Dataset Information

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

ABSTRACT:

Background

Cancer-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.

Methods

The 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.

Results

MiRNA-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?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.

SUBMITTER: Wang R

PROVIDER: S-EPMC6334467 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Wang Ruifen R Sun Yeqi Y Yu Wenwei W Yan Yu Y Qiao Meng M Jiang Ruiqi R Guan Wenbin W Wang Lifeng L

Journal of experimental & clinical cancer research : CR 20190115 1

<h4>Background</h4>Cancer-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.<h4>Methods</h4>The primary CAFs a ...[more]

PMID: 30646925

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Project description:Abstract: Background & Aims: Unusual hypervascularity is a hallmark of human hepatocellular carcinoma (HCC). Although microRNA-214 (miR-214) is upregulated in other human cancers, it is downregulated in HCC. We elucidated the biological and clinical significance of miR-214 downregulation in HCC. Methods: MicroRNAs deregulated in HCC were identified using array-based MicroRNA profiling. A luciferase reporter assay confirmed target association between miR-214 and hepatoma-derived growth factor (HDGF). Tube formation and in vivo angiogenesis assays validated the roles of miR-214/HDGF in angiogenesis. Results: MiR-214 downregulation was associated with higher tumor recurrence and worse clinical outcomes. Ectopic expression of miR-214 suppressed xenograft tumor growth and microvascularity of the tumor and its surrounding tissues. The genes downregulated by ectopic expression of miR-214 were involved in the regulation of apoptosis, cell cycle, and angiogenesis. Integrated analysis disclosed HDGF as a downstream target of miR-214. Conditioned medium of HCC cells contained bioactivity to stimulate tube formation of human umbilical vein endothelial cells, which was abolished by pretreatment of the conditioned media with HDGF antibodies, silencing of HDGF expression or ectopic expression of miR-214 in the donor HCC cells. The angiogenic activity of the conditioned media lost by ectopic expression of miR-214 in the donor cells was restored by supplementation with recombinant HDGF. In vivo tumor angiogenesis assays showed significant suppression of tumor vascularity by ectopic expression of miR-214. Conclusions: A novel role of microRNA in tumrigenesis is identified. Downregulation of miR-214 contributes to unusual hypervascularity of HCC via activation of the HDGF paracrine pathway for tumor angiogenesis. To identify miRNAs that are deregulated in human HCC, 68 HCC and 21 non-tumor liver tissues were subjected to profiling of miRNA expression using miRNA arrays containing 739 human miRNA probes. Differentially expressed microRNAs were identified.

Project description:BackgroundTumour-derived exosomes have recently been shown to participate in the formation and progression of different cancer processes, including tumour microenvironment remodelling, angiogenesis, invasion, metastasis, and drug resistance. However, the function and mechanism of exosome-encapsulated nucleic acids and proteins in bladder cancer remain unclear. This study aimed to investigate the effects of tumour-derived exosomes on the tumorigenesis and development of bladder cancer.MethodsIn this study, gene expression profiles and clinical information were collected from The Cancer Genome Atlas (TCGA) database and two independent Gene Expression Omnibus (GEO) datasets. The nucleic acids and proteins encapsulated in bladder cancer-derived exosomes were obtained from the ExoCarta database. Based on these databases, the expression patterns of exosomal mRNAs and proteins and the matched clinicopathological characteristics were analysed. Furthermore, we carried out a series of experiments to verify the relevant findings.ResultsA total of 7280 differentially expressed mRNAs were found in TCGA data, of which 52 mRNAs were shown to be encapsulated in bladder cancer-derived exosomes. Survival analysis based on the UALCAN database showed that among the top 10 upregulated and the top 10 downregulated exosomal genes, only the expression of KRT6B had a statistically significant effect on the survival of bladder cancer patients. Additionally, clinical correlation analysis showed that the elevated level of KRT6B was highly associated with bladder cancer stage, grade, and metastasis status. GSEA revealed that KRT6B was involved not only in epithelial-mesenchymal transition-related pathways but also in the immune response in bladder cancer. Ultimately, our experimental results were also consistent with the bioinformatic analysis.ConclusionKRT6B, which can be detected in bladder cancer-derived exosomes, plays an important role in the epithelial-mesenchymal transition and immune responses in bladder cancer. Further research will enable its potentially prognostic marker and therapeutic target for bladder cancer.

Dataset Information

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

Background

Methods

Results

Publications

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

Similar Datasets

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