title: Long Noncoding RNA GCASPC, a Target of miR-17-3p, Negatively Regulates Pyruvate Carboxylase-Dependent Cell Proliferation in Gallbladder Cancer.
abstract: Long noncoding RNAs (lncRNA) are being implicated in the development of many cancers. Here, we report the discovery of a critical role for the lncRNA GCASPC in determining the progression of gallbladder cancer. Differentially expressed lncRNAs and mRNAs between gallbladder cancer specimens and paired adjacent nontumor tissues from five patients were identified and validated by an expression microarray analysis. Quantitative real-time PCR was used to measure GCASPC levels in tissues from 42 gallbladder cancer patients, and levels of GCASPC were confirmed further in a separate cohort of 89 gallbladder cancer patients. GCASPC was overexpressed or silenced in several gallbladder cancer cell lines where molecular and biological analyses were performed. GCASPC levels were significantly lower in gallbladder cancer than adjacent nontumor tissues and were associated with tumor size, American Joint Committee on Cancer tumor stage, and patient outcomes. GCASPC overexpression suppressed cell proliferation in vitro and in vivo, whereas GCASPC silencing had opposite effects. By RNA pull-down and mass spectrometry, we identified pyruvate carboxylase as an RNA-binding protein that associated with GCASPC. Because GCASPC is a target of miR-17-3p, we confirmed that both miR-17-3p and GCASPC downregulated pyruvate carboxylase level and activity by limiting protein stability. Taken together, our results defined a novel mechanism of lncRNA-regulated cell proliferation in gallbladder cancer, illuminating a new basis for understanding its pathogenicity. Cancer Res; 76(18); 5361-71. ©2016 AACR.
authors.affiliation: Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Gastric Cancer and Soft Tissue Sarcoma, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Ming-Zhe
authors.initials: MZ
authors.lastname: Ma
authors.affiliation: Department of Gastroenterology, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ming-Zhe
authors.initials: MZ
authors.lastname: Weng
authors.affiliation: Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Shou-Hua
authors.initials: SH
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhao-Yuan
authors.initials: ZY
authors.lastname: Hou
authors.affiliation: Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yi-Yu
authors.initials: YY
authors.lastname: Qin
authors.affiliation: Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.affiliation: Second Department of Biliary Surgery and Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China. zhiwquan@163.com shence201511@sina.com wnmcyaolikx@sina.com.
authors.forename: Xiang
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China. zhiwquan@163.com shence201511@sina.com wnmcyaolikx@sina.com.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China. zhiwquan@163.com shence201511@sina.com wnmcyaolikx@sina.com.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Quan
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation / Q000502:physiology; D005706:Gallbladder Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D053208:Kaplan-Meier Estimate; D013058:Mass Spectrometry; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011766:Pyruvate Carboxylase / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D011766:Pyruvate Carboxylase