Syndecan-2 promotes perineural invasion and cooperates with K-ras to induce an invasive pancreatic cancer cell phenotype

Syndecan-2 (SDC-2) expression was analyzed in human normal pancreas, chronic pancreatitis and PDAC tissues. Functional in vitro assays were carried out to determine its role in invasion, migration and signaling.SDC-2 was expressed in the majority of the tested pancreatic cancer cell lines while it was upregulated in nerve-invasive PDAC cell clones. There were 2 distinct expression patterns of SDC-2 in PDAC tissue samples: SDC-2 positivity in the cancer cell cytoplasm and a peritumoral expression. Though SDC-2 silencing (using specific siRNA oligonucleotides) did not affect anchorage-dependent growth, it significantly reduced cell motility and invasiveness in the pancreatic cancer cell lines T3M4 and Su8686. On the transcriptional level, migration-and invasion-associated genes were down-regulated following SDC-2 RNAi. Furthermore, SDC-2 silencing reduced K-ras activity, phosphorylation of Src and - further downstream - phosphorylation of ERK2 while levels of the putative SDC-2 signal transducer p120GAP remained unaltered.SDC-2 is a novel (perineural) invasion-associated gene in PDAC which cooperates with K-ras to induce a more invasive phenotype.Pancreatic ductal adenocarcinoma (PDAC) is still one of the most lethal human malignancies due to late clinical detection and its innate aggressiveness, stemming from its potential for early local invasion and metastasis [1-3]. Among a variety of genomic alterations in precursor lesions of PDAC (pancreatic intraepithelial neoplasia, PanIN), mutations in the gene encoding the small GTPase K-ras are most frequent and are currently believed to be one of the initiating steps in pancreatic carcinogenesis. Approximately 90% of the later stage pancreatic cancers are found to be K-ras mutated and seem to get "addicted" to K-ras overactivity (induced by K-ras mutation), which might in turn have implications for therapeutically targeting the K-ras pathway [4,5]. Apart from the mitogenic signal transduced by K-ras overactivity, it also