Syndecan-2 Regulates the Migratory Potential of Melanoma Cells

Syndecan-2, a transmembrane heparan sulfate proteoglycan, is a critical mediator in the tumorigenesis of colon carcinoma cells. We explored the function of syndecan-2 in melanoma, one of the most invasive types of cancers, and found that the expression of this protein was elevated in tissue samples from both nevus and malignant human melanomas but not in melanocytes of the normal human skin tissues. Similarly, elevated syndecan-2 expression was observed in various melanoma cell lines. Overexpression of syndecan-2 enhanced migration and invasion of melanoma cells, whereas the opposite was observed when syndecan-2 levels were knocked down using small inhibitory RNAs. Syndecan-2 expression was enhanced by fibroblast growth factor-2, which is known to stimulate melanoma cell migration; however, α-melanocyte-stimulating hormone decreased syndecan-2 expression and melanoma cell migration and invasion in a melanin synthesis-independent manner. Furthermore, syndecan-2 overexpression rescued the migration defects induced by α-melanocyte-stimulating hormone treatment. Together, these data strongly suggest that syndecan-2 plays a crucial role in the migratory potential of melanoma cells.The syndecans, a family of four transmembrane cell surface heparan sulfate proteoglycans, mainly serving as a co-receptor, regulate the adhesion-dependent signal transduction of a variety of cell types, including cancer cells (1, 2). Cell adhesion receptors or co-receptors play a critical role in the neoplastic transformation of normal cells by regulating the induction of cancer-specific cellular behavior and morphology. Thus, cancer cells probably express and utilize a distinct set of syndecans in the regulation of cancer cell growth.Several reports have linked altered syndecan expression to various elements of cancer cell growth. Loss of syndecan-1 correlates with shorter survival times in patients with squamous cell carcinoma of the head, neck, and lung (3) as well as multiple myeloma (4); loss of syndecan-1 is also associated with an elevated potential for metastasis in patients with hepatocellular and colorectal carcinomas (5, 6). Previous studies have shown that syndecan-1 regulates tumor activity in pancreatic (7), gastric (8), and breast carcinomas (9). Syndecan-1 may thus play multiple roles in tumorigenic activity and perform various tissue- and/or tumor stage-specific functions (10). Syndecan-4 expression is reduced in colon carcinoma cells (11, 12) and appears to correlate with increased tumorigenic activity (e.g. cell migration and invasion (13)), implying that syndecan-4 functions as a tumor suppressor.Syndecan-2 is also known to play a crucial role in the regulation of cancer activity. Increased levels of syndecan-2 confer an invasive phenotype in lung (14) and colon cancer cells (15). Reduction in syndecan-2 expression induces cells to switch from the transformed phenotype to flattened monolayers (8) and reduces tumorigenic activity in colon adenocarcinoma and fibrosarcoma cells (8, 16). In addition, syndecan-2 is highly expressed in the microvasculature of mouse gliomas and has been shown to regulate angiogenesis in microvascular endothelial cells (17). On the other hand, an inverse correlation between syndecan-2 expression and metastatic potential has been found in Lewis lung carcinoma cell lines (6). Therefore, changes in syndecan-2 expression may directly or indirectly regulate cancer growth.Melanoma is the most aggressive malignant tumor of melanocytes. Although found predominantly in the skin, primary melanomas are also known to occur in the bowel and eye (18). Malignant melanoma is notoriously one of the most difficult cancers to treat (19). Therefore, identifying and understanding molecules that regulate the aggressive melanoma phenotype is essential for predicting the likelihood of metastasis. Interestingly, previous studies have shown that melanoma cells acquire the ability to recognize components of the extracellular matrix (ECM)² via the ectopic expression of different ECM receptors during invasion of the basement membrane (20). Indeed, invadopodia, the dynamic organelle-like structures that form actin-rich protrusions with ECM proteolytic activity, adhere to and digest collagens, laminins, and fibronectin (21). The adhesive properties of invadopodia are primarily attributed to integrins, a large family of heterodimeric transmembrane receptors composed of α and β subunits (22). For example, β₁ integrins localize within the invadopodia of melanoma cells (23), and the α₅β₁ integrins are enriched peripherally in invadopodia, where they stabilize invadopodia protrusion (24). Ectopic stimulation of α₆β₁ integrin with laminin peptides or with β₁ or α₆ integrin stimulatory antibodies increases invadopodia activity and melanoma invasiveness (23). The invasive behavior of melanoma cells can be attributed to increased cell motility caused by changes in cytoskeletal organization and altered contacts with the ECM. Thus, cell adhesion receptors may play a crucial role in the acquisition of highly migratory behavior.Syndecan-2 acts as a key regulator of cancer cells, suggesting that syndecan-2 may contribute to the aggressive phenotype and metastatic potential of melanoma. Here, we report that syndecan-2 plays a pivotal role in the migratory activity of melanoma cells.