Heat Shock Protein 90 Is a Potential Therapeutic Target in Cholangiocarcinoma
Heat Shock Protein 90 Is a Potential Therapeutic Target in Cholangiocarcinoma
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DOI：
10.1158/1535-7163.mct-15-0069
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发表时间：
2015-09-01
影响因子：
5.7
通讯作者：
Shibata, Tatsuhiro
中科院分区：
文献类型：
--
作者：
Shirota, Tomoki;Ojima, Hidenori;Shibata, Tatsuhiro
胆管细胞癌是一种侵袭性的恶性肿瘤，预后差，除手术切除外没有其他有效的治疗方法。热休克蛋白90(HSP90)是多分子伴侣复合体的重要组成部分，参与了许多客户蛋白的翻译后折叠，其中许多客户蛋白在肿瘤发生中起着重要作用。在这里，我们试图阐明其预后意义和作为胆管细胞癌治疗靶点的潜在用途。本研究回顾分析了399例胆管癌细胞和17株人胆管癌细胞系HSP90的免疫组织化学表达，以及小分子HSP90抑制剂(NVP-AUY922)对胆管癌细胞系和异种移植瘤生长及血管生成的影响。HSP90在肝内胆管细胞癌和肝外胆管细胞癌中的阳性表达率分别为44.6%和32.8%。热休克蛋白90的表达与肝细胞癌(P<；0.001)和肝细胞癌(P<；0.001)的5年生存率显著相关。抑制HSP90对体外培养的人胆管癌细胞表现出很强的抗增殖活性和抑制生长相关信号的作用。此外，NVP-AUY922治疗胆管癌细胞移植瘤小鼠在远低于最大耐受量的剂量下显著抑制了生长。HSP90过表达是胆管细胞癌的预后指标。HSP90靶向治疗可能是胆管癌的一种选择。(C)2015年AACR。
Cholangiocarcinoma is an aggressive malignancy with a poor prognosis, with no effective therapy other than surgical resection. Heat shock protein 90 (HSP90) is a key component of a multi-chaperone complex involved in the posttranslational folding of a number of client proteins, many of which play essential roles in tumorigenesis. Here, we attempted to clarify its prognostic significance and potential utility as a therapeutic target in cholangiocarcinoma. Immunohistochemical expression of HSP90 was assessed retrospectively in 399 cholangiocarcinoma cases and 17 human cholangiocarcinoma cell lines, along with the effect of a small-molecule HSP90 inhibitor (NVP-AUY922) on cholangiocarcinoma tumor growth and angiogenesis in human cholangiocarcinoma cell lines and xenografts. The positivity of HSP90 was 44.6% in intrahepatic cholangiocarcinoma (IHCC) and 32.8% in extrahepatic cholangiocarcinoma (EHCC), respectively. HSP90 expression was significantly associated with the 5-year survival rate for IHCC (P < 0.001) and EHCC (P < 0.001). HSP90 inhibition showed potent antiproliferative activity and reduced growth-associated signaling in human cholangiocarcinoma cells in vitro. Furthermore, treatment of cholangiocarcinoma xenograft-bearingmice with NVP-AUY922 significantly inhibited growth at doses far below the maximum-tolerated dose. HSP90 overexpression is a prognostic marker for cholangiocarcinoma. HSP90-targeted therapy may be an option for a subset of cholangiocarcinoma. (C) 2015 AACR.