KCa3.1 as an Effective Target for Inhibition of Growth and Progression of Intrahepatic Cholangiocarcinoma.
KCa3.1 as an Effective Target for Inhibition of Growth and Progression of Intrahepatic Cholangiocarcinoma.
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KCa3.1 作为抑制肝内胆管癌生长和进展的有效靶点。
DOI：
10.7150/jca.18697
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发表时间：
2017
影响因子：
3.9
通讯作者：
Zheng S
中科院分区：
文献类型：
--
作者：
Song P;Du Y;Song W;Chen H;Xuan Z;Zhao L;Chen J;Chen J;Guo D;Jin C;Zhao Y;Tuo B;Zheng S
背景：肝内胆管癌（ICC）是一种源于肝脏胆管的高度恶性肿瘤，预后较差。由于目前的分子靶向治疗和全身化疗在ICC中成效有限，因此需要新的治疗靶点。在本研究中，我们试图探究中电导钙激活钾通道（KCa3.1）在ICC中的表达及其作用。
方法：检测81例切除的ICC肿瘤标本中KCa3.1通道的表达水平，并确定这些水平的临床病理意义。使用KCa3.1通道抑制剂和小干扰RNA（siRNA）研究KCa3.1在ICC细胞系增殖、迁移和侵袭中的作用。还利用裸鼠移植瘤模型研究KCa3.1通道阻断在体内对肿瘤生长的影响。
结果：KCa3.1通道的蛋白表达在ICC组织中上调，且与年龄、淋巴结转移和TNM分期相关。KCa3.1高表达提示ICC患者预后更差。用特异性抑制剂TRAM - 34阻断KCa3.1通道可降低ICC细胞的增殖和侵袭。敲低KCa3.1可通过降低核因子-κB（NF - κB）的激活达到相同效果。进一步的体内研究表明，KCa3.1通道阻断可抑制ICC肿瘤生长。
结论：我们的观察结果表明，KCa3.1可能是肝内胆管癌一个有前景的新治疗靶点。
Background: Intrahepatic cholangiocarcinoma (ICC) is a high malignant tumor arising from the bile ducts in the liver with a poor prognosis. As current molecular targeted therapies and systemic chemotherapies had limited success in ICC, novel therapeutic targets are needed. In this study, we attempted to investigate the expression and the role of the intermediate conductance calcium-activated potassium channel (KCa3.1) in ICC. Methods: The expression levels of KCa3.1 channel were measured in 81 resected ICC tumor specimens and the clinicopathological significance of these levels were determined. KCa3.1 channel inhibitor and siRNA were used to study the role of KCa3.1 in proliferation, migration, and invasion of ICC cell lines. The effect of KCa3.1 channel blockade on tumor growth in vivo was also studied using xenograft model in nude mice. Results: The protein expression of KCa3.1 channel was upregulated in ICC tissues and was correlated with age, lymph node metastasis and TNM stage. And high KCa3.1 expression indicated a worse prognosis in ICC patients. Blocking KCa3.1 channel with a specific inhibitor TRAM-34 reduced the proliferation and invasion of ICC cells. Knockdown of KCa3.1 could achieve the same effects through decreasing NF-κB activation. Further in vivo studies demonstrated that KCa3.1 channel blockade suppressed ICC tumor growth. Conclusions: Our observations suggested KCa3.1 might be a promising novel therapeutic target in intrahepatic cholangiocarcinoma.
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