<p>miR-503 Inhibits Proliferation, Migration, And Angiogenesis Of Glioma By Acting On VEGFA Through Targeting LRIG2</p>

Abstract

Background: Glioma is a common malignant tumor of the human central nervous system, and the pathological characteristics include invasive growth, angiogenesis, and so on. Ectopic expression of miR-503 works as a critical factor in cancer cell proliferation, migration, and capillary-like tube formation. The potential mechanisms of miR-503 in angiogenesis of glioma cells are still not reported. Methods: The expression levels of miR-503, LRIG2, and VEGFA mRNA and protein were performed by quantitative reverse transcription-PCR or Western blot assay. Dual-Luciferase reporter gene assay was used to determine the interaction between miR-503 and LRIG2. The concentration of VEGFA was measured using the ELISA method. The cell proliferation, migration, and angiogenesis of cocultured HCMEC/D3 cells were analyzed by MTT assay, transwell detection, and tube formation assay, respectively. Results: The expression levels of LRIG2 and VEGFA were reduced in glioma cells with miR-503 overexpression and enhanced with miR-503 inhibition. Moreover, cell proliferation, migration, and angiogenesis of cocultured HCMEC/D3 cells were alleviated with miR-503 mimics transfection. VEGFA and miR-503 inhibitor promoted cell proliferation, cell migration, and angiogenesis. Luciferase reporter gene assay revealed that miR-503 could directly target LRIG2. Furthermore, knockdown of LRIG2 or addition of VEGF inhibitor bevacizumab could abrogate the effect of miR-503 inhibitor on VEGFA expression, as well as the promotion of cell proliferation, migration, and angiogenesis. Conclusion: MiR-503 mediated LRIG2 suppression and regulated the expression of VEGFA, thereby reducing cell proliferation, migration, and angiogenesis of glioma cells. These results provide new insight into the action mechanism of miR-503-modulated signaling pathway in angiogenesis of glioma cells.

The Causes and Consequences of miR-503 Dysregulation and Its Impact on Cardiovascular Disease and Cancer

“…The VEGF family and FGF superfamily are regulators in angiogenesis ( Peter and Rakesh, 2011 ), VEGF (also known as VEGFA) is a predominant regulator in the process of angiogenesis, which stimulates angiogenesis via VEGF receptor-2, thus, blockers of VEGF is widely used as an anti-angiogenic agent ( Peter and Rakesh, 2011 ). In glioma cells, overexpression of miR-503 reduced both LRIG2 (Leucine-rich repeats and immunoglobulin-like domains protein 2) and VEGFA expression levels ( Sun et al, 2019 ), and suppressed angiogenesis in cocultured human cerebral microvascular endothelial cell line D3 (HCMEC/D3), while miR-503 inhibitor promoted angiogenesis in cocultured HCMEC/D3. LRIG2 was proven as miR-503 target by luciferase assay, knockdown of LRIG2 reduced VEGFA expression level along with the condition of miR-503 inhibitor, therefore, miR-503 regulated angiogenesis in glioma by reducing LRIG2 expression followed by downregulation of VEGFA expression ( Sun S. et al, 2019 ).…”

“…In glioma cells, overexpression of miR-503 reduced both LRIG2 (Leucine-rich repeats and immunoglobulin-like domains protein 2) and VEGFA expression levels ( Sun et al, 2019 ), and suppressed angiogenesis in cocultured human cerebral microvascular endothelial cell line D3 (HCMEC/D3), while miR-503 inhibitor promoted angiogenesis in cocultured HCMEC/D3. LRIG2 was proven as miR-503 target by luciferase assay, knockdown of LRIG2 reduced VEGFA expression level along with the condition of miR-503 inhibitor, therefore, miR-503 regulated angiogenesis in glioma by reducing LRIG2 expression followed by downregulation of VEGFA expression ( Sun S. et al, 2019 ). LRIG2 belongs to the leucine-rich repeats and immunoglobulin-like domains family and regulates epidermal growth factor receptor (EGFR) signaling pathway ( Simion et al, 2014 ), and downregulation of LRIG2 suppressed angiogenesis in glioma ( Yang et al, 2017 ).…”

“… Yan W. et al, (2017) reported that lncRNA MALAT1 bound to miR-503 directly as a sponge and downregulated miR-503 expression in silica-induced pulmonary fibrosis. In patients with acute MI and in rat model of myocardial I/R injury, MALAT1 was increased in peripheral blood cells ( Vausort et al, 2014 ) or myocardial tissues ( Sun T. et al, 2019 ). Our unpublished data and Varga et al’s data ( Varga et al, 2014 ) showed that miR-503 expression level was downregulated in myocardial tissues following I/R injury.…”

CircSAMD11 facilitates progression of cervical cancer via regulating miR‐503/SOX4 axis through Wnt/β‐catenin pathway

“…25 For example, Sun et al discovered that miR-503 up-regulation restrained cell growth and angiogenesis in glioma via binding to LRIG2. 26 In addition, miR-503 possessed tumoursuppressor activity in gastric cancer by combining with HMGA2 through inhibition of the WNT signalling pathway. 27 retinoblastoma via negatively regulating PTPN12.…”

Small in Size, but Large in Action: microRNAs as Potential Modulators of PTEN in Breast and Lung Cancers

“…As an explosion has been observed in research about miRNAs, not it is obvious that miRNAs are therapeutic targets in cancer therapy. As normal and cellular events are regulated by miRNAs, and complicated signaling networks comprising upstream and down-stream mediators are involved, miRNA expression disturbance is correlated with cancer development [ 48 , 49 , 50 ]. Such pathways and roles have been examined in different cancers to shed some light on the relationship between miRNA expression and cancer emergence.…”