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      Human Papillomavirus: Current and Future RNAi Therapeutic Strategies for Cervical Cancer

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          Abstract

          Human papillomaviruses (HPVs) are small DNA viruses; some oncogenic ones can cause different types of cancer, in particular cervical cancer. HPV-associated carcinogenesis provides a classical model system for RNA interference (RNAi) based cancer therapies, because the viral oncogenes E6 and E7 that cause cervical cancer are expressed only in cancerous cells. Previous studies on the development of therapeutic RNAi facilitated the advancement of therapeutic siRNAs and demonstrated its versatility by siRNA-mediated depletion of single or multiple cellular/viral targets. Sequence-specific gene silencing using RNAi shows promise as a novel therapeutic approach for the treatment of a variety of diseases that currently lack effective treatments. However, siRNA-based targeting requires further validation of its efficacy in vitro and in vivo, for its potential off-target effects, and of the design of conventional therapies to be used in combination with siRNAs and their drug delivery vehicles. In this review we discuss what is currently known about HPV-associated carcinogenesis and the potential for combining siRNA with other treatment strategies for the development of future therapies. Finally, we present our assessment of the most promising path to the development of RNAi therapeutic strategies for clinical settings.

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          Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.

          Wen Xue, Lars Zender, Cornelius Miething … (2007)
          Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.
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            Worldwide burden of cervical cancer in 2008.

            M Arbyn, X Castellsagué, S de Sanjosé … (2011)
            The knowledge that persistent human papillomavirus infection is the main cause of cervical cancer has resulted in the development of assays that detect nucleic acids of the virus and prophylactic vaccines. Up-to-date and reliable data are needed to assess impact of existing preventive measures and to define priorities for the future. Best estimates on cervical cancer incidence and mortality are presented using recently compiled data from cancer and mortality registries for the year 2008. There were an estimated 530,000 cases of cervical cancer and 275,000 deaths from the disease in 2008. It is the third most common female cancer ranking after breast (1.38 million cases) and colorectal cancer (0.57 million cases). The incidence of cervical cancer varies widely among countries with world age-standardised rates ranging from 50 per 100,000. Cervical cancer is the leading cause of cancer-related death among women in Eastern, Western and Middle Africa; Central America; South-Central Asia and Melanesia. The highest incidence rate is observed in Guinea, with ∼6.5% of women developing cervical cancer before the age of 75 years. India is the country with the highest disease frequency with 134,000 cases and 73 000 deaths. Cervical cancer, more than the other major cancers, affects women <45 years. In spite of effective screening methods, cervical cancer continues to be a major public health problem. New methodologies of cervical cancer prevention should be made available and accessible for women of all countries through well-organised programmes.
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              p53 dynamics control cell fate.

              Jeremy E. Purvis, Kyle Karhohs, Caroline Mock … (2012)
              Cells transmit information through molecular signals that often show complex dynamical patterns. The dynamic behavior of the tumor suppressor p53 varies depending on the stimulus; in response to double-strand DNA breaks, it shows a series of repeated pulses. Using a computational model, we identified a sequence of precisely timed drug additions that alter p53 pulses to instead produce a sustained p53 response. This leads to the expression of a different set of downstream genes and also alters cell fate: Cells that experience p53 pulses recover from DNA damage, whereas cells exposed to sustained p53 signaling frequently undergo senescence. Our results show that protein dynamics can be an important part of a signal, directly influencing cellular fate decisions.
              Article 0 comments Cited 304 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Jacqueline Guidry: Role: Academic Editor
                Stephen K. Tyring: Role: Academic Editor
                Christopher Downing: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): J Clin Med
                Journal ID (iso-abbrev): J Clin Med
                Journal ID (publisher-id): jcm
                Title: Journal of Clinical Medicine
                Publisher: MDPI
                ISSN (Electronic): 2077-0383
                Publication date (Electronic): 21 May 2015
                Publication date Collection: May 2015
                Volume: 4
                Issue: 5
                Pages: 1126-1155
                Affiliations
                [1 ]Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 151-742, Korea; E-Mails: hunsoonjung@ 123456abionbio.com (H.S.J.); nirmalpharma@ 123456gmail.com (N.R.)
                [2 ]ABION Inc., R&D Center, 9th Fl., HanWha Biz Metro Bldg., 242 Digital-ro, Guro-gu, Seoul 152-733, Korea
                [3 ]Department of Obstetrics and Gynecology, School of Medicine, Ewha Womans University, Seoul 158-710, Korea; E-Mail: goodmorning@ 123456ewha.ac.kr
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: ykeeshin@ 123456snu.ac.kr ; Tel.: +82-2-880-9126.
                Article
                Publisher ID: jcm-04-01126
                DOI: 10.3390/jcm4051126
                PMC ID: 4470221
                SO-VID: 5c91c518-164c-4327-83fe-f968f105169c
                Copyright © © 2015 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 27 January 2015
                Date accepted : 08 May 2015
                Categories
                Subject: Review

                Keywords: hpv e6 and e7 oncogenes,sirna pool,cervical cancer
                Data availability:
                Keywords: hpv e6 and e7 oncogenes, sirna pool, cervical cancer

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