Qungen Xiao

Downregulation of LRIG1 expression by RNA interference promotes the aggressive properties of glioma cells via EGFR/Akt/c-Myc activation

The LRIG1 [leucine-rich repeats and immunoglobulin-like domains (LRIG)] gene is not universally downregulated in human cancers, and its role in tumorigenesis and the development of glioma has not been well addressed. In this study, we used short hairpin RNA (shRNA)-triggered RNA interference (RNAi) to block LRIG1 gene expression in the GL15 human glioma cell line. Specific downregulation of LRIG1 by shRNA resulted in significantly enhanced capabilities of proliferation, inhibition of apoptosis and invasion in the GL15 cells. LRIG1 repression induced marked activation of epidermal growth factor receptor (EGFR), protein kinase B (Akt) and c-Myc signaling molecules. Our results demonstrated that RNAi against LRIG1 may effectively downregulate LRIG1 gene expression. LRIG1 functions as a tumor suppressor in the pathogenesis of glioma via EGFR/Akt/c-Myc activation.

A role for LRIG1 in the regulation of malignant glioma aggressiveness

The molecular mechanisms that drive the development and aggressive progression of malignant astrocytic tumors remain obscure. Recently, in the search for endogenous negative regulators of EGF receptor, LRIG1 was cloned and characterized as a putative tumor suppressor gene often downregulated in various human tumors, including astrocytic tumors. Although several studies have implicated the function of LRIG1 in the inhibition of tumorigenesis, its precise role and potential underlying mechanisms remain obscure. Therefore, we generated a full-length expression vector to overexpress LRIG1 in the U251 malignant glioma cell line. Introduction of exogenous LRIG1 into glioma cells inhibited cell proliferation manifested by MTT and soft agar clone assay in vitro and subcutaneously tumor xenografts. On the other hand, LRIG1 overexpression inhibited glioma growth by significantly changing the expression pattern of cyclins, resulting in delayed cell cycle. Employing transwell invasion and wound scratch assay and gelatin zymography, LRIG1 inhibited U-251 MG cell invasion and migration by attenuating MMP2 and MMP9 production. Under ligand-stimulated conditions, p-ERK levels did not change, whereas p-AKT levels were inhibited in cells with LRIG1 upregulation, indicating that LRIG1 exerts more inhibiting effects on the PI3K/AKT pathway. Our findings suggest that LRIG1 restricted glioma aggressiveness by inhibiting cell proliferation, migration and invasion. Restoration of LRIG1 to glioma cells could offer a novel therapeutic strategy.

Comparison of Pituitary Adenomas in Elderly and Younger Adults: Clinical Characteristics, Surgical Outcomes, and Prognosis.

To analyze and summarize the clinical characteristics, surgical outcomes, and prognosis of elderly adults with pituitary adenomas (PAs).

Soluble LRIG2 ectodomain is released from glioblastoma cells and promotes the proliferation and inhibits the apoptosis of glioblastoma cells in vitro and in vivo in a similar manner to the full-length LRIG2.

The human leucine-rich repeats and immunoglobulin-like domains (LRIG) gene family contains LRIG1, 2 and 3, encoding integral membrane proteins with an ectodomain, a transmembrane domain and a cytoplasmic tail. LRIG1 negatively regulates multiple receptor tyrosine kinases signaling including the epidermal growth factor receptor (EGFR) and is a proposed tumor suppressor. The soluble LRIG1 ectodomain is demonstrated to be shed naturally and inhibit the progression of glioma. However, little is known regarding the functions of LRIG2. In oligodendroglioma, LRIG2 expression is associated with poor survival, suggesting that LRIG2 might have different functions compared with LRIG1. Since soluble LRIG1 ectodomain has a similar function to the full-length LRIG1, we hypothesize that the different roles exerted by LRIG2 and LRIG1 result from the difference of their ectodomains. Here, we addressed the functions of LRIG2 and LRIG2 ectodomain in the proliferation and apoptosis of glioma and the possible underlying mechanisms. Firstly, we found that LRIG2 expression levels positively correlated with the grade of glioma. Further, we demonstrated for the first time that soluble LRIG2 ectodomain was capable of being released from glioblastoma cells and exerted a pro-proliferative effect. Overexpression of LRIG2 ectodomain promoted the proliferation and inhibited the apoptosis of glioblastoma cells in vitro and in vivo in a similar manner to the full-length LRIG2. Both full-length LRIG2 and LRIG2 ectodomain were found to physically interact with EGFR, enhance the activation of EGFR and its downstream PI3 K/Akt pathway. To our knowledge, this is the first report demonstrating that soluble LRIG2 ectodomain is capable of being released from glioblastoma cells and exerts a similar role to the full-length LRIG2 in the regulation of EGFR signaling in the progression of glioblastoma. LRIG2 ectodomain, with potent pro-tumor effects, holds promise for providing a new therapeutic target for the treatment of glioblastoma.

