Dataset Information

Low expression of SPARC in gastric cancer-associated fibroblasts leads to stemness transformation and 5-fluorouracil resistance in gastric cancer.

ABSTRACT:

Background

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.

Methods

One 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.

Results

Low 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.

Conclusions

SPARC 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.

SUBMITTER: Ma Y

PROVIDER: S-EPMC6528188 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Low expression of SPARC in gastric cancer-associated fibroblasts leads to stemness transformation and 5-fluorouracil resistance in gastric cancer.

Ma Yongchen Y Zhu Jing J Chen Shanwen S Ma Ju J Zhang Xiaoqian X Huang Sixia S Hu Jianwen J Yue Taohua T Zhang Junling J Wang Pengyuan P Wang Xin X Rong Long L Guo Hongjie H Chen Guowei G Liu Yucun Y

Cancer cell international 20190521

<h4>Background</h4>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.<h4>Methods</h4>One hundred ninety-two patients were enrolled in the present study. SPARC expression levels were evaluated by immunohistochemical staining. Primary GCAFs wer ...[more]

PMID: 31139014

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Project description:BackgroundCancer-associated fibroblasts (CAFs) play important roles in tumor progression. However, the behaviors of activated CAFs in gastric cancer remain to be determined. The aim of the present study was to investigate the correlations between activated gastric CAFs and the prognosis of patients with gastric cancer, and to determine the effects of activated CAFs on the malignant phenotype and 5-fluorouracil resistance in this cancer.MethodsNinety-five patients with primary gastric cancer were enrolled in this study. Activation states of gastric CAFs were evaluated by immunohistochemistry. A modified method for the primary culture of gastric CAFs was employed. Types of CAFs and activation states were identified by immunocytochemical and immunofluorescent staining. Cell co-culture and gastric CAF conditioned medium transfer models were established to investigate the paracrine effects of activated CAFs on the migration and invasion of gastric cell lines. The half maximal inhibitory concentration of 5-fluorouracil and levels of cell apoptosis were examined using cell viability assay and flow cytometry, respectively. Protein expression levels of associated molecules were measured by Western blotting.ResultsKaplan-Meier survival curves showed that activated gastric CAFs identified via fibroblast activation protein were significantly related to poorer cumulative survival in gastric cancer patients. Five strains of CAFs were successfully cultured via the modified culture method, and three gastric CAFs strains were identified as activated gastric CAFs. The migration and invasion abilities of gastric cells were significantly enhanced in both the co-culture group and the conditioned medium group. The half maximal inhibitory concentration for 5-fluorouracil in BGC-823 cells was elevated after treatment with conditioned medium, and early apoptosis was inhibited. Additionally, an obvious elevation of epithelial-mesenchymal transition level was observed in the conditioned medium group.ConclusionsActivated gastric CAFs correlate with a poor prognosis of cancer patients and may contribute to the malignant phenotype and the development of resistance to 5-fluorouracil via paracrine action in gastric cancer. Gastric CAFs with a specific activation state might be used as a tumor biomarker within the microenvironment for prognosis and as a new therapeutic target for chemoresistant gastric cancer.

Project description:Background: Microplastics (MPs) are a new global environmental threat. Previously, we showed the biodistribution of MPs using [64Cu] polystyrene (PS) and PET in mice. Here, we aimed to identify whether PS exposure has malignant effects on the stomach and induces resistance to therapy. Methods: BALB/c nude mice were fed 1.72 × 104 particles/mL of MP. We investigated PS accumulation in the stomach using radioisotope-labeled and fluorescent-conjugated PS. Further, we evaluated whether PS exposure induced cancer stemness and multidrug resistance, and whether it affected tumor development, tumor growth, and survival rate in vivo using a 4-week PS-exposed NCI-N87 mouse model. Using RNA-Seq analysis, we analyzed whether PS exposure induced gene expression changes in gastric tissues of mice. Results: PET imaging results showed that a single dose of [64Cu]-PS remained for 24 h in the mice stomach. The 4-week daily repetitive dose of fluorescent conjugated PS was deposited in the gastric tissues of mice. When PS was exposed, a 2.9-fold increase in migration rate was observed for NCI-N87 cells. Immunocytochemistry results showed decreased E-cadherin and increased N-cadherin expression, and flow cytometry, qPCR, and western blot analysis indicated a 1.9-fold increase in N-cadherin expression after PS exposure. Further, PS-induced multidrug resistance to bortezomib, paclitaxel, gefitinib, lapatinib, and trastuzumab was observed in the NCI-N87 mouse model due to upregulated CD44 expression. RNA-seq results identified increased asialoglycoprotein receptor 2 (ASGR2) expression after PS exposure, and ASGR2 knockdown decreased cell proliferation, migration, invasion, and drug resistance. Conclusion: We demonstrated that ASGR2 enhanced cancer hallmarks on PS exposure and induced resistance to chemo- and monoclonal antibody-therapy. Our preclinical findings may provide an incentive for further epidemiological studies on the role of MP exposure and its association with gastric cancer.

Dataset Information

Low expression of SPARC in gastric cancer-associated fibroblasts leads to stemness transformation and 5-fluorouracil resistance in gastric cancer.

Background

Methods

Results

Conclusions

Publications

Low expression of SPARC in gastric cancer-associated fibroblasts leads to stemness transformation and 5-fluorouracil resistance in gastric cancer.

Similar Datasets

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