title: The Asian-American variant of human papillomavirus type 16 exhibits higher activation of MAPK and PI3K/AKT signaling pathways, transformation, migration and invasion of primary human keratinocytes.
abstract: Asian-American (AA) HPV-16 variants are associated with higher risk of cancer. Abnormal activation of intracellular signaling play a critical role in cancer development and progression. Our aim was to elucidate mechanisms underlying the higher oncogenic potential attributed to AA variant. We evaluated activation of MAPK and PI3K/AKT pathways in primary human keratinocytes (PHKs) transduced with E6/E7 of three HPV-16 variants: E-P, AA, E-350G. Phenotypes examined included migration, anchorage independent growth and invasion. AA PHKs presented the highest levels of active proteins involved in all cascades analyzed: MAPK-ERK, MAPK-p38 and PI3K-AKT. AA PHKs were more efficient in promoting anchorage independent growth, and in stimulating cell migration and invasion. MEK1 inhibition decreased migration. The mesenchymal phenotype marker vimentin was increased in AA PHKs. Our results suggest that MEK1, ERK2, AKT2 hyperactivation influence cellular behavior by means of GSK-3b inactivation and EMT induction prompting AA immortalized PHKs to more efficiently surpass carcinogenesis steps.
authors.affiliation: Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil. Electronic address: jimena.valls@icesp.org.br.
authors.forename: Jimena
authors.initials: J
authors.lastname: Hochmann
authors.affiliation: Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil. Electronic address: simao_j@yahoo.com.br.
authors.forename: João S
authors.initials: JS
authors.lastname: Sobrinho
authors.affiliation: Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil; Department of Radiology and Oncology, School of Medicine, University of São Paulo, Brazil. Electronic address: luisa.villa@hc.fm.usp.br.
authors.forename: Luisa L
authors.initials: LL
authors.lastname: Villa
authors.affiliation: Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil. Electronic address: laura.sichero@hc.fm.usp.br.
authors.forename: Laura
authors.initials: L
authors.lastname: Sichero
mesh_terms: D002465:Cell Movement; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D005838:Genotype; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D054884:Host-Pathogen Interactions; D052162:Human papillomavirus 16 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014161:Transduction, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human
keywords: HPV-16; Intracellular signaling; Migration; Molecular variants; Transformation