Serglycin promotes migration and invasion of esophageal cancer cells

Abstract

Esophageal cancer, of which esophageal squamous cell carcinoma (ESCC) is the major subtype, ranks sixth in mortality rate among cancer diseases. The prognosis of esophageal cancer is greatly dependent on the extent of local invasion and metastasis. Therefore, a better understanding of the molecular mechanisms underlying these processes is needed to identify novel prognostic markers and therapeutic targets. Our previous study showed that SRGN (encoding serglycin) is the top upregulated gene in a highly invasive ESCC cell subline. The significance of serglycin, which is a proteoglycan with a core protein containing an attachment region for glycosaminoglycan (GAG) side chains, in esophageal cancer is not well understood. In the current study, analysis of TCGA database revealed that the tumor mRNA expression of SRGN was up-regulated in patients with esophageal cancer, and that higher SRGN expression was associated with unfavorable prognosis. Analysis of serum samples from patients showed that higher serum concentration of SRGN was significantly correlated with poor prognosis, indicating the significant clinical relevance of SRGN in ESCC patients. Our in vitro and in vivo data showed that SRGN has functional significance in promoting invasion and migration of ESCC cells. We found that up-regulation of SRGN increased the invasiveness and metastatic potential of ESCC cells. These effects were due to activation of the ERK signaling pathway, and were dependent on the integrity of GAG chains attached to the core protein of SRGN. Furthermore, conditioned medium collected from SRGN-overexpressing cells promoted invasion of parental cells. This autocrine effect was partly attributed to SRGN-induced midkine (MDK). We found that MDK has the ability to bind to SRGN, possibly by interacting with its GAG side chains. Up-regulation of SRGN increased the inhibitory effects of MDK inhibitor on ESCC cell viability. Taken together, our findings unveiled the functional significance and mechanism of SRGN in promoting ESCC invasion and metastasis, as well as identified a promising prognostic marker for ESCC patients. [This study is supported by Research Grants Council of the Hong Kong SAR, China, GRF Project No. 17111016]