Abstract
BackgroundProhibitin (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.MethodsPHB 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.ResultsPHB 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.ConclusionOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0346-7) contains supplementary material, which is available to authorized users.
Highlights
Prohibitin (PHB), a pleiotropic protein overexpressed in several tumor types, has been implicated in the regulation of cell proliferation, invasive migration and survival
Our findings suggest that PHB overexpression predicts poor prognosis in gallbladder cancer (GBC) patients and, more importantly, that PHB could potentially serve as a novel therapeutic target in the oncogenic Ras-driven GBCs
PHB expression was upregulated and associated with adverse clinical outcomes in GBC patients To determine the role of PHB in GBC progression, PHB protein expression was measured in 74 GBC and 60 cholecystitis tissue specimens using IHC staining
Summary
Prohibitin (PHB), a pleiotropic protein overexpressed in several tumor types, has been implicated in the regulation of cell proliferation, invasive migration and survival. PHB expression and its biological function in gallbladder cancer (GBC) remain largely unknown. Gallbladder cancer (GBC) represents the most common malignancy of the biliary tract with a poor prognosis. Radical resection at an early stage is considered to be potentially curative therapy for GBCs. due to the lack of typical symptoms and specific biomarkers, most patients are identified at advanced stages and miss the chance for curative resection. Palliative chemotherapy and radiation therapy only offer limited benefits to advanced GBCs [3, 4]. It is desirable to explore the molecular mechanisms involved in GBC progression and to develop effective therapeutic strategies for prognosis improvement
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