Syntenin is a PDZ domain-containing adaptor protein that has been recently shown to regulate migration and invasion in several tumors. Small cell lung cancer (SCLC) is notorious for its invasiveness and strong potential for metastasis. We therefore studied the influence of syntenin on the invasiveness of SCLC. Immunohistochemistry in tumor tissues showed that syntenin was more frequently expressed in small cell carcinomas than other neuroendocrine tumors, such as carcinoids and neuroblastomas, suggesting that syntenin expression may be related to more aggressive forms of neuroendocrine tumors. In SCLC patients, syntenin overexpression in tumor cells was significantly associated with more extensive and advanced disease at the time of diagnosis (P=0.029). Overexpression of syntenin in SCLC cells that were intrinsically syntenin-low increased the invasiveness of cells and led to the induction of extracellular matrix (ECM)-degrading membrane type 1-matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase 2 (MMP2). In contrast, suppression of syntenin in syntenin-high cells was associated with the downregulation of MT1-MMP. Contrary to the results of previous studies using malignant melanomas and breast carcinomas, signaling cascades were shown to be further transduced through p38 MAPK and PI3K/AKT, with activation of SP1 rather than NF-κB, under circumstances not involving ECM interaction. In addition, the upstream molecule focal adhesion kinase was induced by syntenin activation, in spite of the absence of ECM interaction. These results suggest that syntenin might contribute to the invasiveness of SCLC and could be utilized as a new therapeutic target for controlling invasion and metastasis in SCLC.