LRIG2 promotes the proliferation and cell cycle progression of glioblastoma cells in vitro and in vivo through enhancing PDGFRβ signaling

Abstract

The leucine-rich repeats and immunoglobulin-like domains (LRIG) gene family, comprising LRIG1, 2 and 3, encodes integral membrane proteins. It has been well established that LRIG1 negatively regulates multiple growth factor signaling pathways and is considered to be a tumor suppressor; however, the biological functions of LRIG2 remain largely unexplored. It was previously demonstrated that LRIG2 positively regulates epidermal growth factor receptor (EGFR) signaling, the most common aberrant receptor tyrosine kinase (RTK) signaling in glioblastoma multiforme (GBM), which promotes GBM growth. In the present study, the effect of LRIG2 on the proliferation of GBM cells was further addressed, as well as the possible mechanisms underlying the regulatory effect of LRIG2 on platelet-derived growth factor receptor β (PDGFRβ) signaling, another common oncogenic RTK signaling pathway in GBM. First, the expression levels of endogenous LRIG2 and PDGFRβ were found to vary notably in human GBM, and the LRIG2 expression level was positively correlated with the expression level of PDGFRβ. Furthermore, to the best of our knowledge, this is the first study to demonstrate that LRIG2 promoted the PDGF-BB-induced proliferation of GBM cells in vitro and in vivo through regulating the PDGFRβ signaling-mediated cell cycle progression. Mechanistically, LRIG2 has the ability to physically interact with PDGFRβ, promoting the total expression and the activation of PDGFRβ, and enhancing its downstream signaling pathways of Akt and signal transducer and activator of transcription 3 and the effectors of key regulators of cell cycle progression, resulting in increased GBM cell proliferation. Collectively, these data indicated that LRIG2 may serve as a tumor promoter gene in gliomagenesis by positively regulating PDGFRβ signaling, another important oncogenic RTK signaling pathway, in addition to the previously reported EGFR signaling in GBM modulated by LRIG2, and validated LRIG2 as a promising therapeutic target for the treatment of GBM characterized by multiple aberrant RTK signaling.

The transmembrane protein LRIG2 increases tumor progression in skin carcinogenesis

“…LRIG2 expression correlates with poor prognosis in SCC of the cervix and uterus, which show increased LRIG2 RNA levels (Hedman et al , ). It has also been shown that LRIG2 promotes EGFR signaling as a positive feedback loop in glioblastoma cells, supporting the hypothesis that LRIG2 is acting as an oncoprotein (Wang et al , ; Xiao et al , ; ). Importantly, although it is known that LRIG proteins can promote and suppress tumor growth in a tissue‐specific manner (Hedman and Henriksson, ), the molecular mechanisms and their impact on tumorigenesis in the skin are mostly unknown.…”

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

“…LRIG1, negatively regulates several receptor tyrosine kinase (RTK) signaling pathways and is associated with a better prognosis in many cancers (7–10). LRIG2 acts as a tumor promoter, stimulating proliferation and inhibiting apoptosis of glioma cells (11, 12). Several studies have shown that soluble LRIG1 (sLRIG1) and soluble LRIG2 (sLRIG2) have similar functions as their corresponding full-length proteins (11, 13, 14).…”

Expanding the HPSE2 Genotypic Spectrum in Urofacial Syndrome, A Disease Featuring a Peripheral Neuropathy of the Urinary Bladder

“…In this context, an interaction with heparanase-1 is possible because this protein is also detected in pelvic ganglia ( Stuart et al, 2015 ) and, at least in rat phaeochromocytoma cells, heparanase-1 modulates neuritogenesis ( Cui et al, 2011 ). Of note, cell biology experiments implicate LRIG2 in axon guidance ( van Erp et al, 2015 ) and in controlling cell turnover in neural tumour cells ( Xiao et al, 2018 ). Further experiments are now required to determine the possible effects of LRIG2 on bladder nerve precursor cells.…”