RFT2 is overexpressed in esophageal squamous cell carcinoma and promotes tumorigenesis by sustaining cell proliferation and protecting against cell death
RFT2 is overexpressed in esophageal squamous cell carcinoma and promotes tumorigenesis by sustaining cell proliferation and protecting against cell death
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RFT2 在食管鳞状细胞癌中过度表达，并通过维持细胞增殖和防止细胞死亡来促进肿瘤发生。
DOI：
10.1016/j.canlet.2014.07.013
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发表时间：
2014-10-10
期刊：
影响因子：
9.7
通讯作者：
Lu, Shih-Hsin
中科院分区：
文献类型：
--
作者：
Jiang, Xing-Ran;Yu, Xi-Ying;Lu, Shih-Hsin
人核黄素转运蛋白2(RFT2，又称SLC52A3)是新近发现的食管鳞癌易感基因，但其在食管鳞癌中的表达和生物学功能尚不清楚。在这项研究中，我们证明了在ESCC患者的肿瘤组织中，与正常的邻近组织相比，RFT2经常过表达。在ESCC细胞中，RFT2基因的敲除导致细胞内黄素状态、线粒体膜电位和细胞内ATP水平下降，并抑制细胞的增殖、克隆形成和锚定非依赖性生长。RFT2基因敲除后，p21和p27蛋白水平升高，下游靶细胞周期蛋白Cyclin E1和CDK2蛋白水平降低，导致pRb蛋白低磷酸化，导致细胞周期停滞于G1-G1/S期。同时，RFT2基因敲除后，抗凋亡蛋白Bcl2、Bclxl和Survivin水平降低，caspase 3激活，细胞发生凋亡。相反，RFT2在ESCC细胞中的异位过表达促进了限制条件下(软琼脂)下的细胞增殖，增强了对顺铂的耐药性，并增强了裸鼠的致瘤性。这些结果表明，RFT2在食管癌的发生发展中起重要作用，可能成为潜在的治疗靶点。(C)2014爱思唯尔爱尔兰有限公司。保留所有权利。
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.