Abstract 1476: Serglycin in nasopharyngeal carcinoma: A metastasis regulator and prognostic indicator

Abstract

Abstract Serglycin is a proteoglycan consisting of a core protein to which negatively charged glycoaminoglycan (GAG) chains of either chondroitin sulfate or heparin are attached. Serglycin was first shown to be essential for the maturation of mast cell secretory granules, but it has recently been shown to be present within multiple other cell types. In this study we describe for the first time the role of serglycin as a potential metastasis regulator in nasopharyngeal carcinoma (NPC), a tumor that has the highest incidence of metastasis among head and neck cancers. The recognition that serglycin plays an important role in NPC comes from our earlier genomic expression profiles comparing clones derived from the NPC cell line CNE-2, where serglycin (SRGN) was identified as one of the most up-regulated genes in the high-metastasis Clone 18. The genomic expression profiling was performed on samples collected in cultured cells and in xenograft tumors generated from Clone-18, as well as low-metastasis clones (Clone-22, Clone-26) and their parental line, CNE-2. A popliteal lymph node model was used to evaluate the metastasis ability of different cellular populations. A tissue microarray was constructed from 330 NPC tissues and a total of 263 cases were informative for assessing the patients’ survival duration. A deglycosylation assay, lentiviral transduction, quantitative PCR, proliferation assay, Transwell assay, and wound-healing assay were used for the functional studies. The serglycin protein was shown to be secreted by the high-metastasis clone, but not by any of the low-metastasis clones. Suppression of serglycin by shRNA diminished serglycin secretion and subsequently inhibited migration and invasion by the high-metastasis clone, and also significantly reduced its metastasis rate in vivo. Overexpression of serglycin in low-metastasis cells resulted in a significantly increased metastasis rate in vivo. Moreover, secreted serglycin promoted cellular motility in the wild-type low-metastasis cells. Interestingly, suppression of serglycin reduced the protein level of vimentin but did not influence the level of E-cadherin in the high-metastasis clone. Proliferation was not influenced by serglycin in either the high- or low-metastasis clones. Importantly, in direct tumor samples, serglycin expression was significantly elevated in liver metastases from NPC relative to its expression in primary tumors. In conclusion, serglycin appears to play a potentially pivotal role in regulating NPC metastasis by way of enhancing cellular migration, cellular invasiveness, vimentin expression level, and the in vivo spread of cancer cells. Moreover, a high level of serglycin expression can potentially be used to predict shorter disease-free survival and shorter metastasis-free survival of NPC patients. Targeting serglycin could be a novel option for the prevention of NPC metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1476. doi:10.1158/1538-7445.AM2011-1476