Abstract
Farnesoid X receptor (FXR), a nuclear receptor for maintaining bile acid homeostasis, has been recognized as a tumor suppressor in enterohepatic tissues. However, its expression and functional role in non-small cell lung cancer (NSCLC) remain unclear. We report that FXR is significantly increased in NSCLC and that it predicts poor clinical outcomes in NSCLC patients. FXR knockdown in NSCLC cells inhibited in vitro cell proliferation, blocked xenograft growth in nude mice, and delayed the G1/S transition of the cell cycle, whereas ectopic overexpression of FXR promoted NSCLC cell proliferation. Mechanistic analysis demonstrated that FXR could directly bind to an inverted repeat-0 sequence in the CCND1 promoter and activate its transcription. Cyclin D1 overexpression rescued NSCLC cells from the delayed G1/S transition and the impaired cell proliferation induced by FXR knockdown. Importantly, a positive correlation between the expression of FXR and cyclin D1 was confirmed in NSCLC samples, and patients with high expression of both FXR and cyclin D1 had the worst prognosis. In summary, our results suggest that FXR has oncogenic potential in NSCLC development, providing mechanistic insights that could be exploited for both prognostic and therapeutic purposes.
Highlights
Lung cancer is the leading cause of cancer mortality worldwide, and approximately 85% of cases are non-small cell lung cancer (NSCLC)[1]
We found that farnesoid X receptor (FXR) protein was significantly upregulated in carcinous, compared to pericarcinous, lung tissues (Fig. 1B)
We identified FXR as a novel proto-oncogene that is markedly upregulated in NSCLC
Summary
Lung cancer is the leading cause of cancer mortality worldwide, and approximately 85% of cases are non-small cell lung cancer (NSCLC)[1]. Other studies have revealed increased colon cell proliferation and small intestine adenocarcinoma formation in FXR−/− mice; FXR expression is inversely correlated with human colorectal cancer progression[12, 13]. Several other studies have demonstrated a causative role for FXR in the carcinogenesis of organs other than the liver-intestine system. We firstly showed that FXR was upregulated in NSCLC tissues, and its expression levels were positively correlated with poor clinical outcomes. FXR-cyclin D1 signaling was found to predict a poor prognosis for NSCLC patients. This finding may permit the stratification of NSCLC in a novel way and may subsequently provide an intervention option
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