title: Oxidative stress in HPV-driven viral carcinogenesis: redox proteomics analysis of HPV-16 dysplastic and neoplastic tissues.
abstract: Genital infection by high risk Human Papillomavirus (HR-HPV), although recognized as the main etio-pathogenetic factor of cervical cancer, is not per se sufficient to induce tumour development. Oxidative stress (OS) represents an interesting and under-explored candidate as a promoting factor in HPV-initiated carcinogenesis. To gain insight into the role of OS in cervical cancer, HPV-16 positive tissues were collected from patients with invasive squamous cervical carcinoma, from patients with High Grade dysplastic HPV lesions and from patients with no clinical evidence of HPV lesions. After virological characterization, modulation of proteins involved in the redox status regulation was investigated. ERp57 and GST were sharply elevated in dysplastic and neoplastic tissues. TrxR2 peaked in dysplastic samples while iNOS was progressively reduced in dysplastic and neoplastic samples. By redox proteomic approach, five proteins were found to have increased levels of carbonyls in dysplastic samples respect to controls namely: cytokeratin 6, actin, cornulin, retinal dehydrogenase and GAPDH. In carcinoma samples the peptidyl-prolyl cis-trans isomerase A, ERp57, serpin B3, Annexin 2 and GAPDH were found less oxidized than in dysplastic tissues. HPV16 neoplastic progression seems associated with increased oxidant environment. In dysplastic tissues the oxidative modification of DNA and proteins involved in cell morphogenesis and terminal differentiation may provide the conditions for the neoplastic progression. Conversely cancer tissues seem to attain an improved control on oxidative damage as shown by the selective reduction of carbonyl adducts on key detoxifying/pro-survival proteins.
authors.affiliation: Laboratory of Virology, The Regina Elena Cancer Institute, Rome, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: De Marco
authors.forename: Elona
authors.initials: E
authors.lastname: Bucaj
authors.forename: Cesira
authors.initials: C
authors.lastname: Foppoli
authors.forename: Ada
authors.initials: A
authors.lastname: Fiorini
authors.forename: Carla
authors.initials: C
authors.lastname: Blarzino
authors.forename: Kozeta
authors.initials: K
authors.lastname: Filipi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Giorgi
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Schininà
authors.forename: Fabio
authors.initials: F
authors.lastname: Di Domenico
authors.forename: Raffaella
authors.initials: R
authors.lastname: Coccia
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
authors.forename: Marzia
authors.initials: M
authors.lastname: Perluigi
mesh_terms: D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D002471:Cell Transformation, Neoplastic; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D052162:Human papillomavirus 16; D006801:Humans; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D050050:Protein Carbonylation; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D040901:Proteomics; D002578:Uterine Cervical Dysplasia / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D019562:Viral Load
chemical_list: D052247:Nitric Oxide Synthase Type II; D005982:Glutathione Transferase; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human