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.
Highlights
Uveal melanoma is the most common primary intraocular tumor in adults with an incidence rate of about 7 new cases per one million individuals each year [1,2] About 50% of patients develop metastases, mostly to the liver, within ten years from diagnosis and their median survival is 5 to 7 months after detection of metastatic lesions
Our results provide the first evidence that mda-9/syntenin is expressed in human uveal melanoma and that high level of expression of mda-9/syntenin conferres a high risk of metastatic recurrence
Recent findings have demonstrated that the high expression of mda-9/syntenin is related to the metastatic potential of breast and gastric cancer [27] and cutaneous melanoma cells [25]
Summary
Uveal melanoma is the most common primary intraocular tumor in adults with an incidence rate of about 7 new cases per one million individuals each year [1,2] About 50% of patients develop metastases, mostly to the liver, within ten years from diagnosis and their median survival is 5 to 7 months after detection of metastatic lesions. Despite the improvements in diagnosis and the development of more effective local therapies for primary tumors, the rate of metastatic death remains unchanged. It seems important to identify high-risk patients at the time of the initial diagnosis for early detection and treatment of metastatic disease or for the administration of adjuvant therapy. A great effort has been made to understand the biological mechanisms involved in the spreading and growth of uveal melanoma metastases and to discover new prognostic markers. The mechanisms responsible for hematogenous tumor dissemination and liver localization of metastases are still poorly understood
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