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MicroRNA-181a promotes angiogenesis in colorectal cancer by targeting SRCIN1 to promote the SRC/VEGF signaling pathway.

ABSTRACT: Colorectal cancer (CRC) is a very common metastatic tumor with active angiogenesis that requires active angiogenesis. Recently, increased microRNA-181a-5p (miR-181a) expression was found to be significantly associated with liver metastasis and poor outcome in CRC patients. In this study, the role of miR-181a in tumor angiogenesis was further investigated. Capillary tube formation assays were used to demonstrate the ability of miR-181a to promote tumor angiogenesis. Bioinformatics analyses identified SRC kinase signaling inhibitor 1 (SRCIN1) as a potential target of miR-181a. Next, two CRC cell lines (HT29 and SW480) were used to clarify the function of miR-181a through SRCIN1 targeting. In addition, the biological effects of SRCIN1 inhibition by miR-181a were examined in vitro by quantitative RT-PCR, western blotting and enzyme-linked immunosorbent assay and in vivo by Matrigel plug angiogenesis assays and immunohistochemical staining. In clinical samples, Fluorescence in situ hybridization and immunofluorescence were performed to detect the relation between miR-181a and SRCIN1. In addition, SRCIN1 protein and miR-181a expression levels in CRC tissues were also measured by western blot and quantitative real-time polymerase chain reaction. MiR-181a markedly augmented the capability of CRC cells to advance tube formation in endothelial cells in vitro. The Matrigel plug assay showed that miR-181a promoted angiogenesis in vivo. In conclusion, miR-181a inhibited SRCIN1, which caused SRC to transform from an inactive status to an active conformation and to trigger vascular endothelial growth factor secretion, leading to increased angiogenesis. MiR-181a dysregulation contributes to angiogenesis in CRC, and downregulation of miR-181a represents a promising, novel strategy to achieve an efficient antiangiogenic response in anti-CRC therapy.

SUBMITTER: Sun W

PROVIDER: S-EPMC5941226 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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MicroRNA-181a promotes angiogenesis in colorectal cancer by targeting SRCIN1 to promote the SRC/VEGF signaling pathway.

Sun Wu W Wang Xiaojun X Li Jialu J You Chaoying C Lu Pan P Feng Huijin H Kong Yan Y Zhang Haiyang H Liu Yanqing Y Jiao Ruihua R Chen Xi X Ba Yi Y

Cell death & disease 20180401 4

Colorectal cancer (CRC) is a very common metastatic tumor with active angiogenesis that requires active angiogenesis. Recently, increased microRNA-181a-5p (miR-181a) expression was found to be significantly associated with liver metastasis and poor outcome in CRC patients. In this study, the role of miR-181a in tumor angiogenesis was further investigated. Capillary tube formation assays were used to demonstrate the ability of miR-181a to promote tumor angiogenesis. Bioinformatics analyses identi ...[more]

PMID: 29739921

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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

MicroRNA-181a promotes angiogenesis in colorectal cancer by targeting SRCIN1 to promote the SRC/VEGF signaling pathway.

Publications

MicroRNA-181a promotes angiogenesis in colorectal cancer by targeting SRCIN1 to promote the SRC/VEGF signaling pathway.

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