HPV16 Oncoproteins Induce MMPs/RECK-TIMP-2 Imbalance in Primary Keratinocytes: Possible Implications in Cervical Carcinogenesis

Author(s)

da Silva Cardeal, Laura Beatriz ^[1] ; Boccardo, Enrique ^{[2, 3]} ; Termini, Lara ^{[3, 4]} ; Rabachini, Tatiana ^[3] ; Andreoli, Maria Antonieta ^[3] ; di Loreto, Celso ^[5] ; Longatto Filho, Adhemar ^{[6, 7, 8, 9]} ; Villa, Luisa Lina ^{[3, 4]} ; Maria-Engler, Silvya Stuchi ^[1]

Affiliation

^[1] Univ Sao Paulo, Sch Pharmaceut Sci, Clin Chem & Toxicol Dept, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Dept Microbiol, Inst Biomed Sci, Sao Paulo - Brazil

^[3] Ludwig Inst Canc Res, Virol Grp, Sao Paulo - Brazil

^[4] HPV Inst INCT HPV, Sao Paulo - Brazil

^[5] Nucleo Patol Inst Adolfo Lutz, Sao Paulo - Brazil

^[6] Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst ICVS, Braga - Portugal

^[7] ICVS 3Bs PT Govt Associate Lab, Braga - Portugal

^[8] Univ Sao Paulo, Sch Med, Lab Med Invest LIM 14, Sao Paulo - Brazil

^[9] Barretos Canc Hosp, PIO XII Fdn, Barretos - Brazil

• Document type: Journal article
• Source: PLoS One; v. 7, n. 3 MAR 16 2012.
• Web of Science Citations: 34

Abstract

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. (AU)

• FAPESP's process: 08/58817-4 - Generation of human artificial skins and invasive melanomas as a platform for pharmacological testing
• Grantee: Silvya Stuchi Maria-Engler
• Support Opportunities: Regular Research Grants
• FAPESP's process: 08/03232-1 - HPV and tumor microenvironment
• Grantee: Luisa Lina Villa
• Support Opportunities: Research Projects - Thematic Grants