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Open Access 01-12-2019 | Gastric Cancer | Primary research

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

Authors: Yongchen Ma, Jing Zhu, Shanwen Chen, Ju Ma, Xiaoqian Zhang, Sixia Huang, Jianwen Hu, Taohua Yue, Junling Zhang, Pengyuan Wang, Xin Wang, Long Rong, Hongjie Guo, Guowei Chen, Yucun Liu

Published in: Cancer Cell International | Issue 1/2019

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.

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Title: Low expression of SPARC in gastric cancer-associated fibroblasts leads to stemness transformation and 5-fluorouracil resistance in gastric cancer
Authors: Yongchen Ma
Jing Zhu
Shanwen Chen
Ju Ma
Xiaoqian Zhang
Sixia Huang
Jianwen Hu
Taohua Yue
Junling Zhang
Pengyuan Wang
Xin Wang
Long Rong
Hongjie Guo
Guowei Chen
Yucun Liu
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Gastric Cancer
Gastric Cancer
Published in: Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI: https://doi.org/10.1186/s12935-019-0844-8

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