Abstract
Abstract Lung cancer is the leading cause of the human cancer-related death in the world and non-small cell lung cancer (NSCLC) accounts for up to 80 % of those patients. Cholesterol metabolism is especially active in cancer cells, whereas cholesterol synthesis inhibition has been show to reduce tumor cell growth. However, the involvement of farnesyl diphosphate farnesyltransferase (FDFT1) in lung cancer development and progression remains unclear. FDFT1 was involved in cholesterol biosynthesis. In this study, we investigated the clinical significance and biological effects of FDFT1 in NSCLC. Immunohistochemical studies performed on 141 primary NSCLC specimens revealed a high prevalence of FDFT overexpression (51%), which was significantly associated with lymph node metastasis (regional, P = 0.022), advanced tumor stage (P = 0.004), and poorer disease-free survival (P = 0.001, log-rank test; P = 0.001, Cox proportional hazard model). FDFT1 down-regulation by two shRNAs significantly reduced cell migration and invasion in highly invasive lung cancer cell lines in vitro, as well as lung metastases in vivo. Conversely, overexpression of FDFT1 in weakly invasive lung cancer cell lines in vitro and orthotopic metastasis assay in vivo shows enhanced cell motility and lung metastases. In addition, inhibition of FDFT1 decreased AKT activation and thereby suppressing the migration of human lung cancer cell in vitro. The results suggested that FDFT1 can positive feedback to regulate AKT. In weakly invasive lung cancer cell lines, FDFT1 overexpression was associated with the upregulation of secreted phosphoprotein 1(SPP1). The shRNA mediated knockdown of SPP1 was found to block FDFT1-enhanced invasion. Taken together, we have identified cholesterol metabolism regulatory gene FDFT1 as a cancer progression biomarker who overexpression leading to poor prognosis and result tumor metastasis feedback regulation of SPP1-PI3K-AKT signaling pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4612. doi:1538-7445.AM2012-4612
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