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

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

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 (n = 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 vitro 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 (P = 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 (P = 0.0625). HSP110 expression in MKN45 cells was suppressed by KNK437 at the hyperthermic temperature of 43 °C in vitro. 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 in vitro.

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.

Keywords: Drug resistance; Gastric cancer; Heat shock protein 110; Hyperthermia; Hyperthermo-chemotherapy; Peritoneal metastasis.

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Benzhydryl Compounds
  • Cell Line, Tumor
  • Cisplatin / administration & dosage
  • Drug Resistance, Neoplasm*
  • Female
  • HSP110 Heat-Shock Proteins / antagonists & inhibitors
  • HSP110 Heat-Shock Proteins / metabolism*
  • Humans
  • Hyperthermia, Induced
  • Male
  • Middle Aged
  • Peritoneal Neoplasms / drug therapy
  • Peritoneal Neoplasms / secondary*
  • Peritoneum / pathology
  • Pyrrolidinones
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / pathology

Substances

  • Antineoplastic Agents
  • Benzhydryl Compounds
  • HSP110 Heat-Shock Proteins
  • HSPH1 protein, human
  • KNK 437
  • Pyrrolidinones
  • Cisplatin