核热休克蛋白 110 的表达与伴有腹膜转移的胃癌患者不良预后和高温化疗耐药相关。

Nuclear heat shock protein 110 expression is associated with poor prognosis and hyperthermo-chemotherapy resistance in gastric cancer patients with peritoneal metastasis.

机构信息

and Hiroyuki Kuwano, Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.

Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama 350-0844, Japan.

出版信息

World J Gastroenterol. 2017 Nov 14;23(42):7541-7550. doi: 10.3748/wjg.v23.i42.7541.

DOI:10.3748/wjg.v23.i42.7541

PMID:29204054

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5698247/

Abstract

AIM

To investigate the significance of heat shock protein 110 (HSP110) in gastric cancer (GC) patients with peritoneal metastasis undergoing hyperthermo-chemotherapy.

METHODS

Primary GC patients ( = 14) with peritoneal metastasis or positive peritoneal lavage cytology who underwent distal or total gastrectomy between April 2000 and December 2011 were enrolled in this study. The patients underwent postoperative intraperitoneal hyperthermo-chemotherapy using a Thermotron RF-8 heating device two weeks after surgery. We analyzed nuclear HSP110 expression in surgically resected tumors using immunohistochemistry. Additionally, the effect of HSP110 suppression on hyptherthermo-chemosensitivity was assessed in the MKN45 GC cell line using the HSP inhibitor KNK437.

RESULTS

HSP110 immnohistochemical staining in 14 GC patients showed that five (35.7%) samples belonged to the low expression group, and nine (64.3%) samples belonged to the high expression group. Progression-free survival was significantly shorter in the HSP110 high-expression group than in the low-expression group ( = 0.0313). However, no significant relationships were identified between HSP110 expression and the clinicopathological characteristics of patients. Furthermore, high HSP110 expression was not an independent prognostic factor in GC patients with peritoneal metastasis ( = 0.0625). HSP110 expression in MKN45 cells was suppressed by KNK437 at the hyperthermic temperature of 43 °C . Comparison of MKN45 cell proliferation in the presence and absence of KNK437 at 43 °C, revealed that proliferation was significantly decreased when HSP110 was inhibited by KNK437. Additionally, HSP110 suppression via HSP inhibitor treatment increased cellular sensitivity to hyperthermo-chemotherapy .

CONCLUSION

The expression of nuclear HSP110 in GC patients might be a new marker of chemosensitivity and a therapeutic target for patients who are tolerant to existing hyperthermo-chemotherapies.

摘要

目的

探讨热休克蛋白 110（HSP110）在接受热化疗的伴有腹膜转移的胃癌（GC）患者中的意义。

方法

本研究纳入了 2000 年 4 月至 2011 年 12 月期间接受远端或全胃切除术的伴有腹膜转移或阳性腹膜灌洗细胞学的原发性 GC 患者（n=14）。术后 2 周，患者使用 Thermotron RF-8 加热设备行腹腔内热化疗。我们使用免疫组织化学方法分析了手术切除肿瘤中的核 HSP110 表达。此外，我们使用 HSP 抑制剂 KNK437 在 MKN45 GC 细胞系中评估了 HSP110 抑制对低热化疗敏感性的影响。

结果

在 14 例 GC 患者中，HSP110 免疫组化染色显示，5 例（35.7%）患者属于低表达组，9 例（64.3%）患者属于高表达组。HSP110 高表达组的无进展生存期明显短于低表达组（P=0.0313）。然而，HSP110 表达与患者的临床病理特征之间没有显著关系。此外，HSP110 表达不是 GC 伴有腹膜转移患者的独立预后因素（P=0.0625）。在 43°C 的高温下，KNK437 抑制了 MKN45 细胞中的 HSP110 表达。在存在和不存在 KNK437 的情况下比较 MKN45 细胞的增殖，结果显示当 HSP110 被 KNK437 抑制时，细胞增殖明显减少。此外，通过 HSP 抑制剂治疗抑制 HSP110 表达增加了细胞对热化疗的敏感性。