Abstract
BackgroundGolgi Membrane Protein 1 (GOLM1), a protein involved in the trafficking of proteins through the Golgi apparatus, has been shown to be oncogenic in a variety of human cancers. Here, we examined the role of GOLM1 in the development of human glioma.MethodsqRT-PCR, immunohistochemistry, and western blot analysis were performed to evaluate GOLM1 levels in cell lines and a cohort of primary human glioma and non-neoplastic brain tissue samples. Glioma cell lines were modified with lentiviral constructs expressing short hairpin RNAs targeting GOLM1 or overexpressing the protein to assess function in proliferation, viability, and migration and invasion in vitro using EdU, CCK8, clone-forming, Transwell assays, 3D tumor spheroid invasion assay and in vivo in orthotopic implantations. Protein lysates were used to screen a membrane-based antibody array to identify kinases mediated by GOLM1. Specific inhibitors of PDGFRα (AG1296) and AKT (MK-2206) were used to examine the regulation of PDGFA/PDGFRα on GOLM1 and the underlying pathway respectively.ResultsqRT-PCR, immunohistochemistry and western blot analysis revealed GOLM1 expression to be elevated in glioma tissues and cell lines. Silencing of GOLM1 attenuated proliferation, migration, and invasion of U251, A172 and P3#GBM (primary glioma) cells, while overexpression of GOLM1 enhanced malignant behavior of U87MG cells. We further demonstrated that activation of AKT is the driving force of GOLM1-promoted glioma progression. The last finding of this research belongs to the regulation of PDGFA/PDGFRα on GOLM1, while GOLM1 was also a key element of PDGFA/PDGFRα-mediated activation of AKT, as well as the progression of glioma cells.ConclusionsPDGFA/PDGFRα-regulated GOLM1 promotes glioma progression possibly through activation of a key signaling kinase, AKT. GOLM1 interference may therefore provide a novel therapeutic target and improve the efficacy of glioma treatment, particularly in the case of the proneural molecular subtype of human glioma.
Highlights
Golgi Membrane Protein 1 (GOLM1), a protein involved in the trafficking of proteins through the Golgi apparatus, has been shown to be oncogenic in a variety of human cancers
GOLM1 was highly expressed in 9/20 low grade gliomas (LGG; 45.0%) and 40/49 high grade gliomas (HGG; 81.6%) whereas GOLM1 was nearly undetectable in non-neoplastic brain tissue samples (n = 6; Fig. 1b and c; Table 1)
GOLM1 knockdown inhibits glioma progression in P3#Glioblastoma multiforme (GBM) cells in vitro and in vivo Taking the heterogeneity of GBM into consideration, we investigated GOLM1 in P3#GBM which is an in vivo propagated primary GBM tumor cell line [19]
Summary
Golgi Membrane Protein 1 (GOLM1), a protein involved in the trafficking of proteins through the Golgi apparatus, has been shown to be oncogenic in a variety of human cancers. Molecular profiling of primary tumors has led to the identification of critical pathways involved in the development of human glioma. Studies have recently implicated Golgi proteins in the development of human gliomas. Xu et al Journal of Experimental & Clinical Cancer Research (2017) 36:193 been associated with worse prognosis in human glioma patients and was shown to promote glioma progression [4]. An increasing number of studies have revealed GOLM1 as a promoter of proliferation, invasion, and migration in diverse human cancers, including hepatocellular carcinoma, prostate cancer [8], oesophageal cancer [9], gastric cancer [10], cutaneous melanoma [11]
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