Abstract 3150: Serglycin promotes cell migration mediated through the interaction of its GAG moiety with CD44

Abstract

Tumor microenvironment (TME) plays an important role in cancer progression. We have recently shown that serglycin (SRGN), a chondroitin sulfate proteoglycan (CSPG), is overexpressed in primary non-small cell lung cancers (NSCLCs), by carcinoma as well as stromal cells, and that the secreted SRGN can bind to CD44 and promotes NSCLC aggressiveness (Oncogene 36:2457, 2007). In this study, we further examined the molecular mechanisms underlying SRGN-elicited cell migration. By gain- and loss-of-function studies, we first showed that SRGN promoted cell migration in a CD44-dependent manner. SRGN promoted SRC activation, leading to increased phosphorylation of paxillin (PAX) at Y118 as well as reduced PAX/FAK complex formation, suggesting that SRGN promotes cell migration through facilitating focal adhesion turnover. In support, knockdown of SRC or treatment of cells with PP2, a SRC family inhibitor, abolished SRGN-elicited migratory activity. In addition, we showed that SRGN induced actin cytoskeleton reorganization and promoted lamellipodia and filopodia formation at the leading edge, facilitating a directional movement during wound closure in NSCLC cells. In consistence, increased levels of activated RAC1, which is required for lamellipodia formation, and CDC42, which is required for filopodia formation, were detected. We further examined the role of CS modification in SRGN-mediated function. We generated the SRGN(S/A) mutant in which the eight serine residues involved in GAG modification were converted to alanine, and showed that SRGN(S/A) mutant not only failed to induce the phosphorylation of SRC and paxillin, but also failed to promote cell migration. In consistence, pre-treatment of SRGN-containing conditional medium with Chondroitinase ABC also suppressed SRGN-elicited cell migration. Taken together, our data demonstrated that SRGN interacts with CD44 through its GAG modifications, leading to increased cell migration by promoting FA turnover and cytoskeleton reorganization. Citation Format: Joanne Jeou-Yuan Chen, Jing-You Guo, Chu-Hsuan Chiu, Mei-June Wang. Serglycin promotes cell migration mediated through the interaction of its GAG moiety with CD44 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3150.