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

Xiao, Qungen; Tan, Yihu; Guo, Yang; Yang, Hai; Mao, Feng; Xie, Ruifan; Wang, Baofeng; Lei, Ting; Guo, Dongsheng

doi:10.1371/journal.pone.0111419

Cited by 18 publications

(31 citation statements)

References 34 publications

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“…The stable LRIG2-overexpressing U87 cells (U87-LRIG2) and the corresponding control cells (U87-Con) had been established and used previously ( 22 ). U87 cells were stably infected with lentivirus expressing pLKO.1-TRC-scr or pLKO.1-TRC-LRIG2shRNA using Lenti-X lentiviral Expression Systems (Clontech Laboratories, Inc., Mountainview, CA, USA) according to the manufacturer's instructions as described previously ( 22 ). In brief, 1 day before the transfection, 4×10 6 293T cells (ATCC) were seeded in a 100-mm plate and cultured in DMEM containing 10% Tc-free FBS (Clontech Laboratories, Inc.).…”

Section: Methodsmentioning

confidence: 99%

“…It has been reported that LRIG2 expression is associated with poor survival in oligodendroglioma ( 18 ) and uterine cervical carcinoma ( 19 ), and wild-type mice developed PDGFB-induced gliomas at a higher frequency and of higher malignancy compared with LRIG2-deficient mice ( 20 ). Over the past decade, our research team has focused on the functions of LRIGs in gliomagenesis, and demonstrated that LRIG2 promotes the growth of GBM by positively modulating EGFR-mediated signaling ( 21 , 22 ), which adds to the evidence supporting the hypothesis that LRIG2 may play an oncogenic role in the progression of glioma, possibly contrary to the role of LRIG1 ( 23 , 24 ); however, more compelling evidence is required to support the concept of LRIG2 as a tumor promoter in GBM and to elucidate the mechanistic insights.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…Little is known about LRIG2, although it has been shown to be permissive for glial tumour growth in vivo [ 49 ], and in a glioma cell culture model, LRIG2 interacts with epidermal growth factor receptor and modulates intracellular signalling [ 50 ]. UFS phenotypes of HPSE2 or LRIG2 mutation patients appear identical, so HPSE2 and LRIG2 probably work in related pathways.…”

Section: Hpse2 and Lrig2 Mutations Cause mentioning

confidence: 99%

From gene discovery to new biological mechanisms: heparanases and congenital urinary bladder disease

Roberts

Hilton

Woolf

2015

Nephrol. Dial. Transplant.

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We present a scientific investigation into the pathogenesis of a urinary bladder disease. The disease in question is called urofacial syndrome (UFS), a congenital condition inherited in an autosomal recessive manner. UFS features incomplete urinary bladder emptying and vesicoureteric reflux, with a high risk of recurrent urosepsis and end-stage renal disease. The story starts from a human genomic perspective, then proceeds through experiments that seek to determine the roles of the implicated molecules in embryonic frogs and newborn mice. A future aim would be to use such biological knowledge to intelligently choose novel therapies for UFS. We focus on heparanase proteins and the peripheral nervous system, molecules and tissues that appear to be key players in the pathogenesis of UFS and therefore must also be critical for functional differentiation of healthy bladders. These considerations allow the envisioning of novel biological treatments, although the potential difficulties of targeting the developing bladder in vivo should not be underestimated.

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“…In the upregulated set, we highlight three genes FTH1, APIP, and LRIG2 that could potentially counteract the impact of radiation (Table S10). FTH1 en- [64].…”

Section: Differential Translational Efficiencymentioning

confidence: 99%

Integrated analyses of early responses to radiation in glioblastoma identify new alterations in RNA processing and candidate target genes to improve treatment outcomes

Choudhary

Burns

Mirsafian

et al. 2019

Preprint

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Background: High-dose radiation is the main component of glioblastoma therapy. Unfortunately, radioresistance is a common problem and a major contributor to tumor relapse. Understanding the molecular mechanisms driving response to radiation is critical for identifying regulatory routes that could be targeted to improve treatment response. Methods:We conducted an integrated analysis in the U251 and U343 glioblastoma cell lines to map early alterations in the expression of genes at three levels: transcription, splicing, and translation in response to ionizing radiation.Results: Changes at the transcriptional level were the most prevalent response. Downregulated genes are strongly associated with cell cycle and DNA replication and linked to a coordinated module of expression.Alterations in this group are likely driven by decreased expression of the transcription factor FOXM1 and members of the E2F family. Genes involved in RNA regulatory mechanisms were affected at the mRNA, splicing, and translation levels, highlighting their importance in radiation-response. We identified a number of oncogenic factors, with an increased expression upon radiation exposure, including BCL6, RRM2B, IDO1, FTH1, APIP, and LRIG2 and lncRNAs NEAT1 and FTX. Several of these targets have been previously implicated in radioresistance. Therefore, antagonizing their effects post-radiation could increase therapeutic efficacy. Conclusions:Our integrated analysis provides a comprehensive view of early response to radiation in glioblastoma. We identify new biological processes involved in altered expression of various oncogenic factors and suggest new target options to increase radiation sensitivity and prevent relapse.

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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

Cited by 18 publications

References 34 publications

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

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

From gene discovery to new biological mechanisms: heparanases and congenital urinary bladder disease

Integrated analyses of early responses to radiation in glioblastoma identify new alterations in RNA processing and candidate target genes to improve treatment outcomes

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