The Prognostic and Therapeutic Potential of LRIG3 and Soluble LRIG3 in Glioblastoma

Abstract

Glioblastoma is a highly lethal type of primary brain tumor that exhibits unrestricted growth and aggressive invasion capabilities, leading to a dismal prognosis despite a multitude of therapies. Multiple alterations in the expression level of genes and/or proteins have been identified in glioblastomas, including the activation of oncogenes and/or silencing of tumor-suppressor genes. Nevertheless, there are still no effective targeted therapies associated with these changes. In this study, we investigated the expression of human leucine-rich repeats and immunoglobulin-like domains protein 3 (LRIG3) in human glioma specimens through immunohistochemical analysis. The results showed that LRIG3 was weakly expressed in high-grade gliomas (WHO [World Health Organization] grades III and IV) compared with that in low-grade gliomas (WHO grade II). Survival analysis of these patients with glioma indicated that LRIG3 is an important prognostic marker for better survival. Moreover, we confirmed the existence of soluble ectodomain of LRIG3 (sLRIG3) in the cell culture supernatant, serum, and in tumor cystic fluid of patients with glioma. Molecular mechanistic investigation demonstrated that both LRIG3 and sLRIG3 inhibit the growth and invasion capabilities of GL15, U87, and PriGBM cells and tumor xenografts in nude mice through regulating the MET/phosphatidylinositol 3-kinase/Akt signaling pathway. Enzyme-linked immunosorbent assay confirmed the positive correlation between serum sLRIG3 protein levels and overall survival time in patients with high-grade gliomas. Taken together, our data for the first time demonstrate the existence of sLRIG3 and that both LRIG3 and sLRIG3 are potent tumor suppressors, which could be used as prognostic markers for better overall survival and therapeutic agents for glioblastoma.

LRIG3 Suppresses Angiogenesis by Regulating the PI3K/AKT/VEGFA Signaling Pathway in Glioma

“…On the contrary, LRIG2 interacts with EGFR directly and promotes activation of the downstream signaling pathway (29). Besides, LRIG3 can inhibit activation of the Ras/ ERK and PI3K/AKT pathways in glioma, indicating that LRIG3, similar to LRIG1, may have an antagonistic effect against LRIG2 (13,14). Moreover, Zeng et al showed that LRIG3 is required for the interaction between Dual-specificity phosphatase 6 (DUSP6) and ERK in colorectal cancer.…”

“…Immunohistochemical assays were performed on glioma and mouse xenograft tumor tissues as previously described ( 14 ). Expression levels of labeling were stratified and scored according to the following grading system: staining extensity was categorized as 1 (≤ 10% positive cells), 2 (< 10% and ≤ 30% positive cells), 3 (< 30 and ≤ 50% positive cells) or 4 (> 50% positive cells), whereas staining intensity was categorized as 0 (negative), 1 (weak), 2 (moderate) or 3 (strong).…”

“…LRIG3 was the last gene to be discovered in this family and is frequently downregulated in human cancers (10)(11)(12). In fact, LRIG3 acts as a tumor suppressor in GBM, where it modulates proliferation, migration, and invasion of glioma cells by targeting the EGFR and MET signaling pathways (13,14). Moreover, LRIG3 expression is significantly higher in low-grade gliomas than in high-grade gliomas (grades III and IV), and LRIG3 upregulation suggests a better prognosis in malignant glioma patients (14).…”

“…In fact, LRIG3 acts as a tumor suppressor in GBM, where it modulates proliferation, migration, and invasion of glioma cells by targeting the EGFR and MET signaling pathways ( 13 , 14 ). Moreover, LRIG3 expression is significantly higher in low-grade gliomas than in high-grade gliomas (grades III and IV), and LRIG3 upregulation suggests a better prognosis in malignant glioma patients ( 14 ). However, the actual molecular mechanisms underlying LRIG3’s role in angiogenesis are poorly understood.…”

LRIG3 represses cell motility by inhibiting slug via inactivating ERK signaling in human colorectal cancer

“…Hellström et al reported that LRIG3 was lowly expressed in adult mouse hearts and influenced heart function and plasma lipid levels . In cancer, LRIG3 was shown to be significantly decreased in cervical squamous cell carcinoma and glioblastoma . However, the expression level, biological function, and clinical implication of LRIG3 in CRC remain unknown.…”