title: HPV16 oncoproteins induce MMPs/RECK-TIMP-2 imbalance in primary keratinocytes: possible implications in cervical carcinogenesis.
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.
authors.affiliation: Clinical Chemistry and Toxicology Department, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Laura Beatriz da Silva
authors.initials: LB
authors.lastname: Cardeal
authors.forename: Enrique
authors.initials: E
authors.lastname: Boccardo
authors.forename: Lara
authors.initials: L
authors.lastname: Termini
authors.forename: Tatiana
authors.initials: T
authors.lastname: Rabachini
authors.forename: Maria Antonieta
authors.initials: MA
authors.lastname: Andreoli
authors.forename: Celso
authors.initials: C
authors.lastname: di Loreto
authors.forename: Adhemar
authors.initials: A
authors.lastname: Longatto Filho
authors.forename: Luisa Lina
authors.initials: LL
authors.lastname: Villa
authors.forename: Silvya Stuchi
authors.initials: SS
authors.lastname: Maria-Engler
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D052162:Human papillomavirus 16 / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000821:virology*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000502:physiology*; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000502:physiology; D030361:Papillomavirus Infections / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000821:virology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000821:virology
chemical_list: D017931:DNA Primers; D058851:GPI-Linked Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C115460:RECK protein, human; C560823:TIMP2 protein, human; C059731:oncogene protein E7, Human papillomavirus type 16; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14