Tip60 Suppresses Cholangiocarcinoma Proliferation And Metastasis Through PI3K-AKT-dependent Manner

Background & Aims: Aberrant expression of Tip60 is associated with progression of many cancers.However,the role of Tip60 in cancer progression remain contradictory.The aim of this study,for the first time,was to investigate the clinical significance,biological functions and underlying mechanisms of Tip60 deregulation in cholangiocarcinoma(CCA).Methods: Quantitative real-time PCR(QRT-PCR),western blot and immunohistochemistry staining(IHC)were developed to measure Tip60 expression in CCA tissues and cell lines.Kaplan–Meier analysis with the log-rank test was used for survival.In vitro,the cell proliferation was evaluated by CCK-8,colony formation,EDU assay and flow cytometry.and the migration/invasion was evaluated by trans-well assay and wound healing assay.The phosphokinase array was used to confirm the dominant signal regulated by Tip60.The tumor growth and metastasis were demonstrated in a mouse model in vivo.Results: Tip60 was notably downregulated in CCA tissues,which was associated with tumor size,venous invasion,and TNM stage.And down-regulation of Tip60 was remarkably associated with tumor progression and poor survival in CCA patients.Both in vitro and in vivo studies demonstrated that Tip60 could suppress proliferation and metastasis throughout the progression of CCA.We further identified PI3K/AKT pathway as dominant signal of Tip60 and found that Tip60 could regulate CCA cell proliferation and metastasis in a PI3K-AKT dependent manner.Pearson analysis revealed that PTEN was positively correlated with the Tip60 level in CCA tissues Conclusions: Tip60,as a tumor suppressor in CCA through targeting PI3K/AKTpathway,might be a promising therapeutic target or prognostic marker for CCA.