HSP70/HSP90-Organizing Protein Contributes to Gastric Cancer Progression in an Autocrine Fashion and Predicts Poor Survival in Gastric Cancer
HSP70/HSP90-Organizing Protein Contributes to Gastric Cancer Progression in an Autocrine Fashion and Predicts Poor Survival in Gastric Cancer
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HSP70/HSP90 组织蛋白以自分泌方式促进胃癌进展并预测胃癌的不良生存
DOI：
10.1159/000490080
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Peng, Sui
中科院分区：
文献类型：
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作者：
Zhai, Ertao;Liang, Wei;Peng, Sui
背景/目的：HSP70/HSP90组织蛋白(HSP70/HSP90-Organing Protein，HOP)是一种介导热休克蛋白70(HSP70)和HSP90折叠的接头蛋白。HOP可由癌细胞分泌，并以自分泌方式促进恶性细胞生长。在这里，我们研究了它在胃癌(GC)中的作用。方法：采用实时定量聚合酶链式反应和免疫印迹法分别检测HOP基因和蛋白的表达水平，采用酶联免疫吸附试验检测血清HOP水平。采用免疫组织化学方法检测117例胃癌组织和32例癌旁正常组织中HOP的表达。采用细胞计数Kit-8细胞存活率分析、流式细胞术和Western blotting等方法分析HOP对细胞增殖和凋亡的影响及其可能的机制。结果：胃癌组织中HOP基因和蛋白的表达水平显著高于本中心正常组织(P<；0.001)和肿瘤基因组图谱数据库(P<；0.001)。胃癌患者血清HOP水平高于年龄匹配的健康对照组(P<；0.001)；然而，一旦肿瘤切除，血清HOP水平显著下降(P<；0.01)。在人的胃癌组织中，HOP表达增加与肿瘤进展和生存不良有关。值得注意的是，自分泌HOP通过磷脂酶Cγ1-细胞外信号调节激酶1/2依赖的途径促进细胞增殖，并通过调节caspase9、caspase3和B细胞淋巴瘤2的活性抑制细胞凋亡。用中和抗体阻断细胞外HOP抑制GC细胞的增殖，增强氟尿嘧啶诱导的细胞凋亡。结论：HOP是胃癌的重要分子标志物和预后因子，对肿瘤细胞的生长和存活具有重要作用。这些结果为考虑将HOP作为潜在的治疗靶点和GC的化学增敏剂提供了理论依据。
Background/Aims: HSP70/HSP90-organizing protein (HOP) is an adaptor protein that mediates heat shock protein 70 (HSP70) and HSP90 folding. HOP can be secreted by cancer cells and promote malignant cell growth in an autocrine manner. Here, we studied its role in gastric cancer (GC). Methods: HOP mRNA and protein levels were detected by quantitative real-time PCR and western blotting, respectively, and enzyme-linked immunosorbent assay was used to determine the serum levels. Immunohistochemistry was performed to analyze HOP expression in 117 GC tissues and 32 adjacent normal tissues. The Cell Counting Kit-8 cell viability assay, flow cytometry, and western blotting were used to analyze the effects of HOP on cell proliferation and apoptosis, and the potential underlying mechanisms. Results: HOP mRNA and protein levels were significantly higher in GC tissues than in normal tissues in our medical center (P< 0.001) and in The Cancer Genome Atlas database (P< 0.001). GC patients had higher serum levels of HOP than age-matched healthy controls (P< 0.001); however, once tumors were removed, serum levels significantly decreased (P< 0.01). In human GC tissues, increased HOP expression was associated with tumor progression and poor survival. Notably, autocrine HOP promoted cell proliferation through the phospholipase Cγ1-extracellular signal-regulated kinase 1/2-dependent pathway, and inhibited cell apoptosis by regulating the activities of caspase 9, caspase 3, and B-cell lymphoma 2. Blocking extracellular HOP with neutralizing antibody reduced proliferation and enhanced fluorouracil-induced apoptosis of GC cells. Conclusions: Our findings demonstrate that HOP is an important molecular marker and prognostic factor for GC, and functionally contributes to tumor cell growth and survival. These results provide a rationale for considering HOP as a potential therapeutic target and chemosensitizer in GC.