The staining index was calculated as previous descripted [16]. transfectants were treated without (?)/with (+) NRG1 or EGF for 5 and 15 min. Phosphorylation levels of ERK, AKT, total ERK, and AKT were measured by western blotting.(JPG) pone.0198364.s005.jpg (240K) GUID:?0A93563C-D22F-43D6-A0F9-9C52E5D87EC0 Data Availability StatementAll relevant data are within the paper and its Supporting Information files. Abstract Remodeling of the extracellular matrix (ECM) in the tumor microenvironment promotes glioma progression. Chondroitin sulfate (CS) proteoglycans appear in the ECM and on the cell surface, and can be catalyzed by dermatan sulfate epimerase to form chondroitin sulfate/dermatan sulfate (CS/DS) hybrid chains. Dermatan sulfate epimerase 1 (DSE) is usually overexpressed in many types of cancer, and CS/DS chains mediate several growth factor signals. However, the role of DSE in gliomas has never been Hydroxyzine pamoate explored. In the present study, we decided the expression of DSE in gliomas by consulting a public database and conducting immunohistochemistry on a tissue array. Our investigation revealed that DSE was upregulated in gliomas compared with normal brain tissue. Furthermore, high DSE expression was associated with advanced tumor grade and poor survival. We found high DSE expression in several glioblastoma cell lines, and DSE expression directly mediated DS chain formation in glioblastoma cells. Knockdown of DSE suppressed the proliferation, migration, and invasion of glioblastoma cells. In contrast, overexpression of DSE in GL261 cells enhanced these malignant phenotypes and tumor growth. Interestingly, we found that DSE selectively regulated heparin-binding EGF-like growth factor (HB-EGF)-induced signaling in glioblastoma cells. Inhibiting epidermal growth factor receptor (EGFR) and ErbB2 with afatinib suppressed DSE-enhanced malignant phenotypes, establishing the critical role of the ErbB pathway in regulating the effects of DSE expression. This evidence indicates that upregulation of DSE in gliomas contributes to malignant behavior in cancer cells. We provide novel insight Hydroxyzine pamoate into the significance of DS chains in ErbB signaling and glioma pathogenesis. Introduction High grade gliomas, including grade III anaplastic astrocytomas and grade IV glioblastomas, are among the most aggressive human cancers. They are the third best cause of malignancy death in people under the age of 35 worldwide [1]. Currently, glioblastomas are incurable. The average survival rate of glioblastoma is usually less than 2 years, even in patients who have received standard surgical resection followed by radiation and chemotherapy, or enrollment in a clinical trial. The high mortality of this disease is mainly attributable to the limited treatment options, and Rabbit Polyclonal to JAK1 the almost inevitable recurrence after surgical care [2, 3]. In this regard, elucidation of the precise molecular mechanisms underlying glioma progression is crucial for developing new treatments of this fatal disease. The aberrant expression of extracellular matrix (ECM) proteins and an abnormal glycan composition in the tumor microenvironment are hallmarks of all types of cancer [4, 5]. In contrast to other organs, the ECM of the central nervous system (CNS) stroma comprises abundant glycosaminoglycans (GAGs) and proteoglycans (PGs), instead of collagens or laminins [6]. GAGs are composed of unbranched polysaccharide chains such as heparan sulfate (HS), chondroitin sulfate (CS), and dermatan sulfate (DS). They can exist as free chains or may be covalently linked to a core protein, as in chondroitin sulfate proteoglycan (CSPG) and heparan sulfate proteoglycan (HSPG). CS chains are composed of Hydroxyzine pamoate repeating glucuronic acid/N-acetylgalactosamine (GlcA-GalNAc) blocks with complex sulfation at various positions. In certain tissues, C5 epimerase converts Hydroxyzine pamoate GlcA to iduronic acid (IdoA) within the CS chains. These IdoA-GalNAc models constitute dermatan sulfate, and are usually designated as CS/DS chains to demonstrate their hybrid nature [7C9]. In the CNS, CS chains are one of the major components of glial scars, which prevent nerve regeneration. The use of chondroitinase ABC or CSPG inhibitor to eliminate CS chain deposits in the lesioned dorsal columns promotes functional recovery from spinal injuries [10, 11]. Studies have shown that the levels of several CSPGs increase significantly in the ECM of gliomas [8, 12]. The degradation of CSPG in gliomas by oncolytic viruses expressing bacterial chondroitinase ABC promotes the spread and anti-tumor efficacy of the Hydroxyzine pamoate viruses [13]. Moreover, a recent.