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TitleHPV16 oncoproteins induce MMPs/RECK-TIMP-2 imbalance in primary keratinocytes : possible implications in cervical carcinogenesis
Author(s)Cardeal, Laura Beatriz da Silva
Boccardo, Enrique
Termini, Lara
Rabachini, Tatiana
Andreoli, Maria Antonieta
Loreto, Celso di
Filho, A. L.
Villa, Luisa Lina
Engler, Silvya Stuchi Maria
Issue dateMar-2012
PublisherPublic Library of Science
CitationCardeal LBdS, Boccardo E, Termini L, Rabachini T, Andreoli MA, et al. (2012) HPV16 Oncoproteins Induce MMPs/RECK-TIMP-2 Imbalance in Primary Keratinocytes: Possible Implications in Cervical Carcinogenesis. PLoS ONE 7(3): e33585. doi:10.1371/journal.pone.0033585
Abstract(s)Cervical cancer is the third most common cancer in women worldwide. Persistent infection with high-risk HPV types, principally HPV16 and 18 is the main risk factor for the development of this malignancy. However, the onset of invasive tumor occurs many years after initial exposure in a minority of infected women. This suggests that other factors beyond viral infection are necessary for tumor establishment and progression. Tumor progression is characterized by an increase in secretion and activation of matrix metalloproteinases (MMPs) produced by either the tumor cells themselves or tumor-associated fibroblasts or macrophages. Increased MMPs expression, including MMP-2, MMP-9 and MT1-MMP, has been observed during cervical carcinoma progression. These proteins have been associated with degradation of ECM components, tumor invasion, metastasis and recurrence. However, few studies have evaluated the interplay between HPV infection and the expression and activity of MMPs and their regulators in cervical cancer. We analyzed the effect of HPV16 oncoproteins on the expression and activity of MMP-2, MMP-9, MT1-MMP, and their inhibitors TIMP-2 and RECK in cultures of human keratinocytes. We observed that E7 expression is associated with increased pro-MMP-9 activity in the epithelial component of organotypic cultures, while E6 and E7 oncoproteins co-expression down-regulates RECK and TIMP-2 levels in organotypic and monolayers cultures. Finally, a study conducted in human cervical tissues showed a decrease in RECK expression levels in precancer and cancer lesions. Our results indicate that HPV oncoproteins promote MMPs/RECK-TIMP-2 imbalance which may be involved in HPV-associated lesions outcome.
DescriptionWe thank Dr. Alda Wakamatsu, Dr. Venâncio Avancini and Dr. Alexandre Ab'Saber from Faculty of Medicine, University of São Paulo, for technical assistance and selection of tissues samples, and João Simão Pereira Sobrinho for help in protein sample processing.
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AccessOpen access
Appears in Collections:ICVS - Artigos em revistas internacionais / Papers in international journals

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