LRIG3 modulates proliferation, apoptosis and invasion of glioblastoma cells as a potent tumor suppressor.

Leucine-rich repeats and immunoglobulin-like domains (LRIG) 3 gene is mapped to chromosome 12q13.2, a region that is frequently deleted in a subset of glioblastoma multiforme (GBM). It has been reported that perinuclear LRIG3 staining correlated with low WHO grade of glioma and better survival of the patients. However, the relationship between LRIG3 and glioma is not very clear. The purpose of this study is to demonstrate the impacts of LRIG3 on biological characteristics of glioma and its possible mechanisms. We found that transduction of LRIG3 into glioblastoma cells inhibited cell growth in vitro and in vivo, promoted cell apoptosis, and restrained cell invasion and migration. Further studies demonstrated that LRIG3 negatively regulated the epidermal growth factor receptor (EGFR) signaling pathway. Inhibition of EGFR could reduce the effects of LRIG3 knockdown on cell proliferation and EGFR signaling pathway. In conclusion, LRIG3 functions as a tumor suppressor by attenuating EGFR signaling pathway and the restoration of LRIG3 may offer therapeutic potential against malignant gliomas.

LRIG1 enhances cisplatin sensitivity of glioma cell lines.

LRIG family shares similar structures that include a signal peptide, an extracellular region consisting of a leucine-rich repeat domain and three immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tail. After activation of EGFR, the extracellular LRR domain and immunoglobulin-like domains of LRIG1 can bind to the extracellular parts of EGFR, resulting in recruitment of c-Cbl to the cytoplasmic domains, and induction of EGFR degradation. This study investigated the effects of overexpression of leucine-rich repeats and LRIG1 on cisplatin (CDDP) sensitivity in the glioma cell line U251 and explored the possible mechanisms mediating this effect. We found that CDDP could inhibit the growth of U251 cell line and induced activation of the EGFR. Overexpression of LRIG1 increased the inhibitory effect of CDDP on the U251 cell line via the inhibition of proliferation and induction of apoptosis. The mechanisms underlying the effect of the combined treatment of LRIG1 and CDDP could be that LRIG1 blocked CDDP-induced EGFR activation and regulated the apoptosis proteins. These findings suggest that upregulation of LRIG1 expression enhances the CDDP sensitivity in the glioma cell line U251.

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

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.

LRIG proteins in glioma: Functional roles, molecular mechanisms, and potential clinical implications

Gliomas are the most common intracranial tumors of the nervous system. These tumors are characterized by unlimited cell proliferation and excessive invasiveness. Despite the advances in diagnostic imaging, microneurosurgical techniques, radiation therapy, and chemotherapy, significant increases in the progression free survival of glioma patients have not been achieved. Improvements in our understanding of the molecular subtypes of gliomas and the underlying alterations in specific signaling pathways may impact both the diagnosis and the treatment strategies for patients with gliomas. Growth factors and their corresponding receptor tyrosine kinases are associated with oncogenesis and development of tumors in numerous human cancer types, including glioma. Leucine-rich repeats and immunoglobulin-like domains (LRIG) are integral membrane proteins which contain three vertebrate members including LRIG1, LRIG2 and LRIG3. They mainly function as regulators of growth factor signaling. Specifically, LRIG1 has been identified as a tumor suppressor in human cancers. In contrast, LRIG2 appears to function as a tumor promoter, while LRIG3 appears to have a function similar to that of LRIG1. In the present review, we summarize the functional roles, molecular mechanisms, and clinical perspectives of LRIG proteins in gliomas and propose that these proteins may be useful in the future as targets for treatment and prognostication in glioma patients.