title: Enhanced oncogenicity of Asian-American human papillomavirus 16 is associated with impaired E2 repression of E6/E7 oncogene transcription.
abstract: Asian-American (AA) variants of human papillomavirus 16 (HPV-16) are linked to a high incidence of cervical cancer in Mexico, with some evidence strongly suggesting that they are more oncogenic than European (E) variants, including their association with younger women and their higher associated risk of cervical cancer. Differences in the regulation of viral E6/E7 oncogene transcription by the E2 protein may be involved in the higher oncogenicity of AA variants. In E variants, E6/E7 oncogene transcription is repressed by the E2 protein and is frequently up-regulated by the destruction of the E2 gene during viral integration. In contrast, the E2 gene is retained in full in most AA-positive carcinomas, raising the possibility of alternative mechanisms for increasing viral oncogene transcription. The authors investigated whether the higher oncogenicity of AA variants is linked to differences in E6/E7 oncogene transcription and the mechanism of E2 deactivation. E6/E7 and E1/E2 transcripts were explored by RT-PCR in 53 HPV-16-positive cervical carcinomas, 39 retaining (20 European and 19 AA) and 14 having lost (12 European and 2 AA) the E1/E2 genes, and transcription repression activity of the AA E2 genes was tested in four cell lines that constitutively express the beta-galactosidase reporter or E6/E7 genes driven by the viral long control region. E6/E7 oncogene transcripts were found in all carcinomas, but only those positive for AA variants with E1/E2 genes had complete E2 transcripts. E2 transcripts were down-regulated by splicing in E-positive carcinomas retaining E1/E2. AA E2 genes were impaired for repression of E6/E7 oncogene transcription in vivo. These results suggest that E6/E7 oncogene expression starts earlier in AA than E variant infections, since E variants need E2 to be destroyed or down-regulated.
authors.affiliation: Laboratorio de Medicina Genómica, Hospital General de México/UNISER-Facultad de Medicina, UNAM, Dr Balmis # 148, Colonia Doctores, Delegación Cuahutémoc, CP 06726 Ciudad de México, Mexico.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Ordóñez
authors.affiliation: Laboratorio de Medicina Genómica, Hospital General de México/UNISER-Facultad de Medicina, UNAM, Dr Balmis # 148, Colonia Doctores, Delegación Cuahutémoc, CP 06726 Ciudad de México, Mexico.
authors.forename: Ana María
authors.initials: AM
authors.lastname: Espinosa
authors.affiliation: Departamento de Biología Celular, Escuela Médico Militar, Universidad del Ejército y Fuerza Aerea, Cerrada de Palomas s/n, Colonia Lomas de San Isidro, Ciudad de México, Mexico.
authors.forename: Dolores Javier
authors.initials: DJ
authors.lastname: Sánchez-González
authors.affiliation: Instituto de Biología Molecular y Terapia Génica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Apartado Postal 2-123, 44281 Guadalajara, Jalisco, Mexico.
authors.forename: Juan
authors.initials: J
authors.lastname: Armendáriz-Borunda
authors.affiliation: Laboratorio de Medicina Genómica, Hospital General de México/UNISER-Facultad de Medicina, UNAM, Dr Balmis # 148, Colonia Doctores, Delegación Cuahutémoc, CP 06726 Ciudad de México, Mexico.
authors.forename: Jaime
authors.initials: J
authors.lastname: Berumen
mesh_terms: D004268:DNA-Binding Proteins; D005260:Female; D015967:Gene Expression Regulation, Viral; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000502:physiology*; D027383:Papillomaviridae / Q000472:pathogenicity*; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins / Q000502:physiology*; D002583:Uterine Cervical Neoplasms / Q000821:virology*
chemical_list: D004268:DNA-Binding Proteins; C093478:E1 protein, Human papillomavirus 16; C054855:E2 protein, Human papillomavirus type 16; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16