Inhibition of heat shock protein 90 suppresses squamous carcinogenic progression in a mouse model of esophageal cancer
Inhibition of heat shock protein 90 suppresses squamous carcinogenic progression in a mouse model of esophageal cancer
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DOI：
10.1007/s00432-014-1896-8
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发表时间：
2015-08-01
影响因子：
3.6
通讯作者：
Zhong, Xueyun
中科院分区：
文献类型：
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作者：
Wang, Shaoxiang;Du, Zhan;Zhong, Xueyun
目的 热休克蛋白 90 (Hsp90) 是一种潜在的治疗靶点，在免疫缺陷小鼠体内和体外已得到广泛认可。在此，我们的目的是评估Hsp90在免疫活性小鼠食管鳞状细胞癌（ESCC）模型中的作用。方法使用致癌物4-硝基喹啉1-氧化物（4NQO）诱导C57BL/6小鼠食管鳞状细胞癌。通过外观观察、苏木精-伊红染色、免疫组化检测和末端dUTP缺口末端标记分析来分析癌症进展情况。结果4NQO导致食管癌前病变和肿瘤病变逐渐出现，仅在接触致癌物16周后原位食管癌的发生率为100%。即使在 4NQO 停药后（第 16-22 周），大多数病变也会自发演变为高度侵袭性 ESCC。有趣的是，22 周时肿瘤病变中 Hsp90 及其客户蛋白显着上调。在接下来的 2 周内，通过腹腔注射 SNX-2112 抑制 Hsp90，从而下调 AKT 和细胞周期蛋白 D1 的表达，从而显着降低肿瘤发生率并预防 ESCC 进展。此外，SNX-2112治疗降低了ESCC组织中增殖细胞核抗原的表达并增加了凋亡细胞的数量。结论我们的体内研究结果支持Hsp90对ESCC进展的贡献，这是通过刺激细胞凋亡和抑制细胞增殖来实现的，并为进一步评估用于治疗ESCC的Hsp90抑制剂提供了强有力的理论基础。
Purpose Heat shock protein 90 (Hsp90), a potential therapeutic target, has been widely recognized in vitro and in vivo in immunodeficient mice. Here, we aimed to evaluate the role of Hsp90 in an immunocompetent mouse model of esophageal squamous cell cancer (ESCC).Methods The carcinogen 4-nitroquinoline 1-oxide (4NQO) was used to induce ESCC in C57BL/6 mice. Cancer progression was analyzed through observation of appearance, hematoxylin-eosin staining, immunohistochemical detection, and terminal dUTP nick-end labeling analysis.Results 4NQO led to the progressive appearance of preneoplastic and tumoral lesions in the esophagus, with 100 % incidence of ESCC in situ occurring only after 16 weeks of carcinogen exposure. Most of these lesions evolved spontaneously into highly invasive ESCC even after 4NQO withdrawal (weeks 16-22). Interestingly, there was marked upregulation of Hsp90 and its client proteins in tumoral lesions at 22 weeks. Hsp90 inhibition by intraperitoneal injection of SNX-2112 over the following 2 weeks downregulated AKT and cyclin D1 expression, leading to significant reduction in tumor incidence and prevention of ESCC progression. Moreover, SNX-2112 treatment decreased proliferating cell nuclear antigen expression and increased the number of apoptotic cells in ESCC tissues.Conclusions Our in vivo findings support the contribution of Hsp90 to ESCC progression, which was achieved by stimulating apoptosis and inhibition of cell proliferation, and provide a strong rationale for further evaluation of Hsp90 inhibitors for treating ESCC.