Dataset Information

Exosomal miRNA-34 from cancer-associated fibroblasts inhibits growth and invasion of gastric cancer cells in vitro and in vivo.

ABSTRACT: Gastric cancer (GC) is one of the most common malignancies worldwide manifesting high morbidity and mortality. Cancer-associated fibroblasts (CAFs), important components of the tumor microenvironment, are essential for tumorigenesis and progression. Exosomes secreted from CAFs have been reported as the critical molecule-vehicle in intercellular crosstalk. However, the precise mechanism underlying the effect of CAFs remains to be fully investigated. In this study, we aimed to determine the role of CAFs and their exosomes in the progression of GC and related mechanisms. The results revealed that miRNA-34 was downregulated in both GC fibroblasts (GCFs) and GC cell lines while the overexpression of miRNA-34 suppressed the proliferation, invasion, and motility of GC cell lines. Coculturing GC cells with miRNA-34-overexpressing GCFs led to the suppression of cancer progression. Also, exosomes derived from GCFs were taken up by GC cells in vitro and in vivo and exerted antitumor roles in GC. In addition, exosomal miRNA-34 inhibited GC cell proliferation and invasion in vitro and suppressed tumor growth in vivo. Furthermore, 16 genes were identified as potential downstream targeting genes of miRNA-34. Taken together, GCFs-derived exosomal miRNA-34 may be a promising targeting molecule for therapeutic strategies in GC.

SUBMITTER: Shi L

PROVIDER: S-EPMC7244055 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Exosomal miRNA-34 from cancer-associated fibroblasts inhibits growth and invasion of gastric cancer cells <i>in vitro</i> and <i>in vivo</i>.

Shi Liang L Wang Zhenyong Z Geng Xiuchao X Zhang Yuhao Y Xue Ziqing Z

Aging 20200510 9

Gastric cancer (GC) is one of the most common malignancies worldwide manifesting high morbidity and mortality. Cancer-associated fibroblasts (CAFs), important components of the tumor microenvironment, are essential for tumorigenesis and progression. Exosomes secreted from CAFs have been reported as the critical molecule-vehicle in intercellular crosstalk. However, the precise mechanism underlying the effect of CAFs remains to be fully investigated. In this study, we aimed to determine the role o ...[more]

PMID: 32391804

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Project description:BackgroundWe previously showed that arsenic sulfide (As4S4) induced cell cycle arrest and apoptosis in several human solid tumor cell lines, including those of gastric cancer. In this study, we investigated the effect of As4S4 on the migration and invasion of gastric cancer cells both in vitro and in vivo.MethodsThe human gastric cancer cell lines AGS and MGC803 were selected as in vitro models. Wound-healing migration assay and Transwell invasion assay were carried out to determine the effects of As4S4 on cell migration and invasion. The expressions of E-cadherin, β-catenin, Sp1, KLF4, and VEGF were measured by Western blotting analysis. The activities of matrix metalloproteinase (MMP)-2 and MMP-9 in MGC803 cells were demonstrated by zymography assay. A mouse xenograft model was established by inoculation with MGC803 cells, then intraperitoneal injected with As4S4 for 3 weeks and monitored for body weight and tumor changes. Finally, the inhibition rate of tumor growth was calculated, and the expression of proteins and genes associated with tumor invasion and metastasis in tumor tissues were measured by immunohistochemistry, Western blotting, and real-time polymerase chain reaction assay.ResultsAs4S4 significantly inhibited the migration and invasion of gastric cancer cell lines. The expression of E-cadherin and KLF4 was upregulated, while the expressions of β-catenin, VEGF, and Sp1 were downregulated following treatment with As4S4. Moreover, the protease activities of MMP-2 and MMP-9 were suppressed by As4S4 in MGC803 cells. Meanwhile, As4S4 effectively suppressed the abilities of tumor growth and invasion in the xenograft tumor model. We found that As4S4 upregulated the expression of E-cadherin and downregulated the expression of β-catenin, Sp1, VEGF, and CD34 in mouse tumor tissues, consistent with the results in vitro.ConclusionAs4S4 inhibited the migration and invasion of gastric cancer cells by blocking tumor cell adhesion, decreasing the ability of tumor cells to destroy the basement membrane, and therefore suppressing their angiogenesis.

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.

Dataset Information

Exosomal miRNA-34 from cancer-associated fibroblasts inhibits growth and invasion of gastric cancer cells in vitro and in vivo.

Publications

Exosomal miRNA-34 from cancer-associated fibroblasts inhibits growth and invasion of gastric cancer cells <i>in vitro</i> and <i>in vivo</i>.

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