The Expression of Serglycin Is Required for Active Transforming Growth Factor β Receptor I Tumorigenic Signaling in Glioblastoma Cells and Paracrine Activation of Stromal Fibroblasts via CXCR-2

• Published in: Biomolecules (Basel, Switzerland) Switzerland), 2024-04, Vol.14 (4), p.461
• Main Authors: Manou, Dimitra, Golfinopoulou, Maria-Angeliki, Alharbi, Sara Naif D, Alghamdi, Hind A, Alzahrani, Fatimah Mohammed, Theocharis, Achilleas D
• Format: Article
• Language: English
• Subjects: Angiogenesis; Bioavailability; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Breast cancer; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell activation; Cell culture; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Chemokines; Cooperation; Culture media; Cytokines; extracellular matrix; Fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; Gelatinase B; Gene Expression Regulation, Neoplastic; Glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma cells; Glioblastoma multiforme; Glioma; Growth factor receptors; Growth factors; Health aspects; Humans; Inflammation; Interleukins; Medical prognosis; Metastasis; Paracrine Communication; Paracrine signalling; Penicillin; Physiological aspects; Proteoglycans; Proteoglycans - genetics; Proteoglycans - metabolism; Proteolysis; Proteolytic enzymes; Receptor, Transforming Growth Factor-beta Type I - genetics; Receptor, Transforming Growth Factor-beta Type I - metabolism; Receptors, Interleukin-8B - genetics; Receptors, Interleukin-8B - metabolism; serglycin; Signal Transduction; Stromal Cells - metabolism; Stromal Cells - pathology; Transforming growth factor-b; tumor microenvironment; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom14040461

Serglycin (SRGN) is a pro-tumorigenic proteoglycan expressed and secreted by various aggressive tumors including glioblastoma (GBM). In our study, we investigated the interplay and biological outcomes of SRGN with TGFβRI, CXCR-2 and inflammatory mediators in GBM cells and fibroblasts. SRGN overexpression is associated with poor survival in GBM patients. High SRGN levels also exhibit a positive correlation with increased levels of various inflammatory mediators including members of TGFβ signaling pathway, cytokines and receptors including CXCR-2 and proteolytic enzymes in GBM patients. SRGN-suppressed GBM cells show decreased expressions of TGFβRI associated with lower responsiveness to the manipulation of TGFβ/TGFβRI pathway and the regulation of pro-tumorigenic properties. Active TGFβRI signaling in control GBM cells promotes their proliferation, invasion, proteolytic and inflammatory potential. Fibroblasts cultured with culture media derived by control SRGN-expressing GBM cells exhibit increased proliferation, migration and overexpression of cytokines and proteolytic enzymes including CXCL-1, IL-8, IL-6, IL-1β, CCL-20, CCL-2, and MMP-9. Culture media derived by SRGN-suppressed GBM cells fail to induce the above properties to fibroblasts. Importantly, the activation of fibroblasts by GBM cells not only relies on the expression of SRGN in GBM cells but also on active CXCR-2 signaling both in GBM cells and fibroblasts.