Upregulation of LRIG1 suppresses malignant glioma cell growth by attenuating EGFR activity

Abstract

Activated epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target for a variety of solid tumors, particularly malignant gliomas. A recently discovered transmembrane glycoprotein, LRIG1, antagonizes the activity of epidermal growth factor receptor family receptor tyrosine kinases and acts as a negative feedback loop of EGFR and proposed tumor suppressors. The aim of this study was to investigate the impact of LRIG1 on the biological features of glioma cells and the possible mechanisms of enhanced apoptosis induced by upregulation of LRIG1. We observed that the expression of LRIG1 was decreased, while the expression of EGFR was increased in the majority of astrocytomas, and the ratio of EGFR/LRIG1 was increased by sixfold in tumors versus corresponding non-neoplastic tissue. Upregulation of LRIG1, followed by a decrease of EGFR on the cytomembrane of the cells, induced cell apoptosis and cell growth inhibition, and further reversed invasion in glioma cell lines and primary glioma cells. Our study now clearly indicates that LRIG1 indeed affects cell fate and biology behaviors of the cells in vitro by inhibiting phosphorylation of downstream MAPK and AKT signaling pathway, and the elevated release level of caspase-8 might contribute to the enhanced apoptosis in LRIG1 transfected glioma cells. Taken together, these findings provide us with an insight into LRIG1 function, and we conclude that LRIG1 evolved in gliomas as a rare feedback negative attenuator of EGFR and could offer a novel therapeutic target to treat patients with malignant gliomas.

LRIG1 Enhances Chemosensitivity by Modulating BCL-2 Expression and Receptor Tyrosine Kinase Signaling in Glioma Cells

“…LRIG1 is a negative regulator of RTKs that enhances receptor ubiquitination and degradation 15,40,41. In the resistant cell line, the expression of EGFR and c-Met increased compared to the U251 cells, and LRIG1 expression was negatively correlated with the expression of EGFR and c-Met.…”

MicroRNA-590-3p enhances the radioresistance in glioblastoma cells by targeting LRIG1

“…Previous studies have indicated that LRIG1 was frequently decreased in gliomas (21), and the expression level of LRIG1 is significantly correlated with the malignancy of glioma (21,33). It has also been reported that upregulation of LRIG1 expression suppresses malignant glioma cell growth and induces cell apoptosis (21,(34)(35)(36), whereas downregulation of LRIG1 expression promotes the proliferation and aggressive properties of glioma cells (37,38). Furthermore, previous studies have suggested that LRIG1 is associated with the regulation of chemosensitivity of human cancer cells (39,40).…”

“…Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is considered to be a tumor suppressor in various types of cancer and is frequently downregulated in gliomas (18)(19)(20)(21). Therefore, the present study elucidated whether LRIG1 is a novel direct target by which miR-590-3p exerts its effect on radiosensitivity, as LRIG1 is predicted to be a target of miR-590-3p (http://www.microrna.org/microrna/home.do) and the expression of LRIG1 is associated with radiosensitivity in human glioblastoma (22).…”

The emerging role of miR‐19 in glioma

“…Overexpression of LRIG1 suppresses U251 malignant glioma cell migration and invasion by reducing MMP2/9 level 50. Besides, LRIG1 inhibits phosphorylation of MAPK, EGFR and AKT signalling molecules and affects biological behaviours including migration and invasion by inactivation of EGFR/AKT signalling pathway 51, 52. Thus, the other alternative pathway that MiR‐19 promoting glioma migration might by directly inhibiting LRIG1 expression and indirect activation of EGFR/AKT signalling pathway.…”