J Cancer 2016; 7(14):1950-1959. doi:10.7150/jca.15536 This issue

Research Paper

In vivo Antitumor Effect of an HPV-specific Promoter driving IL-12 Expression in an HPV 16-positive Murine Model of Cervical Cancer

Victor Hugo Bermúdez-Morales1, Geny Fierros-Zarate1, Celina García-Meléndrez2, Juan Manuel Alcocer-Gonzalez3, Ausencio Morales-Ortega1, Oscar Peralta-Zaragoza1, Kirvis Torres-Poveda1, Ana Isabel Burguete-García1, Eva Hernández-Márquez1, Vicente Madrid-Marina1✉

1. Division of Chronic Infection and Cancer, National Institute of Public Health. Av. Universidad 655, Cuernavaca, Morelos. México. 62100.
2. Biotecnhgology Institute. National Autonomous University of Mexico, Cuernavaca Morelos, México.
3. School of Biological Sciences, Autonomous University of Nuevo León, Monterrey, México.

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Bermúdez-Morales VH, Fierros-Zarate G, García-Meléndrez C, Alcocer-Gonzalez JM, Morales-Ortega A, Peralta-Zaragoza O, Torres-Poveda K, Burguete-García AI, Hernández-Márquez E, Madrid-Marina V. In vivo Antitumor Effect of an HPV-specific Promoter driving IL-12 Expression in an HPV 16-positive Murine Model of Cervical Cancer. J Cancer 2016; 7(14):1950-1959. doi:10.7150/jca.15536. Available from https://www.jcancer.org/v07p1950.htm

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Human papillomavirus (HPV) is a DNA virus that infects epithelial cells and has been implicated in the development of cervical cancer. Few therapeutic strategies have been designed for the treatment of cervical intraepithelial neoplasia, a precursor of cervical cancer. In these early stages, the HPV E2 protein is the most important viral factor involved in viral gene expression and plays crucial roles during the vegetative viral cycle in epithelial cells. Papillomavirus E2 binds specifically to palindromic ACCN6GGT sequences, referred to as the E2 binding sites (E2BS), which are concentrated within the viral long control region, and which are responsible for regulation of the HPV protein's expression. Here, we consider E2BS as a candidate sequence to induce the expression of antiviral therapeutic genes selectively in HPV-infected cells expressing the E2 protein. This study focuses on the use of an HPV-specific promoter comprised of four E2BS to drive the expression of IL-12, leading to an antitumor effect in an HPV-positive murine tumor model. The therapeutic strategy was implemented via viral gene therapy using adenoviral vectors with recombinant E2 and IL-12 genes and E2BS-IL-12. We demonstrate that the HPV-specific promoter E2BS is functional in vitro and in vivo through transactivation of HPV E2 transcription factor.

Keywords: HPV, promoter, IL-12, gene therapy, adenovirus, HPV E2, antitumor.