Entrance of the Tat protein of HIV-1 into human uterine cervical carcinoma cells causes upregulation of HPV-E6 expression and a decrease in p53 protein levels

Barillari,Giovanni; Palladino,Clelia; Bacigalupo,Ilaria; Leone,Patrizia; Falchi,Mario; Ensoli,Barbara

doi:10.3892/ol.2016.4921

Entrance of the Tat protein of HIV-1 into human uterine cervical carcinoma cells causes upregulation of HPV-E6 expression and a decrease in p53 protein levels

Authors:
- Giovanni Barillari
- Clelia Palladino
- Ilaria Bacigalupo
- Patrizia Leone
- Mario Falchi
- Barbara Ensoli
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Affiliations: Department of Clinical Sciences and Translational Medicine, University ‘Tor Vergata’, I-00133 Rome, Italy, National AIDS Center, National Institute of Health, I‑00161 Rome, Italy
Published online on: July 29, 2016 https://doi.org/10.3892/ol.2016.4921
Pages: 2389-2394
Copyright: © Barillari et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The infection of uterine cervical epithelial cells by oncogenic, high-risk human papilloma viruses (HR‑HPVs) may lead to the development of cervical carcinoma. Of note, the incidence of this tumor is significantly increased in women infected by both HR‑HPV and human immunodeficiency virus (HIV)‑1. In this regard, previous studies have linked the HIV‑1 Tat protein, a trans‑activator of viral gene expression, to the pathogenesis of HIV‑associated malignancies. In particular, it has been shown that upon its release by acutely infected cells, Tat protein can enter human cells, thus modifying their phenotype. Based on these findings, the present study evaluated whether extracellular Tat protein could be taken up by human uterine cervical carcinoma cells, and whether this could affect the expression of HPV (E6 or E7) or cellular (p16 or p53) molecules, which are key to cervical carcinoma development or progression. The results indicated that extracellular, biologically active HIV‑1 Tat protein is taken up by human uterine cervical carcinoma cells, and that this is followed by an increase in the expression of the E6 protein of HPV, and by a reduction in the protein levels of the cellular oncosuppressor p53. Since p53 loss is associated with cell dedifferentiation and immortalization, these findings suggest a possible link between extracellular Tat protein and the high incidence and clinical aggressiveness of uterine cervical carcinoma observed in HIV/HPV doubly infected women.

