Dataset Information

EphA2 affects the sensitivity of oxaliplatin by inducing EMT in oxaliplatin-resistant gastric cancer cells.

ABSTRACT: Erythropoietin-producing hepatocellular receptor A2 (EphA2) is upregulated in gastric cancer tissues and cells, which is accompanied by epithelial-mesenchymal transition (EMT). The current study was designed to establish the oxaliplatin-resistant human gastric cancer cell line SGC-7901/L-OHP, to determine if EMT in these cells could be reversed, and to determine if the susceptibility of these cells to oxaliplatin was affected by silencing EphA2 expression. We found that EphA2 expression levels were upregulated in gastric cancer and associated with chemotherapy sensitivity. EphA2 and the EMT molecular markers N-cadherin and Snail were upregulated in SGC-7901/L-OHP cells, while silencing of EphA2 using small interfering RNA had the opposite effect. Moreover, silencing of EphA2 inhibited cell migration and invasion, and significantly enhanced the sensitivity of oxaliplatin-resistant gastric cancer cells to oxaliplatin. These observations demonstrate that EphA2 affects the sensitivity to oxaliplatin by inducing EMT in oxaliplatin-resistant gastric cancer cells.

SUBMITTER: Wen Q

PROVIDER: S-EPMC5564621 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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EphA2 affects the sensitivity of oxaliplatin by inducing EMT in oxaliplatin-resistant gastric cancer cells.

Wen Qiaocheng Q Chen Zihua Z Chen Zhikang Z Chen Jinxiang J Wang Ran R Huang Changhao C Yuan Weijie W

Oncotarget 20170701 29

Erythropoietin-producing hepatocellular receptor A2 (EphA2) is upregulated in gastric cancer tissues and cells, which is accompanied by epithelial-mesenchymal transition (EMT). The current study was designed to establish the oxaliplatin-resistant human gastric cancer cell line SGC-7901/L-OHP, to determine if EMT in these cells could be reversed, and to determine if the susceptibility of these cells to oxaliplatin was affected by silencing EphA2 expression. We found that EphA2 expression levels w ...[more]

PMID: 28624791

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Project description:BackgroundCancer-associated fibroblasts (CAFs), one of the principal constituents of the tumor microenvironment, have a pivotal role in tumor progression. Dysregulation of microRNAs (miRNAs) in CAFs contributes to the tumor-promoting ability of CAFs. However, the mechanism underlying the involvement of miRNAs in CAFs of gastric cancer (GC) is not fully understood. This study aimed to explore the effects of miRNA-214 in CAFs on GC migration and invasion.MethodsThe primary CAFs and corresponding normal fibroblasts (NFs) were isolated. Cell counting kit-8, EdU cell proliferation staining and Transwell assays were used to determine the role of miRNA-214 in GC progression. Real-time polymerase chain reaction, Western blot analysis, and dual-luciferase reporter assay were performed to verify the target genes of miRNA-214. Immunofluorescence and Western blot analysis were applied to detect the expression of epithelial-mesenchymal transition (EMT) markers. Immunohistochemistry and in situ hybridization were implemented to analyze the fibroblast growth factor 9 (FGF9) and miRNA-214 expression in human GC tissues, respectively. Finally, to assess its prognostic relevance, Kaplan-Meier survival analysis was conducted.ResultsMiRNA-214 was significantly downregulated in CAFs of GC compared with NFs. The upregulation of miRNA-214 in CAFs inhibited GC cell migration and invasion in vitro but failed to affect proliferation. Moreover, GC cells cultured with conditioned medium from CAFs transfected with miR-214 mimic showed increased expression of E-cadherin and decreased expression of Vimentin, N-cadherin and Snail, indicating the suppression of EMT of GC cells. Furthermore, FGF9 was proved to be a direct target gene of miR-214. The expression of FGF9 was higher in CAFs than that in tumor cells not only in primary tumor but also in lymph node metastatic sites (30.0% vs 11.9%, P < 0.01 and 32.1% vs 12.3%, P < 0.01, respectively). Abnormal expression of FGF9 in CAFs of lymph node metastatic sites was significantly associated with poor prognosis in patients with GC (P < 0.05).ConclusionsThis study showed that miR-214 inhibited the tumor-promoting effect of CAFs on GC through targeting FGF9 in CAFs and regulating the EMT process in GC cells, suggesting miRNA-214/FGF9 in CAFs as a potential target for therapeutic approaches in GC.

Project description:Objective A significant proportion of patients can not benefit from neoadjuvant chemotherapy (NCT) due to drug resistance. Cancer-associated fibroblasts (CAFs) influence many biological behaviours of tumors, including chemo-resistance. This study aims to explore whether CAFs expressing FAP, CD10, and GPR77 affect the efficacy of NCT and the prognosis of patients with gastric cancer, and its mechanism. Methods One hundred seventy-one patients with locally progressive gastric adenocarcinoma who had undergone NCT and radical surgery were collected. Immunohistochemistry was used to detect the expression of FAP, CD10, and GPR77 in CAFs; the EMT markers (N-cadherin, Snail1, and Twist1) and the CSC markers (ALDH1, CD44, and LGR5) in gastric cancer cells. The χ2 test was used to analyze the relationship between the expression of CAF, EMT, and CSC markers and the clinicopathological factors, as well as the relationship between CAF markers and EMT, and CSC markers. Logistic regression and Cox risk regression were used to analyze the relationship between the expression of CAF, EMT, and CSC markers and TRG grading and OS; Kaplan-Meier analysis was used for survival analysis and plotting the curves. Results The expression of CAF markers FAP, CD10, and GPR77 was closely associated with that of EMT markers; FAP and CD10 were closely related to CSC markers. In the univariate analysis of pathological response, CAF markers (FAP, CD10, GPR77), EMT markers (N-cadherin, Snail1, Twist1), and CSC markers (ALDH1, LGR5, CD44), were all closely associated with pathological response (all p < 0.05). Only Twist1 was an independent factor affecting pathological response in multifactorial analysis (p = 0.001). In a univariate analysis of OS, expression of FAP and CD10 in CAF, as well as expression of EMT biomarkers (N-cadherin, Snail1), were significant factors influencing patient prognosis (all p < 0.05). Multifactorial analysis revealed N-cadherin (p = 0.032) and Snail1 (p = 0.028), as independent prognostic factors affecting OS. Conclusion FAP, CD10, and GPR77 labeled CAF subgroup may lead to NCT resistance and poor prognosis by inducing EMT and CSC of gastric cancer cells in locally advanced gastric cancer patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-023-11011-0.

Dataset Information

EphA2 affects the sensitivity of oxaliplatin by inducing EMT in oxaliplatin-resistant gastric cancer cells.

Publications

EphA2 affects the sensitivity of oxaliplatin by inducing EMT in oxaliplatin-resistant gastric cancer cells.

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