Theranostics 2021; 11(6):2722-2741. doi:10.7150/thno.49547

Research Paper

Significance of serglycin and its binding partners in autocrine promotion of metastasis in esophageal cancer

Yun Zhu1, Alfred K.Y. Lam2, Daisy K.Y. Shum1, Di Cui1, Jun Zhang1, Dong Dong Yan1, Bin Li3, Wen Wen Xu4, Nikki P.Y. Lee5, Kin Tak Chan5, Simon Law5, Sai Wah Tsao1, Annie L.M. Cheung1✉

1. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
2. Department of Pathology, Griffith Medical School, Queensland, Gold Coast, QLD, Australia
3. MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan University, Guangzhou, China
4. MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
5. Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China

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Citation:
Zhu Y, Lam AKY, Shum DKY, Cui D, Zhang J, Yan DD, Li B, Xu WW, Lee NPY, Chan KT, Law S, Tsao SW, Cheung ALM. Significance of serglycin and its binding partners in autocrine promotion of metastasis in esophageal cancer. Theranostics 2021; 11(6):2722-2741. doi:10.7150/thno.49547. Available from https://www.thno.org/v11p2722.htm

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Abstract

Rationale: Little is known about the roles of proteoglycans in esophageal cancer. This study aims to investigate the roles and mechanisms of serglycin (SRGN) proteoglycan in promoting metastasis of esophageal squamous cell carcinoma (ESCC).

Methods: Reverse phase protein array analysis was used to identify activated signaling pathways in SRGN-overexpressing cells. Chemokine array was used to identify differentially secreted factors from SRGN-overexpressing cells. Binding between SRGN and potential interacting partners was evaluated using proximity ligation assay and co-immunoprecipitation. The glycosaminoglycan (GAG) chains of SRGN were characterized using fluorophore-assisted carbohydrate electrophoresis. Tissue microarray and serum samples were used to determine the correlation of SRGN expression with clinicopathological parameters and patient survival.

Results: In vitro and in vivo experiments showed that SRGN promoted invasion and metastasis in ESCC via activating ERK pathway, stabilizing c-Myc and upregulating the secretion of matrix metalloproteinases. SRGN-knockdown suppressed tumorigenic hallmarks. These SRGN-elicited functions were carried out in an autocrine manner by inducing the secretion of midkine (MDK), which was further identified as a novel binding partner of SRGN for the formation of a SRGN/MDK/CD44 complex. In addition, SRGN interacted with MDK and matrix metalloproteinase 2 in ESCC via its GAG chains, which were mainly decorated with chondroitin sulfate comprising of ∆di-4S and ∆di-6S CS. Clinically, high expression of serum SRGN in serum of patients with ESCC was an independent prognostic marker for poor survival.

Conclusions: This study provides the first evidence that elevated serum SRGN has prognostic significance in patients with ESCC, and sheds light on the molecular mechanism by which elevated circulating SRGN in cancer patients might promote cancer progression.

Keywords: Serglycin, midkine, esophageal squamous cell carcinoma, metastasis, biomarker