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

Cancer Cell International

Long Rong¹  Jianwen Hu²  Pengyuan Wang²  Shanwen Chen²  Junling Zhang²  Taohua Yue²  Yongchen Ma²  Xin Wang²  Guowei Chen²  Ju Ma²  Yucun Liu²  Jing Zhu²  Xiaoqian Zhang²  Hongjie Guo³  Sixia Huang⁴ 

[1] 0000 0004 1764 1621, grid.411472.5, Department of Endoscopic Center, Peking University First Hospital, 100034, Beijing, People’s Republic of China;0000 0004 1764 1621, grid.411472.5, Department of General Surgery, Peking University First Hospital, 100034, Beijing, People’s Republic of China;0000 0004 1764 1621, grid.411472.5, Department of Interventional Radiology and Vascular Surgery, Peking University First Hospital, 100034, Beijing, People’s Republic of China;0000 0004 1764 1621, grid.411472.5, Department of Pathology, Peking University First Hospital, 100034, Beijing, People’s Republic of China;

关键词: SPARC;    Cancer-associated fibroblasts;    Gastric cancer;    Stemness;    Drug resistance;   

DOI  :  10.1186/s12935-019-0844-8

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY