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Tobacco carcinogen mediated up‐regulation of AP‐1 dependent pro‐angiogenic cytokines in head and neck carcinogenesis
Author(s) -
Swenson Wade G.,
Wuertz Beverly R.K.,
Ondrey Frank G.
Publication year - 2011
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20775
Subject(s) - biology , carcinogenesis , cancer research , vascular endothelial growth factor , angiogenesis , carcinogen , transfection , reporter gene , microbiology and biotechnology , gene expression , cell culture , cancer , gene , genetics , vegf receptors
Tobacco is notably genotoxic and associated with head and neck carcinogenesis. Cigarette carcinogens have the capacity to alter early response gene expression in tobacco‐related malignancies via genes such as nuclear factor kappa B (NFκB). A number of early response gene activation events are also facilitated by fos/jun activator protein 1 (AP‐1) associated pathways. In the present study, we hypothesize that tobacco products may induce microenvironment alterations, promoting angiogenesis and providing a permissive environment for head and neck cancer progression. In an in vitro analysis, we employed immortalized oral keratinocyte (HOK‐16B) and laryngeal squamous carcinoma (UM‐SCC‐11A) cells to investigate interleukin (IL)‐8 and vascular endothelial growth factor (VEGF) induction by cigarette smoke condensate (CSC). IL‐8 and VEGF expression is based on interactions between NFκB, AP‐1, and NF‐IL6. We identified at least 1.5‐fold dose‐dependent induction of AP‐1, VEGF, and IL‐8 promoter/reporter gene activity after 24 h exposure to CSC. Next, we stably transfected UM‐SCC‐11A cells with A‐Fos, a dominant negative AP‐1 protein. Treatment with CSC of the A‐Fos cell lines compared to empty vector controls significantly down‐regulated AP‐1, VEGF, and IL‐8 promoter/reporter gene expression. We also performed ELISAs and discovered significant up‐regulation of IL‐8 and VEGF secretion by UMSCC 11A after treatment with phorbol 12‐myristate 13‐acetate, tumor necrosis factor alpha, and CSC, which was down‐regulated by the A‐Fos dominant negative protein. We conclude tobacco carcinogens up‐regulate AP‐1 activity and AP‐1 dependent IL‐8 and VEGF gene expression in head and neck cancer. This up‐regulation may promote an angiogenic phenotype favoring invasion in both premalignant and squamous cancer cells of the head and neck. © 2011 Wiley‐Liss, Inc.