Downregulation of miRNA-214 in cancer-associated fibroblasts contributes to migration and invasion of gastric cancer cells through targeting FGF9 and inducing EMT

Abstract

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.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0995-9) contains supplementary material, which is available to authorized users.

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

“…The tumor-promoting ability of CAFs is enhanced by microRNA dysregulation [254]. CAFs stimulate EMT in gastric cancer cells in a microRNA-214-dependent manner-it induces tumor-promoting ability of CAFs through fibroblast growth factor 9 (FGF9) targeting [255,256]. Likewise, suppression of microRNA-149 (through regulation of IL-6 levels) induces EMT, promoting protumor activity of CAFs [257].…”

MicroRNA-1224-5p Inhibits Metastasis and Epithelial-Mesenchymal Transition in Colorectal Cancer by Targeting SP1-Mediated NF-κB Signaling Pathways

“…miRNAs have been reported to play crucial roles in tumor biological processes, including proliferation, apoptosis, migration, invasion, and differentiation (9). The association of non-coding RNAs especially miRNA dysregulation with the occurrence and development of cancer has been supported by evidence (10)(11)(12)(13).…”

Identification of differentially expressed miRNAs in differentiating benign from malignant pleural effusion

“…While in bladder cancer miR-182-5p can regulate the expression levels of Smad4 and RECK, and high-expression of miR-182-5p can significantly shorten the overall survival of bladder cancer patients [11]. By regulate the expression of FGF9, miR-182-5p can probably induce malignant lesions by inducing Epithelial-Mesenchymal, cell proliferation and growth of tumor cells, as various studies have identified FGF9 participate in the tumor development such as gastric cancer [28], hepatocellular carcinoma [32], NSCLC [21] and so on. All these results indicated that as an important upstream regulator, miR-182-5p participate in the biology functions related to malignant lesions development.…”