Dataset Information

MiR-874 functions as a tumor suppressor by inhibiting angiogenesis through STAT3/VEGF-A pathway in gastric cancer.

ABSTRACT: MicroRNAs are endogenously expressed, small non-coding RNAs that regulate gene expression by targeting mRNAs for translational repression or degradation. Our previous studies indicated that miR-874 played a suppressive role in gastric cancer (GC) development and progression. However, the role of miR-874 in tumor angiogenesis and the mechanisms underlying its function in GC remained to be clarified. Here, gain- and loss-of-function assays demonstrated that miR-874 inhibited the tumor angiogenesis of GC cells in vitro and in vivo. Through reporter gene and western blot assays, STAT3 was shown to be a direct target of miR-874. Overexpression of STAT3 rescued the loss of tumor angiogenesis caused by miR-874. Conversely, the STAT3-shRNA attenuated the increased tumor angiogenesis caused by the miR-874-inhibitor. Furthermore, the levels of miR-874 were inversely correlated with those of STAT3 protein in GC tissues. Taken together, these findings indicate that down-regulation of miR-874 contributes to tumor angiogenesis through STAT3 in GC, highlighting the potential of miR-874 as a target for human GC therapy.

SUBMITTER: Zhang X

PROVIDER: S-EPMC4359318 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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miR-874 functions as a tumor suppressor by inhibiting angiogenesis through STAT3/VEGF-A pathway in gastric cancer.

Zhang Xiaoyu X Tang Jie J Zhi Xiaofei X Xie Kunling K Wang Weizhi W Li Zheng Z Zhu Yi Y Yang Li L Xu Hao H Xu Zekuan Z

Oncotarget 20150101 3

MicroRNAs are endogenously expressed, small non-coding RNAs that regulate gene expression by targeting mRNAs for translational repression or degradation. Our previous studies indicated that miR-874 played a suppressive role in gastric cancer (GC) development and progression. However, the role of miR-874 in tumor angiogenesis and the mechanisms underlying its function in GC remained to be clarified. Here, gain- and loss-of-function assays demonstrated that miR-874 inhibited the tumor angiogenesis ...[more]

PMID: 25596740

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Project description:BackgroundSpalt-like protein 4 (SALL4) is a stemness-related transcription factor whose abnormal re-expression contributes to cancer initiation and progression. However, the role of SALL4 in cancer angiogenesis remains unknown.MethodsAnalyses of clinical specimens via TCGA datasets were performed to determine the expression level and clinical significance of SALL4 in STAD (Stomach Adenocarcinoma). SALL4 knockdown, knockout, and overexpression were achieved by siRNA, CRISPR/Cas9, and plasmid transfection. The effects of conditioned medium (CM) from SALL4 knockdown or overexpression of gastric cancer cells on endothelial cell proliferation, migration, and tube formation were investigated by CCK-8 assay, transwell migration assay, and tube formation assay. The regulation of VEGF gene expression by SALL4 was studied by qRT-PCR, western blot, chromatin immunoprecipitation (ChIP) assay, and electrophoretic mobility shift assay (EMSA). Engineered exosomes from 293T cells loaded with si-SALL4-B and thalidomide were produced to test their therapeutic effect on gastric cancer progression.ResultsSALL4 expression was increased in STAD and positively correlated with tumor progression and poor prognosis. SALL4-B knockdown or knockout decreased while over-expression increased the promotion of human umbilical vein endothelial cells (HUVEC) cell proliferation, migration, and tube formation by gastric cancer cell-derived CM. Further investigation revealed a widespread association of SALL4 with angiogenic gene transcription through the TCGA datasets. Additionally, SALL4-B knockdown reduced, while over-expression enhanced the expression levels of VEGF-A, B, and C genes. The results of ChIP and EMSA assays indicated that SALL4 could directly bind to the promoters of VEGF-A, B, and C genes and activate their transcription, which may be associated with increased histone H3-K79 and H3-K4 modifications in their promoter regions. Furthermore, si-SALL4-B and thalidomide-loaded exosomes could be efficiently uptaken by gastric cancer cells and significantly reduced SALL4-B and Vascular Endothelial Growth Factor (VEGF) expression levels in gastric cancer cells, thus inhibiting the pro-angiogenic role of their derived CM.ConclusionThese findings suggest that SALL4 plays an important role in angiogenesis by transcriptionally regulating VEGF expression. Co-delivery of the functional siRNA and anticancer drug via exosomes represents a useful approach to inhibiting cancer angiogenesis by targeting SALL4/VEGF pathway.

Dataset Information

MiR-874 functions as a tumor suppressor by inhibiting angiogenesis through STAT3/VEGF-A pathway in gastric cancer.

Publications

miR-874 functions as a tumor suppressor by inhibiting angiogenesis through STAT3/VEGF-A pathway in gastric cancer.

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