Mda-9/Syntenin Is Expressed in Uveal Melanoma and Correlates with Metastatic Progression

Abstract

Uveal melanoma is an aggressive cancer that metastasizes to the liver in about half of the patients, with a high lethality rate. Identification of patients at high risk of metastases may provide indication for a frequent follow-up for early detection of metastases and treatment. The analysis of the gene expression profiles of primary human uveal melanomas showed high expression of SDCBP gene (encoding for syndecan-binding protein-1 or mda-9/syntenin), which appeared higher in patients with recurrence, whereas expression of syndecans was lower and unrelated to progression. Moreover, we found that high expression of SDCBP gene was related to metastatic progression in two additional independent datasets of uveal melanoma patients. More importantly, immunohistochemistry showed that high expression of mda-9/syntenin protein in primary tumors was significantly related to metastatic recurrence in our cohort of patients. Mda-9/syntenin expression was confirmed by RT-PCR, immunofluorescence and immunohistochemistry in cultured uveal melanoma cells or primary tumors. Interestingly, mda-9/syntenin showed both cytoplasmic and nuclear localization in cell lines and in a fraction of patients, suggesting its possible involvement in nuclear functions. A pseudo-metastatic model of uveal melanoma to the liver was developed in NOD/SCID/IL2Rγ null mice and the study of mda-9/syntenin expression in primary and metastatic lesions revealed higher mda-9/syntenin in metastases. The inhibition of SDCBP expression by siRNA impaired the ability of uveal melanoma cells to migrate in a wound–healing assay. Moreover, silencing of SDCBP in mda-9/syntenin-high uveal melanoma cells inhibited the hepatocyte growth factor (HGF)-triggered invasion of matrigel membranes and inhibited the activation of FAK, AKT and Src. Conversely syntenin overexpression in mda-9/syntenin-low uveal melanoma cells mediated opposite effects. These results suggest that mda-9/syntenin is involved in uveal melanoma progression and that it warrants further investigation as a candidate molecular marker of metastases and a potential therapeutic target.

Overexpression of syntenin enhances hepatoma cell proliferation and invasion: Potential roles in human hepatoma

“…Syntenin is also known as mda-9 and was originally cloned from human melanoma cells. As a PDZ domain-containing molecule, syntenin can exert multiple roles and regulate diverse and central physiologic processes (8,9). The function of syntenin in cancer has attracted increasing attention for its important roles in the development of various cancers, including melanoma, breast and bladder cancer (10,12,13).…”

“…The function of syntenin in cancer has attracted increasing attention for its important roles in the development of various cancers, including melanoma, breast and bladder cancer (10,12,13). It has been confirmed that syntenin is highly expressed in several cancer cells and tissues, and it is involved in the progression of cancer, including cancer cell growth, invasion and metastasis (9,21,22). However, its function in the development of hepatoma remains unclear.…”

“…Syntenin comprises four separate structural domains; the presence of two tandem PDZ domains (PDZ1 and PDZ2) is the notable feature, reflecting its indispensable role in assembling cell signaling processes. The function of syntenin has attracted increasing attention regarding its critical roles in cancer growth, invasion and metastasis (9)(10)(11). Extensive studies have demonstrated that syntenin is upregulated in several types of cancer, including breast cancer, melanoma and bladder cancer (10,12,13).…”

Expression analysis of genes and pathways associated with liver metastases of the uveal melanoma

“…The patients in the two datasets were composed of 63 and 29 samples, respectively [17,18]. All the samples were performed on Affymetrix Human Genome U133 Plus 2.0 Array.…”

Uveal Melanoma Metastasis Models

“…Hepatic tumors formed within 4-6 weeks after injection [71]. This method facilitates tumor cells to colonize the liver through the portal circulation system, is applicable for many tumors, and readily lends itself to the evaluation of immunotherapeutic and chemotherapeutic approaches for the treatment of liver metastases; it has also been used to study the mechanisms that lead to hepatic metastases from primary uveal melanoma [67,72,73]. …”