title: Apoptosis-related protein-1 acts as a tumor suppressor in cholangiocarcinoma cells by inducing cell cycle arrest via downregulation of cyclin-dependent kinase subunits.
abstract: Cholangiocarcinoma, a malignancy arising from the biliary tract, is associated with high mortality due to the late diagnosis and lack of effective therapeutic approaches. Our knowledge of the molecular alterations during the carcinogenesis of cholangiocarcinoma is limited. Previous study suggests that apoptosis-related protein-1 (Apr-1) is involved in cancer cell proliferation and survival. In the present study, we first detected the expression pattern of Apr-1 in human cholangiocarcinoma tissues and the effects of forced Apr-1 expression on cell proliferation and cell cycle progression. Cell cycle gene array analysis was used to identify downstream molecules that were regulated by Apr-1, and their expression levels were further evaluated in human cholangiocarcinoma tissues. We showed that Apr-1 expression was downregulated in human cholangiocarcinoma tissues. Forced expression of Apr-1 inhibited cell proliferation of cholangiocarcinoma cell line QBC939 and induced G2/M phase arrest. Downregulation of cell cycle-related genes cyclin-dependent kinase (Cdk) 2, and cyclin-dependent kinase subunits (Cks) 1 and 2 was involved in Apr-1-induced cell cycle arrest. Furthermore, we found that Cdk2 and Cks1/2 expression levels were elevated in human cholangiocarcinoma tissues. Taken together, our data showed that Apr-1 plays a crucial role in cell proliferation by controlling cell cycle progression, implying a tumor-suppressor function of Apr-1 in cholangiocarcinoma carcinogenesis. Thus, the present study provides a rationale to further study the underlying mechanisms of Apr-1 downregulation in cholangiocarcinoma for exploring potential diagnostic and therapeutic targets.
authors.affiliation: Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Cancer Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Qinlong
authors.initials: Q
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cancer Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cancer Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Cancer Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Wenyong
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cancer Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Linni
authors.initials: L
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Cancer Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
mesh_terms: D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D021122:Protein Subunits / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D021122:Protein Subunits; C076744:cytoplasmic linker protein 170; D018844:Cyclin-Dependent Kinases