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PI3K/Akt/HIF-1? signaling pathway mediates HPV-16 oncoprotein-induced expression of EMT-related transcription factors in non-small cell lung cancer cells.

ABSTRACT: Background: Our previous studies have demonstrated that human papillomaviruse (HPV)-16 oncoproteins promoted epithelial-mesenchymal transition (EMT), leading to non-small cell lung cancer (NSCLC) progression, but the underlying molecular mechanisms still remain unclear. PI3K/Akt/HIF-1? signaling pathway has been reported to mediate hypoxia-induced EMT. In this study, we further explored the role of PI3K/Akt/HIF-1? signaling pathway in HPV-16 oncoprotein-induced EMT in NSCLC cells. Methods: A549 and NCI-H460 NSCLC cells were transiently transfected with pEGFP-HPV-16 E6 or E7 constructs. Western blotting and RT-qPCR were respectively performed to determine the protein and mRNA expression of EMT-related transcription factors. HPV-16 E6 or E7-transfected NSCLC cells were co-transfected with specific HIF-1?-siRNA or pretreated with different concentrations of LY294002, a specific PI3K inhibitor, followed by the analysis of expression of EMT-related transcription factors. The correlation between HIF-1? and EMT-related transcription factors in NSCLC tissues was analyzed by immunohistochemical staining and Spearman rank correlation coefficient. Results: HPV-16 E6 and E7 oncoproteins upregulated the expression of Slug and Twist1, the EMT-related transcription factors, at both protein and mRNA levels in A549 and NCI-H460 cells. The co-transfection with specific HIF-1?-siRNA, but not the non-specific (NS)-siRNA, significantly abrogated HPV-16 oncoprotein-induced upregulation of ZEB1, Snail1, Slug, and Twist1 at both protein and mRNA levels. Additionally, pretreatment with LY294002 obviously blocked HPV-16 E6- and E7-induced Snail1, Slug, and Twist1 protein expression in A549 and NCI-H460 cells. Further analysis of clinical specimens showed that HIF-1? protein was strongly expressed in NSCLC tissues, which was positively correlated with ZEB1, Snail1, Slug, and Twist1 protein expression. Conclusions: PI3K/Akt/HIF-1? may contribute to the progression of HPV-associated NSCLC via mediating the expression of EMT-related transcription factors in NSCLC cells.

SUBMITTER: Liu J

PROVIDER: S-EPMC6171031 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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PI3K/Akt/HIF-1α signaling pathway mediates HPV-16 oncoprotein-induced expression of EMT-related transcription factors in non-small cell lung cancer cells.

Liu Jinhua J Huang Bingyu B Xiu Zihan Z Zhou Zhiyuan Z Liu Jiao J Li Xiangyong X Tang Xudong X

Journal of Cancer 20180908 19

<b>Background:</b> Our previous studies have demonstrated that human papillomaviruse (HPV)-16 oncoproteins promoted epithelial-mesenchymal transition (EMT), leading to non-small cell lung cancer (NSCLC) progression, but the underlying molecular mechanisms still remain unclear. PI3K/Akt/HIF-1α signaling pathway has been reported to mediate hypoxia-induced EMT. In this study, we further explored the role of PI3K/Akt/HIF-1α signaling pathway in HPV-16 oncoprotein-induced EMT in NSCLC cells. <b>Meth ...[more]

PMID: 30310502

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Project description: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.

Dataset Information

PI3K/Akt/HIF-1? signaling pathway mediates HPV-16 oncoprotein-induced expression of EMT-related transcription factors in non-small cell lung cancer cells.

Publications

PI3K/Akt/HIF-1α signaling pathway mediates HPV-16 oncoprotein-induced expression of EMT-related transcription factors in non-small cell lung cancer cells.

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