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Abstract
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.
Highlights
The major characteristics of malignant tumor cells are their ability to invade foreign tissues and form metastatic foci at distant locations in the body
Overexpression of syntenin activates the p38 mitogenactivated protein kinase and AKT pathways in Small cell lung cancer (SCLC), along with focal adhesion kinase activation, without interaction with the extracellular matrix To reveal what signaling pathways are involved in the synteninmediated induction of MT1-matrix metalloproteinase (MMP) and MMP2 in SCLC, we investigated the alteration of p38 mitogen-activated protein kinase (MAPK), AKT and c-jun activity after syntenin overexpression and knockdown
Syntenin induces membrane type 1-matrix metalloproteinase (MT1-MMP) and MMP2 through activation of focal adhesion kinase, p38 MAPK and PI3K/AKT pathways To confirm whether the signaling pathways activated by syntenin are associated with increased invasiveness, we evaluated the influence of a p38 inhibitor (SB203580), a PI3K/ AKT inhibitor (LY294002) and a FAK inhibitor (PF-573228) on MT1-MMP and MMP2 expression in syntenin-overexpressed cells
Summary
The major characteristics of malignant tumor cells are their ability to invade foreign tissues and form metastatic foci at distant locations in the body. Such processes require tumor cell attachment to various matrix proteins and the degradation of the extracellular matrix (ECM), mainly by matrix metalloproteinase (MMP), followed by the migration of tumor cells into the surrounding stroma. The invasiveness-associated role of syntenin was first observed in malignant melanoma.[5,6,7,8] Results from recent studies using malignant melanoma cell lines have shown that syntenin might function as an important regulator, controlling the invasiveness and metastatic potential in malignant melanoma.[9] In a matched set of melanoma cell lines of lowly and highly metastatic cells, syntenin expression was significantly higher in highly metastatic cells; overexpression of syntenin significantly accelerated migration and invasion, whereas forced inhibition of syntenin significantly suppressed invasiveness.[9]
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