Abstract 2079: FGFR1/MAPK pathway regulates transcription factor brachyury-driven epithelial-mesenchymal transition in lung cancer

Abstract

Abstract Lung cancer is the leading cause of cancer-related death worldwide. Failure of treatment is attributed to recurrence, metastasis, and chemotherapeutic resistance. Previous studies have demonstrated that the transcription factor brachyury is a potential regulator of epithelial-mesenchymal transition (EMT) and plays a role in tumor resistance to conventional antitumor therapies. However, the mechanisms underlining brachyury-induced EMT are unknown. Recent studies have revealed that fibroblast growth factor (FGF)/ fibroblast growth factor receptor (FGFR) signaling is activated in lung cancer, and suppression of FGFR results in cell growth inhibition and apoptosis. Here we investigated the role of FGFR signaling, a critical component of mesoderm induction during normal embryogenesis and a regulator of normal brachyury expression, in brachyury-driven lung cancer. Quantitative RT-PCR and Western Blot analysis showed that the chemotherapy-insensitive/metastatic lung cancer cell line H460 and adenocarcinoma tissues in patients had significantly high expressions of brachyury and FGFR1, 3 and 4 compared to the chemotherapy-sensitive/non-metastatic lung cancer cell line H440 and normal tissues adjacent to tumor. To further explore the association between FGFR and brachyury expression and its function, we specifically silenced FGFR using siRNAs for FGFR1, 2, 3 and 4 in H460 cells or overexpressed FGFR1, 3 and 4 in H441 cells. We found that only FGFR1 inhibition led to suppression of brachyury, whereas overexpression of FGFR1 induced brachyury expression, suggesting that brachyury is a potential target of FGFR1. Immunofluorescence staining and RT-PCR showed that silencing of FGFR1 led to inhibitions of brachyury and EMT (an increased epithelial marker E-cadherin expression and decreased mesenchymal biomarker Snail expression) in H460 cells. Overexpression of FGFR1 promoted EMT in H441 cells, but this effect was suppressed by concomitant knockdown of brachyury. In addition, the mitogen-activated protein kinases (MAPK)/extracellular signal-related kinase (ERK) inhibitor, PD184352, suppressed FGF1-upregulated brachyury and Snail expressions and invasion in H460 cells. PD184352 also inhibited FGFR1 overexpression-induced brachyury expression, EMT and invasion in H440 cells, indicating an important regulatory role of FGFR1 in brachyury-driven EMT through MAPK/ERK. These findings provide novel insights into the molecular mechanism of brachyury-driven EMT and highlight the FGFR1/MAPK/ERK pathway as a new therapeutic target for brachyury-driven lung cancer. Citation Format: Yunping Hu, Wesley Hsu. FGFR1/MAPK pathway regulates transcription factor brachyury-driven epithelial-mesenchymal transition in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2079. doi:10.1158/1538-7445.AM2015-2079