1. LRIG2 promotes the proliferation and cell cycle progression of glioblastoma cells in vitro and in vivo through enhancing PDGFRβ signaling
- Author
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Feng Mao, Minghai Dong, Heping Wang, Baofeng Wang, Kang Wu, Weifeng Zong, Qungen Xiao, Fangling Cheng, Ting Lei, Rui-fan Xie, and Dongsheng Guo
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Carcinogenesis ,Receptor tyrosine kinase ,Mice ,0302 clinical medicine ,Epidermal growth factor receptor ,RNA, Small Interfering ,Mice, Inbred BALB C ,Membrane Glycoproteins ,biology ,Brain Neoplasms ,Articles ,Middle Aged ,Cell cycle ,ErbB Receptors ,Gene Expression Regulation, Neoplastic ,Oncology ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,Female ,cell cycle ,Signal transduction ,Corrigendum ,Cell Division ,Signal Transduction ,Adult ,STAT3 Transcription Factor ,proliferation ,Mice, Nude ,Receptor, Platelet-Derived Growth Factor beta ,03 medical and health sciences ,platelet-derived growth factor receptor β ,Growth factor receptor ,leucine-rich repeats and immunoglobulin-like domains ,Cell Line, Tumor ,Animals ,Humans ,Protein kinase B ,Aged ,Cell Proliferation ,Cell growth ,glioblastoma ,Cell Cycle Checkpoints ,Xenograft Model Antitumor Assays ,030104 developmental biology ,STAT protein ,Cancer research ,biology.protein ,Proto-Oncogene Proteins c-akt - 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.
- Published
- 2018