Inhibition of STRA6 suppresses NSCLC growth via blocking STAT3/SREBP-1c axis-mediated lipogenesis.

Abstract

Dysregulation in lipid metabolism is among the most prominent metabolic alterations in cancer. Stimulated by retinoic acid 6 (STRA6), a vitamin A transporter has shown to be involved in the pathogenesis of cancers. Nevertheless, the function of STRA6 in non-small cell lung cancer (NSCLC) progression remains undefined. We obtained cancer and adjacent tissues from NSCLC patients and conducted functional experiments on STRA6 on NSCLC cell lines and mice. High STRA6 expression is correlated with poor prognosis in patients with NSCLC. Results from in vitro and in vivo animal studies showed that STRA6 knockdown suppressed the proliferation, migration, and invasion of NSCLC cells in vitro and tumor growth in vivo through regulation of lipid synthesis. Mechanistically, STRA6 activated a Janus kinase 2/signal transducer and activator of transcription 3 (JAK2-STAT3) signaling cascade which inducing the expression of STAT3 target gene. By inducing the expression of the target gene of STAT3, sterol regulatory element binding protein 1 (SREBP-1), STRA6 promotes SREBP-1-mediated adipogenesis and provides energy for NSCLC cell growth. Our study uncovers a novel STRA6/STAT3/SREBP-1 regulatory axis that enhances NSCLC metastasis by reprogramming of lipid metabolism. These results demonstrate the potential use of STRA6 as a biomarker for diagnosing NSCLC, which may therefore potentially serve as a therapeutic target for NSCLC.