Farnesoid X receptor promotes non-small cell lung cancer metastasis by activating Jak2/STAT3 signaling via transactivation of IL-6ST and IL-6 genes

Abstract

Metastasis accounts for the majority of cases of cancer recurrence and death in patients with advanced non-small cell lung cancer (NSCLC). Farnesoid X Receptor (FXR) is a bile acid nuclear receptor that was recently found to be upregulated in NSCLC tissues. However, whether and how FXR regulates NSCLC metastasis remains unclear. In the present study, it was found that FXR promoted the migration, invasion, and angiogenic ability of NSCLC cells in vitro, and increased NSCLC metastasis in a mouse model in vivo. Mechanistic investigation demonstrated that FXR specifically bound to the promoters of IL-6ST and IL-6 genes to upregulate their transcription, thereby leading to activation of the Jak2/STAT3 signaling pathway, which facilitated tumor migration, invasion, and angiogenesis in NSCLC. Notably, Z-guggulsterone, a natural FXR inhibitor, significantly reduced FXRhigh NSCLC metastasis, and decreased the expression of FXR, IL-6, IL-6ST, and p-STAT3 in the mouse model. Clinical analysis verified that FXR was positively correlated with IL-6, IL-6ST and p-STAT3 expression in NSCLC patients, and was indicative of a poor prognosis. Collectively, these results highlight a novel FXR-induced IL-6/IL-6ST/Jak2/STAT3 axis in NSCLC metastasis, and a promising therapeutic means for treating FXRhigh metastatic NSCLC.