Zhang Yaodong, Ji Guwei, Han Sheng, Shao Zicheng, Lu Zefa, Huo Liqun, Zhang Jiawei, Yang Renjie, Feng Qinchao, Shen Hao, Wang Hongwei, Li Xiangcheng
Cell Physiol Biochem. 2018;50(2):612-628. doi: 10.1159/000494183. Epub 2018 Oct 11.
BACKGROUND/AIMS: Aberrant expression of Tip60 is associated with progression in many cancers. However, the role of Tip60 in cancer progression remains contradictory. The aim of this study was to investigate the clinical significance, biological functions and underlying mechanisms of Tip60 deregulation in cholangiocarcinoma (CCA) for the first time.
Quantitative real-time PCR (QRT-PCR), western blotting and immunohistochemistry staining (IHC) were carried out to measure Tip60 expression in CCA tissues and cell lines. Kaplan-Meier analysis and the log-rank test were used for survival analysis. In vitro, cell proliferation was evaluated by flow cytometry and CCK-8, colony formation, and EDU assays. Migration/ invasion was evaluated by trans-well assays. Phosphokinase array was used to confirm the dominant signal regulated by Tip60. Tumor growth and metastasis were demonstrated in vivo using a mouse model.
Tip60 was notably downregulated in CCA tissues, which was associated with greater tumor size, venous invasion, and TNM stage. Down-regulation of Tip60 was associated with tumor progression and poorer survival in CCA patients. In vitro and in vivo studies demonstrated that Tip60 suppressed growth and metastasis throughout the progression of CCA. We further identified the PI3K/AKT pathway as a dominant signal of Tip60 and suggested that Tip60 regulated CCA cell proliferation and metastasis via PT3K-AKT pathway. Pearson analysis revealed that PTEN was positively correlated with the Tip60 level in CCA tissues.
Tip60, as a tumor suppressor in CCA via the PI3K/AKT pathway, might be a promising therapeutic target or prognostic marker for CCA.
背景/目的：Tip60的异常表达与多种癌症的进展相关。然而，Tip60在癌症进展中的作用仍存在矛盾。本研究的目的是首次探讨Tip60失调在胆管癌（CCA）中的临床意义、生物学功能及潜在机制。
采用定量实时PCR（QRT-PCR）、蛋白质印迹法和免疫组织化学染色（IHC）检测Tip60在CCA组织和细胞系中的表达。采用Kaplan-Meier分析和对数秩检验进行生存分析。在体外，通过流式细胞术、CCK-8、集落形成和EDU试验评估细胞增殖。通过Transwell试验评估迁移/侵袭。使用磷酸激酶阵列确认Tip60调节的主要信号。使用小鼠模型在体内证实肿瘤生长和转移。
Tip60在CCA组织中显著下调，这与更大的肿瘤大小、静脉侵犯和TNM分期相关。Tip60的下调与CCA患者的肿瘤进展和较差的生存率相关。体外和体内研究表明，Tip60在CCA进展过程中抑制生长和转移。我们进一步确定PI3K/AKT途径是Tip60的主要信号，并表明Tip60通过PT3K-AKT途径调节CCA细胞增殖和转移。Pearson分析显示，PTEN与CCA组织中Tip60水平呈正相关。
Tip60作为CCA中通过PI3K/AKT途径的肿瘤抑制因子，可能是CCA有前景的治疗靶点或预后标志物。
