Vasodilator-stimulated phosphoprotein (VASP), a novel target of miR-4455, promotes gastric cancer cell proliferation, migration, and invasion, through activating the PI3K/AKT signaling pathway

Abstract

BackgroundMicroRNAs (miRNAs) are small non-coding RNAs which play important roles in the carcinogenesis of gastric cancer (GC). Expression profiling of miRNAs in paired gastric cancer and adjacent normal gastric tissues has demonstrated that miR-4455 is down-regulated in gastric cancer tissues, but its functional role in the carcinogenesis of GC had not previously been investigated.AimsThe purpose of this study was to investigate the functional and biological mechanisms of miR-4455 in the progression of GC, in vitro.MethodsExpression of miR-4455 was compared in human GC tissue samples and paired adjacent normal tissue samples. The in vitro effects of miR-4455 expression in MGC-803 cells on their proliferation, invasion, and migration were assessed by MTT assays and 5-bromo-2′-deoxyuridine staining, matrigel-invasion analysis and wound healing assays. Bioinformatics analysis (using PicTar, target scan and miRBase target) was used to identify potential targets for miR-4455, and the luciferase reporter assay, qRT-PCR and Western-blotting analyses were used to confirm VASP as the target of miR-4455. In addition, the effects of downregulation of VASP on the activation of PI3K/AKT signaling pathway were measured using Western-blot analysis.ResultsThe expression of miR-4455 was markedly down-regulated in gastric cancer tissues vs. adjacent normal tissues, and miR-4455 expression inhibited the proliferation, invasion and migration of MGC-803 GC cells in vitro. Luciferase reporter assays revealed that miR-4455 inhibited VASP expression by targeting the 3′-UTR sequence of VASP. Furthermore, silencing of VASP markedly inhibited the activation of the PI3K/AKT signaling pathway.ConclusionOur results suggest that miR-4455 functions as a tumor suppressor in gastric cancer, by targeting VASP leading to activation of the PI3K/AKT signaling pathway and the inhibition of VASP mediated proliferation, migration and invasion of gastric cancer cells.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0573-4) contains supplementary material, which is available to authorized users.

Impaired miRNA degradation by post-transcriptional addition of 3’ cytosine and adenine in T cell activation

“…Consistently, miR-4455 increased apoptosis and reduced proliferation, invasion and migration in a gastric cancer cell line (MGC-803) (Chen et al 2018). MiR-4455 targets VASP 3'-UTR and a decrease in VASP levels results in PI3K/AKT inhibition (Chen et al 2018). VASP is a key mediator of actin cytoskeleton remodeling, polarization and cell migration (Krause et al 2003;Bailly 2004).…”

miRNAs as potential biomarkers for the progression of gastric cancer inhibit CREBZF and regulate migration of gastric adenocarcinoma cells

“…miR-99b-5p/203a-3p and miR-99b-5p/203a-3p may function as tumor suppressive miRNAs by negatively regulating IGF-1R expression in GC cells [15]. miR-4455 functions as a tumor suppressor in GC by targeting VASP, leading to the activation of the PI3K/AKT signaling pathway and inhibition of VASP-mediated proliferation, migration, and invasion of GC cells [16]. miR-23a/27a/24-2 cluster may mediate the progression of GC through the suppression of SOCS6 expression [17].…”

Cytoskeletal Remodeling in Cancer

“…Wang et al showed that miRNA-610 inhibits the invasion of gastric cancer cells by suppressing the expression of VASP, which could be used therapeutically to inhibit gastric cancer progression and metastasis [238]. VASP is inhibited by miR-4455 functions as a tumor suppressor in gastric cancer cells which decreased VASP-mediated proliferation, migration, and invasion [239]. In hepatocellular carcinoma (HCC) hypoxia upregulated VASP by binding to hypoxia response elements (HRE) in the VASP promoter region.…”