Abstract
Background and ObjectivesHuman papillomavirus (HPV)-16 infection may be related to non-smoking associated lung cancer. Our previous studies have found that HPV-16 oncoproteins promoted angiogenesis via enhancing hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) expression in non-small cell lung cancer (NSCLC) cells. In this study, we further investigated the roles of PI3K/Akt and c-Jun signaling pathways in it.MethodsHuman NSCLC cell lines, A549 and NCI-H460, were stably transfected with pEGFP-16 E6 or E7 plasmids. Western blotting was performed to analyze the expression of HIF-1α, p-Akt, p-P70S6K, p-P85S6K, p-mTOR, p-JNK, and p-c-Jun proteins. VEGF and IL-8 protein secretion and mRNA levels were determined by ELISA and Real-time PCR, respectively. The in vitro angiogenesis was observed by human umbilical vein endothelial cells (HUVECs) tube formation assay. Co-immunoprecipitation was performed to analyze the interaction between c-Jun and HIF-1α.ResultsHPV-16 E6 and E7 oncoproteins promoted the activation of Akt, P70S6K, P85S6K, mTOR, JNK, and c-Jun. LY294002, a PI3K inhibitor, inhibited HPV-16 oncoprotein-induced activation of Akt, P70S6K, and P85S6K, expression of HIF-1α, VEGF, and IL-8, and in vitro angiogenesis. c-Jun knockdown by specific siRNA abolished HPV-16 oncoprotein-induced HIF-1α, VEGF, and IL-8 expression and in vitro angiogenesis. Additionally, HPV-16 oncoproteins promoted HIF-1α protein stability via blocking proteasome degradation pathway, but c-Jun knockdown abrogated this effect. Furthermore, HPV-16 oncoproteins increased the quantity of c-Jun binding to HIF-1α.ConclusionsPI3K/Akt signaling pathway and c-Jun are involved in HPV-16 oncoprotein-induced HIF-1α, VEGF, and IL-8 expression and in vitro angiogenesis. Moreover, HPV-16 oncoproteins promoted HIF-1α protein stability possibly through enhancing the interaction between c-Jun and HIF-1α, thus making a contribution to angiogenesis in NSCLC cells.
Highlights
Lung cancer is the leading cause of cancer-related deaths worldwide, and mortality rates continue to increase among older women with lung cancer in many countries [1]
We investigated the roles of phosphoinositide 3-kinase (PI3K)/Akt and Jun Nterminal kinase (JNK)/cJun signaling pathways in hypoxiainducible factor-1a (HIF-1a), vascular endothelial growth factor (VEGF), and IL-8 expression, and in vitro angiogenesis induced by Human papillomavirus (HPV)-16 E6 and E7 oncoproteins in non-small cell lung cancer (NSCLC) cells
To investigate the effect of HPV-16 oncoproteins on PI3K/Akt/mammalian target of rapamycin (mTOR) activation in NSCLC cells, we determined the phosphorylated levels of Akt, P70S6K, P85S6K, and mTOR in stable-transfected A549 cells
Summary
Lung cancer is the leading cause of cancer-related deaths worldwide, and mortality rates continue to increase among older women with lung cancer in many countries [1]. Non-small cell lung cancer (NSCLC) comprises the majority of lung cancer. Cigarette smoking is considered the major risk factor for NSCLC. It was reported that there are different epidemiologic evidences, clinicopathologic features, and survival rates between ever-smoking and neversmoking NSCLC patients [4,5,6], implying that never-smoking NSCLC might be a different disease and have different risk factors [5,7]. Other non-smoking risk factors might contribute to never-smoking NSCLC. Human papillomavirus (HPV)-16 infection may be related to non-smoking associated lung cancer. Our previous studies have found that HPV-16 oncoproteins promoted angiogenesis via enhancing hypoxiainducible factor-1a (HIF-1a), vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) expression in non-small cell lung cancer (NSCLC) cells. We further investigated the roles of PI3K/Akt and c-Jun signaling pathways in it
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