Glypican-1 in human glioblastoma: implications in tumorigenesis and chemotherapy

Abstract

Glioblastoma is one of the most common malignant brain tumors, with which patients have a mean survival of 24 months. Glypican-1 has been previously shown to be overexpressed in human glioblastoma and to be negatively correlated with patient's survival. This study aimed to investigate how glypican-1 influences the tumoral profile of human glioblastoma using in vitro cell line models. By downregulating the expression of glypican-1 in U-251 MG cells, we observed that the cellular growth and proliferation were highly reduced, in which cells were significantly shifted towards G0 as opposed to G1 phases. Cellular migration was severely affected, and glypican-1 majorly impacted the affinity towards laminin-binding of glioblastoma U-251 MG cells. This proteoglycan was highly prevalent in glioblastoma cells, being primarily localized in the cellular membrane and extracellular vesicles, occasionally with glypican-3. Glypican-1 could also be found in cell-cell junctions with syndecan-4 but was not identified in lipid rafts in this study. Glypican-1-silenced cells were much more susceptible to temozolomide than in U-251 MG itself. Therefore, we present evidence not only to support facts that glypican-1 is an elementary macromolecule in glioblastoma tumoral microenvironment but also to introduce this proteoglycan as a promising therapeutic target for this lethal tumor.

Infrared Microspectroscopy and Imaging Analysis of Inflammatory and Non-Inflammatory Breast Cancer Cells and Their GAG Secretome

“…The signal detected in the cytoplasm might also be attributed to GAGs linked to other PGs during their intracellular synthesis and traffic [ 52 ]. For example, Listik and collaborators have shown that DS is a GAG that is produced through the epimerization of the glucuronic acid in CS into iduronic acid (IduA) by DS epimerase (DS-epi) 1 and 2 [ 20 ]. They have described the expression of DS-epi1 in MCF7, MDA-MB-231, and SKBR3 cell lines, its involvement in cancer progression and showed that the localization of the enzyme in intracytoplasmic organelles may play a decisive role in the tumor growth [ 20 ].…”

“…CSPGs and their biosynthetic pathways play a major role in aggressive breast cancer metastasis, thus considering promising targets for antimetastatic-therapies [ 19 ]. PGs play essential physiological and pathological roles during cellular development, proliferation, differentiation, and cancer metastasis [ 20 , 21 ]. The GAG chains are able to interact with molecules such as growth factors which are essential for cell differentiation and maintenance of tissue organization during embryo development but also during tumor progression.…”

Overexpression of Annexin A2 Promotes Proliferation by Forming a Glypican 1 / c-Myc Positive Feedback Loop: Prognostic Significance in Human Glioma

“…GPCs are known to be expressed in several cancers and gained attention as possible biomarkers for various cancer progression. At present, the roles for GPC1 and GPC3 in controlling the proliferation of glioma cells have been reported; the overexpression of GPC1 in U87 glioma cells enhanced FGF-2stimulated proliferation of cells through enhancing FGF-2 signaling [18], whereas knockdown of GPC1 in U251 glioma cells reduced the cellular growth and proliferation [19]; GPC3 drived gliomagenesis and initiated the brain hyperexcitability [43]. In fact, the expression of GPC1 and GPC3 appears to be highly tissue speci c. Of six GPCs, GPC1 is abundantly expressed in brain [44].…”

“…GPCs have been suggested to act as biomarkers for tumor progression, such as GPC3 for hepatocellular carcinoma [13,14], GPC1 for pancreatic ductal adenocarcinoma [15], GPC5 and GPC1 for prostate cancer [16,17]. GPC1 is universally overexpressed in human glioma [18,19]. It was reported that overexpression of GPC1 in U87 glioma cells enhanced FGF-2stimulated proliferation of cells through enhancing FGF-2 signaling [18], while knockdown of GPC1 in U251 glioma cells reduced the cellular growth and proliferation [19].…”

“…GPC1 is universally overexpressed in human glioma [18,19]. It was reported that overexpression of GPC1 in U87 glioma cells enhanced FGF-2stimulated proliferation of cells through enhancing FGF-2 signaling [18], while knockdown of GPC1 in U251 glioma cells reduced the cellular growth and proliferation [19]. Furthermore, the higher expression of GPC1 has been suggested to predict poor prognosis of glioblastoma through examining the expression of GPC1 in 53 patients [20].…”