title: Cyclophilin J is a novel peptidyl-prolyl isomerase and target for repressing the growth of hepatocellular carcinoma.
abstract: Cyclophilin J (CYPJ) is a new member of the peptidyl-prolyl cis/trans-isomerase (PPIase) identified with upregulated expression in human glioma. However, the biological function of CYPJ remained unclear. We aimed to study the role of CYPJ in hepatocellular carcinoma (HCC) carcinogenesis and its therapeutic potential. We determined the expression of CYPJ in HCC/adjacent normal tissues using Western blot, Northern blot and semi-quantitative RT-PCR, analyzed the biochemical characteristics of CYPJ, and resolved the 3D-structure of CYPJ/Cyclosporin A (CsA) complex. We also studied the roles of CYPJ in cell cycle, cyclin D1 regulation, in vitro and in vivo tumor growth. We found that CYPJ expression was upregulated in over 60% HCC tissues. The PPIase activity of CYPJ could be inhibited by the widely used immunosuppressive drug CsA. CYPJ was found expressed in the whole cell of HCC with preferential location at the cell nucleus. CYPJ promoted the transition of cells from G1 phase to S phase in a PPIase-dependent manner by activating cyclin D1 promoter. CYPJ overexpression accelerated liver cell growth in vitro (cell growth assay, colony formation) and in vivo (xenograft tumor formation). Inhibition of CYPJ by its inhibitor CsA or CYPJ-specific RNAi diminished the growth of liver cancer cells in vitro and in vivo. In conclusion, CYPJ could facilitate HCC growth by promoting cell cycle transition from G1 to S phase through the upregulation of cyclin D1. Suppression of CYPJ could repress the growth of HCC, which makes CYPJ a potential target for the development of new strategies to treat this malignancy.
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, P.R. China; Shandong Research Center of Stem Cell Engineering, Yantai Yuhuangding Hospital, Affiliated Hospital of Qingdao University, Yantai, Shandong, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Chen
authors.affiliation: Shandong Research Center of Stem Cell Engineering, Yantai Yuhuangding Hospital, Affiliated Hospital of Qingdao University, Yantai, Shandong, P.R. China.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Mingjun
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Yantai Yuhuangding Hospital, Affiliated Hospital of Qingdao University, Yantai, Shandong, P.R. China.
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Gong
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Youheng
authors.initials: Y
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Songmin
authors.initials: S
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Long
authors.initials: L
authors.lastname: Yu
mesh_terms: D000818:Animals; D019556:COS Cells; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002522:Chlorocebus aethiops; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016572:Cyclosporine / Q000737:chemistry / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016196:S Phase / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C530104:CCND1 protein, human; D009363:Neoplasm Proteins; D019938:Cyclin D1; D016572:Cyclosporine; D021983:Cyclophilins; C503209:PPIL3 protein, human