title: Gankyrin promotes tumor growth and metastasis through activation of IL-6/STAT3 signaling in human cholangiocarcinoma.
abstract: Although gankyrin is involved in the tumorigenicity and metastasis of some malignancies, the role of gankyrin in cholangiocarcinoma (CCA) is unclear. In this study we investigated the expression of gankyrin in human CCA tissues and cell lines. The effects of gankyrin on CCA tumor growth and metastasis were determined both in vivo and in vitro. The results showed that gankyrin was overexpressed in CCA tissues and cell lines. Gankyrin expression was associated with CCA histological differentiation, TNM stage, and metastasis. The multivariate Cox analysis revealed that gankyrin was an independent prognostic indicator for overall survival. Gankyrin overexpression promoted CCA cell proliferation, migration, and invasion, while gankyrin knockdown inhibited CCA tumor growth, metastasis, and induced Rb-dependent senescence and G1 phase cell cycle arrest. Gankyrin increased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and promoted the nuclear translocation of p-STAT3. Suppression of STAT3 signaling by small interfering RNA (siRNA) or STAT3 inhibitor interfered with gankyrin-mediated carcinogenesis and metastasis, while interleukin (IL)-6, a known upstream activator of STAT3, could restore the proliferation and migration of gankyrin-silenced CCA cells. The IL-6 level was decreased by gankyrin knockdown, while increased by gankyrin overexpression. Gankyrin regulated IL-6 expression by way of facilitating the phosphorylation of Rb; meanwhile, rIL-6 treatment increased the expression of gankyrin, suggesting that IL-6 was regulated by a positive feedback loop involving gankyrin in CCA. In the xenograft experiments, gankyrin overexpression accelerated tumor formation and increased tumor weight, whereas gankyrin knockdown showed the opposite effects. The in vivo spontaneous metastasis assay revealed that gankyrin promoted CCA metastasis through IL-6/STAT3 signaling pathway.
  
  
  CONCLUSIONS
  Gankyrin is crucial for CCA carcinogenesis and metastasis by activating IL-6/STAT3 signaling pathway through down-regulating Rb protein.
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Tongsen
authors.initials: T
authors.lastname: Zheng
authors.forename: Xuehui
authors.initials: X
authors.lastname: Hong
authors.forename: Jiabei
authors.initials: J
authors.lastname: Wang
authors.forename: Tiemin
authors.initials: T
authors.lastname: Pei
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Liang
authors.forename: Dalong
authors.initials: D
authors.lastname: Yin
authors.forename: Ruipeng
authors.initials: R
authors.lastname: Song
authors.forename: Xuan
authors.initials: X
authors.lastname: Song
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Lu
authors.forename: Shuyi
authors.initials: S
authors.lastname: Qi
authors.forename: Jiaren
authors.initials: J
authors.lastname: Liu
authors.forename: Boshi
authors.initials: B
authors.lastname: Sun
authors.forename: Changming
authors.initials: C
authors.lastname: Xie
authors.forename: Shangha
authors.initials: S
authors.lastname: Pan
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Li
authors.forename: Xiaohe
authors.initials: X
authors.lastname: Luo
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.forename: Xiang
authors.initials: X
authors.lastname: Fang
authors.forename: Nishant
authors.initials: N
authors.lastname: Bhatta
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
authors.forename: Lianxin
authors.initials: L
authors.lastname: Liu
mesh_terms: D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; C403591:PSMD10 protein, human; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D046988:Proteasome Endopeptidase Complex