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.
Highlights
Glioblastoma (World Health Organization [WHO] grade IV) is a type of highly malignant brain tumor associated with high mortality, and has a median overall survival of 14.5–16.6 months [1]
Our previous study demonstrated that LRIG3 could modulate the proliferation, apoptosis, and invasion of glioma cells and functions as a tumor suppressor by attenuating the epidermal growth factor receptor (EGFR) signaling pathway [19]
Representative images of LRIG3 IHC staining from different grade gliomas are shown in Figure 1A, while the representative images of HE, GFAP, Iba-1, CD163, and CD31 of each grade glioma are shown in Figure S1 demonstrating that LRIG3 is mainly stained on the glial cells and low grade glioma cells
Summary
Glioblastoma (World Health Organization [WHO] grade IV) is a type of highly malignant brain tumor associated with high mortality, and has a median overall survival of 14.5–16.6 months [1]. Even low-grade gliomas (LGGs; WHO grades I and II), most are inevitably recur and eventually progress to highgrade gliomas (HGGs; WHO grades III and IV [glioblastoma]) [2]. Despite various salvage therapies (maximal safe resection, followed by radiochemotherapy and targeted therapy), once tumor progression occurs, the majority of patients succumb to the disease within 2 years of diagnosis [3]. Multiple alterations in the expression level of genes and/or proteins have been identified in glioblastomas, including activation of oncogenes and/or silencing of tumor-suppressor genes [4]. Many of them have been used as therapeutic targets and have their limitations in therapeutic applications [4]. Further research is urgently needed to identify novel biomarkers for glioma, which can be used for screening high-risk patients, predicting prognosis, and application as a therapeutic target or agent
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