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1	Kang M and Cu-Uvin S: Association of HIV viral load and CD4 cell count with human papillomavirus detection and clearance in HIV-infected women initiating highly active antiretroviral therapy. HIV Med. 13:372–378. 2012. View Article : Google Scholar : PubMed/NCBI
2	Kim RH, Yochim JM, Kang MK, Shin KH, Christensen R and Park NH: HIV-1 Tat enhances replicative potential of human oral keratinocytes harboring HPV-16 genome. Int J Oncol. 33:777–782. 2008.PubMed/NCBI
3	Pol SB Vande and Klingelhutz AJ: Papillomavirus E6 oncoproteins. Virology. 445:115–137. 2013. View Article : Google Scholar : PubMed/NCBI
4	Shen R, Richter HE and Smith PD: Early HIV-1 target cells in human vaginal and ectocervical mucosa. Am J Reprod Immunol. 65:261–267. 2011. View Article : Google Scholar : PubMed/NCBI
5	Barillari G and Ensoli B: Angiogenic effects of extracellular HIV-1 Tat protein and its role in the pathogenesis of AIDS-associated Kaposi's sarcoma. Clin Microbiol Rev. 15:310–326. 2002. View Article : Google Scholar : PubMed/NCBI
6	Henning TR, Kissinger P, Lacour N, Meyaski-Schluter M, Clark R and Amedee AM: Elevated cervical white blood cell infiltrate is associated with genital HIV detection in a longitudinal cohort of antiretroviral therapy-adherent women. J Infect Dis. 202:1543–1552. 2010. View Article : Google Scholar : PubMed/NCBI
7	Calil LN, Edelweiss MI, Meurer L, Igansi CN and Bozzetti MC: p16 INK4a and Ki67 expression in normal, dysplastic and neoplastic uterine cervical epithelium and human papillomavirus (HPV) infection. Pathol Res Pract. 210:482–487. 2014. View Article : Google Scholar : PubMed/NCBI
8	Fanales-Belasio E, Moretti S, Nappi F, Barillari G, Micheletti F, Cafaro A and Ensoli B: Native HIV-1 Tat protein targets monocyte-derived dendritic cells and enhances their maturation, function, and antigen-specific T cell responses. J Immunol. 168:197–206. 2002. View Article : Google Scholar : PubMed/NCBI
9	Barillari G, Iovane A, Bacigalupo I, Palladino C, Bellino S, Leone P, Monini P and Ensoli B: Ritonavir or saquinavir impairs the invasion of cervical intraepithelial neoplasia cells via a reduction of MMP expression and activity. AIDS. 26:909–919. 2012. View Article : Google Scholar : PubMed/NCBI
10	Suh DS, Kim SC, An WG, Lee CH, Choi KU, Song JM, Jung JS, Lee KS and Yoon MS: Differential apoptotic response in HPV-infected cancer cells of the uterine cervix after doxorubicin treatment. Oncol Rep. 23:751–756. 2010.PubMed/NCBI
11	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
12	Bachman H, Nicosia J, Dysart M and Barker TH: Utilizing fibronectin integrin-binding specificity to control cellular responses. Adv Wound Care (New Rochelle). 4:501–511. 2015. View Article : Google Scholar : PubMed/NCBI
13	Engelholm LH, List K, Netzel-Arnett S, Cukierman E, Mitola DJ, Aaronson H, Kjøller L, Larsen JK, Yamada KM, Strickland DK, et al: uPARAP/Endo180 is essential for cellular uptake of collagen and promotes fibroblast collagen adhesion. J Cell Biol. 160:1009–1015. 2003. View Article : Google Scholar : PubMed/NCBI
14	Mwakigonja AR, Torres LM, Mwakyoma HA and Kaaya EE: Cervical cytological changes in HIV-infected patients attending care and treatment clinic at muhimbili national hospital, Dar es salaam, Tanzania. Infect Agent Cancer. 7:32012. View Article : Google Scholar : PubMed/NCBI
15	Conesa-Zamora P, Doménech-Peris A, Orantes-Casado FJ, Ortiz-Reina S, Sahuquillo-Frías L, Acosta-Ortega J, García-Solano J and Pérez-Guillermo M: Effect of human papillomavirus on cell cycle-related proteins p16, Ki-67, Cyclin D1, p53 and ProEx C in precursor lesions of cervical carcinoma: A tissue microarray study. Am J Clin Pathol. 132:378–390. 2009. View Article : Google Scholar : PubMed/NCBI
16	Coleman N, Greenfield IM, Hare J, Kruger-Gray H, Chain BM and Stanley MA: Characterization and functional analysis of the expression of intercellular adhesion molecule-1 in human papillomavirus-related disease of cervical keratinocytes. Am J Pathol. 143:355–367. 1993.PubMed/NCBI
17	Guo J, Si L and Wang Y: An in situ study on immunostimulatory molecules in cancer cells within the cervical carcinoma tissues. Zhonghua Yi Xue Za Zhi. 80:342–345. 2000.(In Chinese). PubMed/NCBI
18	Chancey CJ, Khanna KV, Seegers JF, Zhang GW, Hildreth J, Langan A and Markham RB: Lactobacilli-expressed single-chain variable fragment (scFv) specific for intercellular adhesion molecule 1 (ICAM-1) blocks cell-associated HIV-1 transmission across a cervical epithelial monolayer. J Immunol. 176:5627–5636. 2006. View Article : Google Scholar : PubMed/NCBI
19	Nkwanyana NN, Gumbi PP, Roberts L, Denny L, Hanekom W, Soares A, Allan B, Williamson AL, Coetzee D, Olivier AJ, et al: Impact of human immunodeficiency virus 1 infection and inflammation on the composition and yield of cervical mononuclear cells in the female genital tract. Immunology. 128(Suppl 1): e746–e757. 2009. View Article : Google Scholar : PubMed/NCBI
20	Mitchell C, Balkus JE, McKernan-Mullin J, Cohn SE, Luque AE, Mwachari C, Cohen CR, Coombs R, Frenkel LM and Hitti J: Associations between genital tract infections, genital tract inflammation, and cervical cytobrush HIV-1 DNA in US versus Kenyan women. J Acquir Immune Defic Syndr. 62:143–148. 2013. View Article : Google Scholar : PubMed/NCBI
21	Xie M, Hu A, Luo Y, Sun W, Hu X and Tang S: Interleukin-4 and melatonin ameliorate high glucose and interleukin-1β stimulated inflammatory reaction in human retinal endothelial cells and retinal pigment epithelial cells. Mol Vis. 20:921–928. 2014.PubMed/NCBI
22	Thichanpiang P and Wongprasert K: Green tea polyphenol epigallocatechin-3-gallate attenuates TNF-α-induced intercellular adhesion molecule-1 expression and monocyte adhesion to retinal pigment epithelial cells. Am J Chin Med. 43:103–119. 2015. View Article : Google Scholar : PubMed/NCBI