Zhang, QunzhouTang, XudongZhang, Zuo-fengVelikina, RitaShi, ShihongLe, Anh D2023-05-222023-05-222007-08-152022-06-22https://repository.upenn.edu/handle/20.500.14332/9321Purpose: Nicotine, the major component in cigarette smoke, can promote tumor growth and angiogenesis in various cancers, including lung cancer. Hypoxia-inducible factor-1α (HIF-1α) is overexpressed in human lung cancers, particularly in non - small cell lung cancers (NSCLC), and is closely associated with an advanced tumor grade, increased angiogenesis, and resistance to chemotherapy and radiotherapy. The purpose of this study was to investigate the effects of nicotine on the expression of HIF-1aand its downstream target gene, vascular endothelial growth factor (VEGF), in human lung cancer cells. Experimental Design: Human NSCLC cell lines A549 and H157 were treated with nicotine and examined for expression of HIF-1α and VEGF using Western blot or ELISA. Loss of HIF-1α function using specific small interfering RNA was used to determine whether HIF-1α is directly involved in nicotine-induced tumor angiogenic activities, including VEGF expression, cancer cell migration, and invasion. Results: Nicotine increased HIF-1α and VEGF expression in NSCLC cells. Pharmacologically blocking nicotinic acetylcholine receptor - mediated signaling cascades, including the Ca2+/ calmodulin, c-Src, protein kinase C, phosphatidylinositol 3-kinase, mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2, and the mammalian target of rapamycin pathways, significantly attenuated nicotine-induced up-regulation of HIF-1α protein. Functionally, nicotine potently stimulated in vitro tumor angiogenesis by promoting tumor cell migration and invasion. These proangiogenic and invasive effects were partially abrogated by treatment with small interfering RNA specific for HIF-1α. Conclusion: These findings identify novel mechanisms by which nicotine promotes tumor angiogenesis and metastasis and provide further evidences that HIF-1α is a potential anticancer target in nicotine-associated lung cancer. © 2007 American Association for Cancer Research.MeSH: 1-Phosphatidylinositol 3-KinaseCarcinomaNon-Small-Cell LungCell LineTumorCell MovementHumansHypoxia-Inducible Factor 1alpha SubunitLung NeoplasmsNeoplasm InvasivenessNicotineReceptorsNicotinicRNASmall InterferingSignal TransductionVascular Endothelial Growth Factor A EMTREE drug terms: hypoxia inducible factor 1alphamammalian target of rapamycinmitogen activated protein kinasemitogen activated protein kinase 1mitogen activated protein kinase 3nicotinenicotinic receptorphosphatidylinositol 3 kinaseprotein kinase (calciumcalmodulin)protein kinase Cprotein tyrosine kinasesmall interfering RNAvasculotropin EMTREE medical terms: angiogenesisarticlecancer cellcell invasioncell migrationcontrolled studyenzyme linked immunosorbent assaygene targetinghumanhuman cellin vitro studylung non small cell cancerpriority journalprotein analysisprotein depletionprotein expressionprotein functionsignal transductiontumor vascularizationupregulationWestern blottingDentistryOral Biology and Oral PathologyPeriodontics and PeriodontologyArticle