Abstract
Extracellular signal-regulated kinase (ERK)1/2 signaling pathway plays a critical role in regulating tumor angiogenesis. Our previous studies have demonstrated that HPV-16 oncoproteins enhanced hypoxia-inducible factor-1α (HIF-1α) protein accumulation and vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) expression in non-small cell lung cancer (NSCLC) cells, thus contributing to angiogenesis. In this study, we further investigated the role of ERK1/2 signaling pathway in HPV-16 oncoprotein-induced HIF-1α, VEGF, and IL-8 expression and in vitro angiogenesis in NSCLC cells. Our results showed that HPV-16 E6 and HPV-16 E7 oncoproteins promoted the activation of ERK1/2 signaling pathway in A549 and NCI-H460 cells. Moreover, PD98059, a specific inhibitor of ERK1/2, blocked in vitro angiogenesis stimulated by HPV-16 E6 but not E7 oncoprotein. Additionally, HIF-1α protein accumulation and VEGF and IL-8 expression in NSCLC cells induced by HPV-16 E6 but not E7 oncoprotein were significantly inhibited by PD98059. Taken together, our results suggest that ERK1/2 signaling pathway is involved in HPV-16 E6 but not E7 oncoprotein-induced HIF-1α, VEGF, and IL-8 expression in NSCLC cells, leading to the enhanced angiogenesis in vitro.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / genetics*
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Flavonoids / administration & dosage
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Gene Expression Regulation, Neoplastic / drug effects
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Human papillomavirus 16 / genetics
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Human papillomavirus 16 / pathogenicity
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis*
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Interleukin-8 / biosynthesis*
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Interleukin-8 / genetics
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MAP Kinase Signaling System / drug effects
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / pathology
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Oncogene Proteins, Viral / metabolism*
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Papillomavirus E7 Proteins / metabolism
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Repressor Proteins / metabolism*
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Vascular Endothelial Growth Factor A / biosynthesis*
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Vascular Endothelial Growth Factor A / genetics
Substances
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E6 protein, Human papillomavirus type 16
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Flavonoids
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Interleukin-8
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Oncogene Proteins, Viral
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Papillomavirus E7 Proteins
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Repressor Proteins
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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oncogene protein E7, Human papillomavirus type 16
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one