CAPS1 Suppresses Tumorigenesis in Cholangiocarcinoma.
CAPS1 Suppresses Tumorigenesis in Cholangiocarcinoma.
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CAPS1 抑制胆管癌的肿瘤发生。
DOI：
10.1007/s10620-019-05843-9
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发表时间：
2020
影响因子：
3.1
通讯作者：
Dong Ling
中科院分区：
文献类型：
--
作者：
Weng Shuqiang;Janssen Harry L A;Zhang Ningping;Tang Wenqing;Bai Encheng;Yang Biwei;Dong Ling
CAPS1是一种多结构域蛋白，参与调节突触小泡和致密核小泡的胞吐。然而，CAPS1在胆管细胞癌(CCA)中的表达和功能尚不清楚。本研究旨在探讨CAPS1在CCA发生发展中的作用。方法采用免疫印迹和免疫组织化学方法检测CAPS1在4株CCA细胞系和90例CCA临床标本中的表达。分析CAPS1的临床意义。体外和体内检测CAPS1在CCA细胞中的生物学功能。通过检测CAPS1相关信号通路中关键分子的表达，探讨CAPS1功能的内在机制。结果CAPS1在CCA细胞系和人肿瘤组织中表达下调。肿瘤组织中CAPS1的缺失与CCA患者预后不良密切相关。此外，CAPS1的表达与肿瘤转移分期、淋巴结转移和血管侵犯显著相关。慢病毒介导的CAPS1过表达实质上阻止了克隆形成、细胞增殖和细胞周期进展。CAPS1的过表达也抑制了裸鼠的致癌作用。在机制上，CAPS1的过表达大大加速了ERK和p38MAPK信号通路的激活。此外，microRNA miR-30E-5p对CAPS1的表达有负性调节作用。结论CAPS1在CCA中具有抑癌作用。CAPS1表达降低提示CCA患者预后不良。
BackgroundCAPS1 (calcium-dependent activator protein for secretion) is a multi-domain protein involved in regulating exocytosis of synaptic vesicles and dense-core vesicles. However, the expression and function of CAPS1 in cholangiocarcinoma (CCA) remains unclear. In the present study, we explored the role of CAPS1 in CCA carcinogenesis.MethodsCAPS1 expression was explored using western blotting and immunohistochemistry in four CCA cell lines and clinical samples from 90 cases of CCA. The clinical significance of CAPS1 was analyzed. The biological function of CAPS1 in CCA cells was detected in vitro and in vivo. The underlying mechanism of CAPS1 function was explored by detecting the expression of critical molecules in its associated signaling pathways. The mechanism of CAPS1 downregulation in tumor tissues was explored using in silico prediction and luciferase reporter assays.ResultsCAPS1 expression was reduced in CCA cell lines and human tumor tissues. Loss of CAPS1 in tumor tissues was closely associated with poor prognosis of patients with CCA. Moreover, CAPS1 expression correlated significantly with tumor–node–metastasis stage, lymph node metastasis, and vascular invasion. Lentivirus-mediated CAPS1 overexpression substantially prevented clone formation, cell proliferation, and cell cycle progression. CAPS1 overexpression also suppressed carcinogenesis in nude mice. Mechanistically, CAPS1 overexpression greatly accelerated the ERK and p38 MAPK signal pathways. In addition, microRNA miR-30e-5p negatively regulatedCAPS1expression.ConclusionThese data showed that CAPS1 functions as a tumor suppressor in CCA. Reduced CAPS1 expression could indicate poor prognosis of patients with CCA.