Dataset Information

Extracellular serglycin upregulates the CD44 receptor in an autocrine manner to maintain self-renewal in nasopharyngeal carcinoma cells by reciprocally activating the MAPK/?-catenin axis.

ABSTRACT: Serglycin is a proteoglycan that was first found to be secreted by hematopoietic cells. As an extracellular matrix (ECM) component, serglycin promotes nasopharyngeal carcinoma (NPC) metastasis and serves as an independent, unfavorable NPC prognostic indicator. The detailed mechanism underlying the roles of serglycin in cancer progression remains to be clarified. Here, we report that serglycin knockdown in NPC cells inhibited cell sphere formation and tumor seeding abilities. Serglycin downregulation enhanced high-metastasis NPC cell sensitivity to chemotherapy. It has been reported that serglycin is a novel ligand for the stem cell marker CD44. Interestingly, we found a positive correlation between serglycin expression and CD44 in nasopharyngeal tissues and NPC cell lines. Further study revealed that CD44 was an ERK-dependent downstream effector of serglycin signaling, and serglycin activated the MAPK/?-catenin axis to induce CD44 receptor expression in a positive feedback loop. Taken together, our novel findings suggest that ECM serglycin upregulated CD44 receptor expression to maintain NPC stemness by interacting with CD44 and activating the MAPK/?-catenin pathway, resulting in NPC cell chemoresistance. These findings suggest that the intervention of serglycin/CD44 axis and downstream signaling pathway is a rational strategy for targeting NPC cancer stem cell therapy.

SUBMITTER: Chu Q

PROVIDER: S-EPMC5260886 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Extracellular serglycin upregulates the CD44 receptor in an autocrine manner to maintain self-renewal in nasopharyngeal carcinoma cells by reciprocally activating the MAPK/β-catenin axis.

Chu Qiaoqiao Q Huang Hongbing H Huang Tiejun T Cao Li L Peng Lixia L Shi Simei S Zheng Lisheng L Xu Liang L Zhang Shijun S Huang Jialing J Li Xinjian X Qian Chaonan C Huang Bijun B

Cell death & disease 20161103 11

Serglycin is a proteoglycan that was first found to be secreted by hematopoietic cells. As an extracellular matrix (ECM) component, serglycin promotes nasopharyngeal carcinoma (NPC) metastasis and serves as an independent, unfavorable NPC prognostic indicator. The detailed mechanism underlying the roles of serglycin in cancer progression remains to be clarified. Here, we report that serglycin knockdown in NPC cells inhibited cell sphere formation and tumor seeding abilities. Serglycin downregula ...[more]

PMID: 27809309

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Project description:BACKGROUND:Serglycin (SRGN), previously recognized as an intracellular proteoglycan involved in the storage processes of secretory granules, has recently been shown to be upregulated in several solid tumors. We have previously shown that SRGN in non-small cell lung cancer (NSCLC) promotes malignant phenotypes in a CD44-dependent manner and increased expression of SRGN predicts poor prognosis of primary lung adenocarcinomas. However, the underlying mechanism remains to be defined. METHODS:Overexpression, knockdown and knockout approaches were performed to assess the role of SRGN in cell motility using wound healing and Boyden chamber migration assays. SRGN devoid of glycosaminoglycan (GAG) modification was produced by site-directed mutagenesis or chondroitinase treatment. Liquid chromatography/tandem mass spectrometry was applied for quantitative analysis of the disaccharide compositions and sulfation extent of SRGN GAGs. Western blot and co-immunoprecipitation analyses were performed to determine the expression and interaction of proteins of interest. Actin cytoskeleton organization was monitored by immunofluorescence staining. RESULTS:SRGN expressed by NSCLC cells is readily secreted to the extracellular matrix in a heavily glycosylated form attached with mainly chondroitin sulfate (CS)-GAG chains, and to a lesser extent with heparin sulfate (HS). The CS-GAG moiety serves as the structural motif for SRGN binding to tumor cell surface CD44 and promotes cell migration. SRGN devoid of CS-GAG modification fails to interact with CD44 and has lost the ability to promote cell migration. SRGN/CD44 interaction promotes focal adhesion turnover via Src-mediated paxillin phosphorylation and disassembly of paxillin/FAK adhesion complex, facilitating cell migration. In support, depletion of Src activity or removal of CS-GAGs efficiently blocks SRGN-mediated Src activation and cell migration. SRGN also promotes cell migration via inducing cytoskeleton reorganization mediated through RAC1 and CDC42 activation accompanied with increased lamellipodia and filopodia formation. CONCLUSIONS:Proteoglycan SRGN promotes NSCLC cell migration via the binding of its GAG motif to CD44. SRGN/CD44 interaction induces Rho-family GTPase-mediated cytoskeleton reorganization and facilitates Src-mediated focal adhesion turnover, leading to increased cell migration. These findings suggest that targeting specific glycans in tumor microenvironment that serve as ligands for oncogenic pathways may be a potential strategy for cancer therapy.

Dataset Information

Extracellular serglycin upregulates the CD44 receptor in an autocrine manner to maintain self-renewal in nasopharyngeal carcinoma cells by reciprocally activating the MAPK/?-catenin axis.

Publications

Extracellular serglycin upregulates the CD44 receptor in an autocrine manner to maintain self-renewal in nasopharyngeal carcinoma cells by reciprocally activating the MAPK/β-catenin axis.

Similar Datasets

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