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.

High SLC17A9 Expression Correlates with Poor Survival in Gastric Carcinoma

“…Evaluation of the IHC-stained slides was performed by two independent investigators who were blinded to the specimens. Results were scored by a semiquantitative method [12]. First, no staining or less than 10% of the tumor cells stained was considered negative (IHC 0).…”

Increased expression of heat shock factor 1 (HSF1) is associated with poor survival in gastric cancer patients

“…Our previous studies confirmed that HSP70/HSP90-organizing protein (HOP) could act as an oncogene by regulating malignant progression of gastric cancer, and high HOP expression predicted worse long-term outcome in GC patients [ 23 , 25 ]. HSF1 is an upstream transcription factor of HOP [ 26 ].…”

“…Paraffin-embedded GC tissues were obtained from the Department of Pathology and made into tissues microarrays for IHC staining. IHC staining was conducted as previously described [ 23 ]. The anti-HSF1 antibody (1:100, ab52757, Abcam, USA) was detected by IHC.…”

“…Cell lysates were obtained as previously described [ 23 ]. Total protein was extracted with cell lysis buffer (KeyGene, Nanjing, China), and protein concentration was quantified using an Enhanced BCA Protein Assay Kit (KeyGene, Nanjing, China).…”

The heat shock protein 70 inhibitor VER155008 suppresses the expression of HSP27, HOP and HSP90β and the androgen receptor, induces apoptosis, and attenuates prostate cancer cell growth

“…5 HSPs are potential therapeutic targets due to their overexpression in a broad tumor spectrum and have a regulatory function in tumor cell survival and expansion. 8 As HSP70 plays a critical role in cell survival in tumor cells, 9 HSP70 inhibitors are being developed. 7 The HSP70/HSP90-organizing protein (HOP) is an adaptor protein that can be secreted by cancer cells, and mediates the correct folding of heat shock protein 70 (HSP70) and HSP90.…”