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

• Published in: Virology (New York, N.Y.) N.Y.), 2016-05, Vol.492, p.145-154
• Main Authors: Hochmann, Jimena, Sobrinho, João S, Villa, Luisa L, Sichero, Laura
• Format: Article
• Language: English
• Subjects: Cell Movement; Cell Proliferation; Gene Expression Regulation; Genotype; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Host-Pathogen Interactions; HPV-16; Human papillomavirus 16; Human papillomavirus 16 - genetics; Human papillomavirus 16 - metabolism; Humans; Infectious Disease; Intracellular signaling; Keratinocytes - metabolism; Keratinocytes - pathology; Keratinocytes - virology; Male; MAP Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Kinase 1 - genetics; MAP Kinase Kinase 1 - metabolism; Migration; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Molecular variants; Oncogene Proteins, Viral - genetics; Oncogene Proteins, Viral - metabolism; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Papillomavirus E7 Proteins - genetics; Papillomavirus E7 Proteins - metabolism; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Primary Cell Culture; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction; Transduction, Genetic; Transformation
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2016.02.015

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.