Downregulation of LRIG2 expression inhibits angiogenesis of glioma via EGFR/VEGF-A pathway

Abstract

Active angiogenesis is the basic pathological feature of glioma. Tumor angiogenesis is involved in vascular endothelial cell migration to the tumor tissue and in the formation of tube-like structures. The present study aimed to investigate the role of leucine-rich repeats and immunoglobulin-like domains 2 (LRIG2) in glioma angiogenesis. Glioma (n=50) and normal brain (n=20) tissue samples were collected from patients to detect the expression of LRIG2, epidermal growth factor receptor (EGFR), vascular endothelial growth factor A (VEGF-A), and cluster of differentiation 31 (CD31) using immunohistochemistry. In addition, the association between the expression of LRIG2 in glioma tissue and the microvessel density (MVD) was analyzed. In vitro, the expression of LRIG2 in human glioma U87 and U251 cell lines was knocked down. Subsequently, cell migration and tube formation assays of human umbilical vein endothelial cells (HUVECs) were performed using a coculture system. The protein expression levels of LRIG2, EGFR, phosphorylated-EGFR and VEGF-A were determined using western blotting. The results demonstrated that the expression levels of LRIG2, EGFR, VEGF-A and CD31 were highly upregulated in glioma tissue samples. Furthermore, LRIG2 expression in glioma tissue samples was significantly correlated with the MVD. In vitro, the downregulation of LRIG2 inhibited HUVEC migration and tube formation induced by coculture with glioma cells. The downregulation of LRIG2 resulted in decreased expression of EGFR and VEGF-A. The effects of the LRIG2 knockdown were reversed following EGF treatment. These findings suggest that LRIG2 is a potential target for the inhibition of glioma angiogenesis, which is possibly mediated via the EGFR/VEGF-A signaling pathway.

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

“…LRIG2 promotes platelet-derived growth factor (PDGF)induced glioma and involved in the regulation of angiogenesis in glioma via the EGFR/VEGFA signaling pathway. 6,22,23 In this work, it was identified that miR-503 directly bound to LRIG2 by using Dual-Luciferase reporter assay (Figure 2A and B). Besides, the expression of LRIG2 was upregulated in cells with miR-503 inhibition and reduced in cells with miR-503 mimics transfection ( Figure 2C and D).…”

“…In addition, a series of molecular and genetic analyses have indicated that LRIG2 plays an important role in glioma through ERGF/VEGFA pathway, and the expression of LRIG2 is related to angiogenesis. 6,29 Downregulation of LRIG2 inhibits glioma cell growth by decreasing EGFR phosphorylation and VEGFA expression. 6 Our results showed that knockdown of LRIG2 could attenuate the effects of miR-503 inhibitor on glioma cell function and VEGFA expression, suggesting that knockdown of miR-503 could promote glioma proliferation, migration, and angiogenesis via targeting LRIG2 to increase VEGFA expression ( Figure 4A-D).…”

“…6,29 Downregulation of LRIG2 inhibits glioma cell growth by decreasing EGFR phosphorylation and VEGFA expression. 6 Our results showed that knockdown of LRIG2 could attenuate the effects of miR-503 inhibitor on glioma cell function and VEGFA expression, suggesting that knockdown of miR-503 could promote glioma proliferation, migration, and angiogenesis via targeting LRIG2 to increase VEGFA expression ( Figure 4A-D). These findings imply that miR-503 not only inhibits glioma proliferation, migration, and angiogenesis by directly regulating VEGFA but also repressed the above glioma function by targeting LRIG2 to regulate VEGFA expression.…”

“…5 Moreover, the reduced expression of LRIG2 can inhibit the angiogenesis of glioma cells by decreasing the expression of epidermal growth factor receptor (EGFR) as well as vascular endothelial growth factor A (VEGFA). 6 miRNAs are endogenous noncoding RNAs, consisting of 18 to 24 nucleotides, which plays inhibition or promotion effects on cell proliferation, apoptosis, differentiation, induction of angiogenesis, and activation of metastasis and invasion. 7 The recent studies have been identified that the abnormal expression of miRNAs is closely related to cell proliferation, apoptosis, and drug resistance in glioblastoma.…”

Connexin 43 Controls the Astrocyte Immunoregulatory Phenotype

“…Several pro-angiogenic markers were upregulated by Cx43KO astrocytes, such as the Netrin receptor Unc5b [ 31 ] and the leucine-rich repeats and immunoglobulin-like domains 2 protein Lrig2 [ 32 ]. We thus hypothesized that an angiogenic activity might be increased in Cx43KO brains and could modify the brain vascular network.…”