primary tumors and lymph nodes. J Med Virol. 61:65–69. 2000. View Article : Google Scholar : PubMed/NCBI
20	Cupp MR, Malek RS, Goellner JR, Smith TF and Espy MJ: The detection of human papillomavirus deoxyribonucleic acid in intraepithelial, in situ, verrucous and invasive carcinoma of the penis. J Urol. 154:1024–1029. 1995. View Article : Google Scholar : PubMed/NCBI
21	Sarkar FH, Miles BJ, Plieth DH and Crissman JD: Detection of human papillomavirus in squamous neoplasm of the penis. J Urol. 147:389–392. 1992.PubMed/NCBI
22	Tornesello ML, Buonaguro FM, Beth-Giraldo E, Kyalwazi SK and Giraldo G: Human papillomavirus (HPV) DNA in penile carcinomas and in two cell lines from high-incidence areas for genital cancers in Africa. Int J Cancer. 51:587–592. 1992. View Article : Google Scholar : PubMed/NCBI
23	Rubin MA, Kleter B, Zhou M, et al: Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis. Am J Pathol. 159:1211–1218. 2001. View Article : Google Scholar : PubMed/NCBI
24	Cubilla AL, Reuter VE, Gregoire L, et al: Basaloid squamous cell carcinoma: a distinctive human papilloma virus-related penile neoplasm. A report of 20 cases. Am J Surg Pathol. 22:755–761. 1998. View Article : Google Scholar : PubMed/NCBI
25	Nguyen DX, Nguyen MM, Lee D, Griep AE and Lambert PF: Human papillomavirus type 16 E7 maintains elevated levels of the cdk25A tyrosine phosphatase during deregulation of cell cycle arrest. J Virol. 77:619–632. 2002. View Article : Google Scholar : PubMed/NCBI
26	Lam KY and Chan KW: Molecular pathology and clinicopathologic features of penile tumors: with special reference to analyses of p21 and p53 expression and unusual histologic features. Arch Pathol Lab Med. 123:895–904. 1999.PubMed/NCBI
27	Lopes A, Bezerra AL, Pino CA, Serrano SV, Mello CA and Villa LL: p53 as a new prognostic factor for lymph node metastasis in penile carcinoma: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. J Urol. 168:81–86. 2002. View Article : Google Scholar : PubMed/NCBI
28	Milde-Langosch K, Riethdorf S, Kraus-Poppinghaus A, Riethdorf L and Loning T: Expression of cyclin-dependent kinase inhibitors p16^MTS1, p21^WAF1, and p27^KIP1 in HPV-positive and HPV-negative cervical adenocarcinomas. Virch Arch. 439:55–61. 2001. View Article : Google Scholar : PubMed/NCBI
29	Zielinski GD, Snijders PJ, Rozendaal L, et al: The presence of high-risk HPV combined with specific p53 and p16^INK4a expression patterns points to high-risk HPV as the main causative agent for adenocarcinoma in situ and adenocarcinoma of the cervix. J Pathol. 201:535–543. 2003.PubMed/NCBI
30	Kalof AN, Evans MF, Simmons-Arnold L, Beatty BG and Cooper K: p16^INK4a immunoexpression and HPV in situ hybridization signal patterns: potential markers of high-grade cervical intraepithelial neoplasia. Am J Surg Pathol. 29:674–679. 2005.PubMed/NCBI
31	Dehn D, Torkko KC and Shroyer KR: Human papillomavirus testing and molecular markers of cervical dysplasia and carcinoma. Cancer. 111:1–14. 2007. View Article : Google Scholar : PubMed/NCBI
32	Naugler WE and Karin M: NF-κB and cancer – identifying targets and mechanisms. Curr Opin Genet Dev. 18:19–26. 2008.
33	Nees M, Geoghegan JM, Hyman T, Frank S, Miller L and Woodworth CD: Papillomavirus type 16 oncogenes downregulate expression of interferon-responsive genes and upregulate proliferation-associated and NF-κB-responsive genes in cervical keratinocytes. J Virol. 75:4283–4296. 2001.PubMed/NCBI
34	Spitkovsky D, Hehner SP, Hofmann TG, Moller A and Schmitz ML: The human papillomavirus oncoprotein E7 attenuates NF-κB activation by targeting IκB kinase complex. J Bio Chem. 277:25576–25582. 2002.PubMed/NCBI
35	Havard L, Delvenne P, Frare P, Boniver J and Giannini SL: Differential production of cytokines and activation of NF-κB in HPV transformed keratinocytes. Virology. 298:271–285. 2002.
36	Havard L, Rahmouni S, Boniver J and Delvenne P: High levels of p105 (NF-κB1) and p100 (NF-κB2) proteins in HPV 16-transformed keratinocytes: role of E6 and E7 oncoproteins. Virology. 331:357–366. 2005.
37	Mishra A, Bharti AC, Varghese P, Saluja D and Das BC: Differential expression and activation of NF-κB family proteins during oral carcinogenesis: role of high risk human papillomavirus infection. Int J Cancer. 119:2840–2850. 2006.
38	James MA, Lee JH and Klingelhutz AJ: Human papillomavirus type 16 E6 activates NF-κB, induces cIAP-2 expression, and protects against apoptosis in a PDZ binding motif-dependent manner. J Virol. 80:5301–5307. 2006.