Serglycin promotes invasion and metastasis of esophageal cancer

Abstract

Esophageal cancer is the 6th most common cause of cancer­related deaths worldwide. Patients diagnosed with locally advanced disease or distant metastasis have a particularly poor prognosis. Understanding the molecular mechanisms that promote invasion of cancer cells is therefore essential to tackle this highly aggressive disease. We previously identified serglycin (SRGN) as the top upregulated gene in a highly invasive esophageal squamous cell carcinoma (ESCC) cell subline. Serglycin is a proteoglycan mainly expressed in hematopoietic cells. Its significance in tumorigenesis is less well understood. Western blot and immunohistochemical analyses showed that serglycin expression was higher in ESCC compared with normal esophageal epithelium, and in lymph node metastases compared with primary ESCC. Ectopic overexpression of serglycin in ESCC cells promoted cancer cell invasion in vitro and experimental metastasis in vivo. In invasion chamber assay, conditioned medium from serglycin­overexpressing cells enhanced the invasion of untransfected ESCC cells. Conditioned medium from ESCC cells expressing serglycin lacking the glycosaminoglycan attachment site had no such effect. Gene Ontology analysis suggested involvement of the CXC chemokine receptor 2 (CXCR2) signaling pathway. Western blot analysis showed that forced expression of serglycin increased the expression level of CXCR2, phosphorylated extracellular signal­regulated kinase (pERK) and matrix metalloproteinase 2 (MMP­2) in ESCC cells. Blockade of CXCR2 with neutralizing antibody abrogated the stimulating effects of serglycin on the ERK pathway, MMP2 expression, and esophageal cancer cell invasion. In conclusion, serglycin promotes cancer invasion and metastasis in ESCC through activation of a CXCR2­MEK/ERK­MMP2 signaling axis in an autocrine manner, and its GAG binding domain is critical in this process. [This study was supported by Research Grants Council of the Hong Kong SAR, China, GRF Project No. 17111016]