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Aryl hydrocarbon receptor activation and overexpression upregulated fibroblast growth factor‐9 in human lung adenocarcinomas

We had previously reported that aryl hydrocarbon receptors (AhRs) are overexpressed in lung adenocarcinomas. Benzo[a]pyrene (BaP), an AhR agonist, increased FGF‐9 expression in human lung adenocarcinoma cells. Similarly, several AhR agonists increased FGF‐9 mRNA levels, and BaP‐induced FGF‐9 expression was prevented by cotreatment with AhR antagonist in human lung adenocarcinoma cells. Furthermore, AhR agonists increased transcriptional activity of FGF‐9 promoter. Modulation of AhR expression via RNA interference or transient overexpression respectively reduced or increased both constitutive and BaP‐induced FGF‐9 expression in human lung cells. These results suggested that AhR activation and overexpression increased FGF‐9 expression in lung cells. FGF‐9 increased growth of lung fibroblasts but not that of lung adenocarcinoma cells. However, conditioned media collected from FGF‐9‐treated fibroblasts increased cell growth of lung adenocarcinoma cells. Furthermore, lung adenocarcinoma cells expressed FGF receptor 2 and cotreatment with anti‐FGF receptor 2 prevented the interaction between fibroblasts and tumor cells. It is likely that FGF‐9‐stimulated fibroblasts secreted unknown factors, which activated FGF receptor 2 and subsequently promoted growth of lung adenocarcinoma cells. We further compared AhR and FGF‐9 expression in 146 non‐small cell lung cancer (NSCLC) cases by immunohistochemistry. FGF‐9 expression was more common in adenocarcinomas than in squamous cell carcinomas. Furthermore, FGF‐9 and AhR expression were well correlated in lung adenocarcinomas. These results suggest that AhR expression correlated positively with FGF‐9 expression in lung adenocarcinomas, which might promote tumor growth by modulating communication between tumor cells and fibroblasts. Preventing AhR overexpression or disturbing FGF‐9 function may reduce the development of lung adenocarcinomas. © 2009 UICC