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.
Highlights
Colorectal cancer (CRC) is a very common metastatic tumor with active angiogenesis that requires active angiogenesis
We found miR-181a were involved in angiogenesis related signaling pathway, like vascular endothelial growth factor (VEGF) and VEGFR signaling network (Supplementary Fig. 1B)
We showed that miR-181a is capable of promoting angiogenesis by directly suppressing SRCIN1 expression and promoting the SRC/VEGF pathway, leading to elevated VEGF secretion
Summary
Colorectal cancer (CRC) is a very common metastatic tumor with active angiogenesis that requires active angiogenesis. 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. Some miRNAs (miR-23a, miR-21, and the miR-17-92 cluster) promote proangiogenic activity[5,6,7], whereas some (miR-29b, miR-29c, and miR192) inhibit tumor angiogenesis[8,9,10] These authors contributed : Wu Sun, Xiaojun Wang, Jialu Li, Chaoying You. miRNAs represent a potential therapeutic target for the treatment of pathological neovascularization-related diseases because of their influence on multiple pathways[11]. A previous study showed that microRNA-181a-5p (miR-181a) can promote colorectal tumor growth and liver metastasis via the inhibition of WIF-113. The role of miR-181a in CRC angiogenesis has not yet been fully elucidated
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