title: Prohibitin overexpression predicts poor prognosis and promotes cell proliferation and invasion through ERK pathway activation in gallbladder cancer.
abstract: BACKGROUND
  Prohibitin (PHB), a pleiotropic protein overexpressed in several tumor types, has been implicated in the regulation of cell proliferation, invasive migration and survival. However, PHB expression and its biological function in gallbladder cancer (GBC) remain largely unknown.
  
  
  METHODS
  PHB and p-ERK protein expressions were determined in human GBC tissues by immunohistochemistry (IHC). The effects of PHB knockdown on GBC cell proliferation and invasiveness were evaluated using Cell Counting Kit-8 (CCK-8) cell viability, cell cycle analysis, transwell invasion and gelatin zymography assays. Subcutaneous xenograft and tail vein-lung metastasis tumor models in nude mice were employed to further substantiate the role of PHB in GBC progression.
  
  
  RESULTS
  PHB protein was overexpressed in GBC tissues and was significantly associated with histological grade, tumor stage and perineural invasion. Furthermore, PHB expression was negatively associated with overall survival in GBC patients. In vitro experimental studies demonstrated that the downregulation of PHB expression by lentivirus-mediated shRNA interference not only inhibited the ERK pathway activation but also reduced the proliferative and invasive capacities of GBC cells. Moreover, PD0325901, a specific inhibitor of MEK, markedly impaired PHB- mediated phosphorylation of ERK protein. IHC statistical analyses further validated that PHB expression was positively correlated with ERK protein phosphorylation levels in GBC tissue samples. In vivo, PHB depletion also resulted in dramatic reductions in the growth and metastasis of GBC cells.
  
  
  CONCLUSIONS
  Our findings demonstrate that PHB overexpression predicts poor survival in GBC patients. PHB could serve as a novel prognostic biomarker and a potential therapeutic target for GBCs.
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China.
authors.forename: Haibin
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, Hubei, 430030, P.R. China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Luan
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China.
authors.forename: Xu-An
authors.initials: XA
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China.
authors.forename: Shibo
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China.
authors.forename: Runfa
authors.initials: R
authors.lastname: Bao
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Shu
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China. 69zj@sina.com.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China. 69zj@sina.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China. liuybphd@126.com.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China. liuybphd@126.com.
authors.forename: Yingbin
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005706:Gallbladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008875:Middle Aged; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011379:Prognosis; D000091402:Prohibitins; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: C000717328:PHB protein, human; D000091402:Prohibitins; D012097:Repressor Proteins
keywords: ERK; Gallbladder cancer; Invasion; Prognosis; Prohibitin; Proliferation