RFT2 is overexpressed in esophageal squamous cell carcinoma and promotes tumorigenesis by sustaining cell proliferation and protecting against cell death

Human riboflavin transporter 2 (RFT2, also termed as SLC52A3) was recently identified as a susceptibility gene to esophageal squamous cell carcinoma (ESCC), however, its expression and biologic function has remained unclear in ESCC. In this study, we demonstrated that RFT2 was frequently overexpressed in tumor samples compared with normal adjacent tissue in ESCC patients. Knockdown of RFT2 in ESCC cells resulted in decreases of intracellular flavin status, mitochondrial membrane potential and cellular ATP levels, and inhibitions of cell proliferation, colony formation and anchorage-independent growth. Knockdown of RFT2 increased p21 and p27 protein levels, decreased their downstream targets cyclin E1 and Cdk2 protein levels and caused pRb hypophosphorylation, leading to cell cycle arrest at G1-G1/S. Knockdown of RFT2 also reduced anti-apoptotic proteins Bcl-2, Bcl-xl and survivin levels, caused activation of caspase-3 and apoptosis. In contrast, ectopic overexpression of RFT2 in ESCC cells promoted cell proliferation under restricted conditions (soft agar), conferred resistance to cisplatin, and enhanced tumorigenicity in nude mice. These results suggest that RFT2 contributes to ESCC tumorigenesis and may serve as a potential therapeutic target. (C) 2014 Elsevier Ireland Ltd. All rights reserved.