Abstract
BackgroundThe aim of the present study was to clarify the correlations between SPARC expression in gastric cancer-associated fibroblasts (GCAFs) and the prognosis of patients with gastric cancer and to elucidate the role of GCAF-derived SPARC in stemness transformation and 5-fluorouracil resistance in gastric cancer.MethodsOne hundred ninety-two patients were enrolled in the present study. SPARC expression levels were evaluated by immunohistochemical staining. Primary GCAFs were obtained and cultured from cancer patients for in vitro study, and a lentivirus infection method was employed to knock down SPARC expression in GCAFs. The stemness phenotype and 5-fluorouracil (5-FU) response of gastric cancer cells were assessed via a 3D co-culture model. The apoptotic status and stemness alterations were monitored by flow cytometry and western blotting. Additionally, label-free quantification proteomics was used to identify the differentially expressed proteins and potential pathways in gastric cancer cells treated with GCAF-derived SPARC.ResultsLow expression of GCAF-derived SPARC was associated with decreased differentiation and reduced 5-year overall survival and was an independent predictive factor for prognosis in gastric cancer. The 3D tumour growth and 5-FU resistance abilities of gastric cancer cells were elevated after treatment with GCAFs with SPARC knockdown relative to these abilities in negative control cells. Additionally, suppressing SPARC expression in GCAFs facilitated the phenotypic alteration of gastric cancer cells towards CD44+/CD24− cancer stem cell (CSC)-like cells. Quantification proteomics analysis revealed that the differentially expressed proteins in gastric cancer cells were mainly involved in the AKT/mTOR and MEK/ERK signalling pathways.ConclusionsSPARC expression in GCAFs is a useful prognostic factor in patients with gastric cancer. Low expression of GCAF-derived SPARC can lead to CSC transformation and 5-FU resistance. Additionally, the AKT/mTOR and MEK/ERK signalling pathways may participate in the malignant process.
Highlights
The aim of the present study was to clarify the correlations between Secreted protein acidic and rich in cysteine (SPARC) expression in gastric cancer-associated fibroblasts (GCAFs) and the prognosis of patients with gastric cancer and to elucidate the role of GCAF-derived SPARC in stemness transformation and 5-fluorouracil resistance in gastric cancer
Chen et al [7] found that SPARC was mainly expressed in gastric cancer-associated fibroblasts (GCAFs) and that the low expression level of SPARC in gastric cancer cells may be due to aberrant methylation of the SPARC gene promoter
We investigated the correlations between clinicopathological features and both GCAF-derived SPARC and cancer cell-derived SPARC (Table 1)
Summary
The aim of the present study was to clarify the correlations between SPARC expression in gastric cancer-associated fibroblasts (GCAFs) and the prognosis of patients with gastric cancer and to elucidate the role of GCAF-derived SPARC in stemness transformation and 5-fluorouracil resistance in gastric cancer. The resistance of gastric cancer to chemotherapeutic drugs partially accounts for the failure of radical and palliative treatment, which leads to poor prognosis. The mechanisms underlying this phenomenon mainly include the efflux function of ATPbinding cassette membrane transporters, autophagy, and cancer stem cells (CSCs), which participate in many resistance processes [2, 3]. Chen et al [7] found that SPARC was mainly expressed in gastric cancer-associated fibroblasts (GCAFs) and that the low expression level of SPARC in gastric cancer cells may be due to aberrant methylation of the SPARC gene promoter
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