HSP70/HSP90-Organizing Protein Contributes to Gastric Cancer Progression in an Autocrine Fashion and Predicts Poor Survival in Gastric Cancer.

Abstract

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.

• Authors: Ertao Zhai, Wei Liang, Yi Lin, Linlin Huang, Xin He, Shirong Cai, Jianhui Chen, Ning Zhang, Jiali Li, Qiuyang Zhang, Yulong He, Zhirong Zeng, Minhu Chen, Lixia Xu, Sui Peng
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 47 Issue 2 Pg. 879-892 ( 2018) ISSN: 1421-9778 [Electronic] Germany
• PMID: 29843139 (Publication Type: Journal Article)
• Copyright: © 2018 The Author(s). Published by S. Karger AG, Basel.

Chemical References

• HSP70 Heat-Shock Proteins
• HSP90 Heat-Shock Proteins
• Proto-Oncogene Proteins c-bcl-2
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Phospholipase C gamma
• Caspases
• Fluorouracil

Topics

• Apoptosis (drug effects)
• Autocrine Communication (drug effects)
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Databases, Genetic
• Drug Resistance, Neoplasm (drug effects)
• Female
• Fluorouracil (pharmacology)
• HSP70 Heat-Shock Proteins (blood, genetics, metabolism)
• HSP90 Heat-Shock Proteins (blood, genetics, metabolism)
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Phospholipase C gamma (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Stomach Neoplasms (metabolism, mortality, pathology)