title: RFT2 is overexpressed in esophageal squamous cell carcinoma and promotes tumorigenesis by sustaining cell proliferation and protecting against cell death.
abstract: 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.
authors.affiliation: Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Xing-Ran
authors.initials: XR
authors.lastname: Jiang
authors.affiliation: Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Xi-Ying
authors.initials: XY
authors.lastname: Yu
authors.affiliation: Department of Cancer Epidemiology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Jin-Hu
authors.initials: JH
authors.lastname: Fan
authors.affiliation: Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Guo
authors.affiliation: Key Laboratory of Molecular and Cellular Systems Biology and Department of Cell Biology, Tianjin Normal University, Tianjin, China.
authors.forename: Changjun
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Key Laboratory of Molecular and Cellular Systems Biology and Department of Cell Biology, Tianjin Normal University, Tianjin, China. Electronic address: wjiang6138@cicams.ac.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: shlu1212@gmail.com.
authors.forename: Shih-Hsin
authors.initials: SH
authors.lastname: Lu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D026901:Membrane Transport Proteins; C548553:SLC52A3 protein, human; D000255:Adenosine Triphosphate; D002945:Cisplatin
keywords: Cell death; Cell proliferation; Esophageal cancer; Riboflavin transporter; Tumorigenesis