Abstract
Syndecan family proteins are heparan sulfate proteoglycans, which involved in various cellular activities and associating with metastatic potential and chemosensitivity of tumor cells. Melanoma is one of malignant tumors with poor prognosis upon metastasis. Previously, we had shown that melanoma cells remained survived under cell detachment, which was similar to the initial steps of tumor metastasis. Downregulation of syndecan-1 and upregulation of syndecan-2 in melanoma A375 cells were observed by different suspension conditions. Specific gene alterations also increased melanoma malignancy under anchorage independency. Thus, we would like to investigate in further the role of specific gene alteration, so that it could be used to develop novel strategy to treat melanoma.In this paper, we found that syndecan-2 expression level as well the kinase phosphorylation levels increased upon anchorage independency. The pathway to regulate syndecan-2 expression shifted from PKCα/β-dependent under adhesion into PKCδ-dependent under cell suspension. Manipulation of syndecan-2 expression showed that PI3K and ERK phosphorylation as well the migratory ability increased with increased syndecan-2 expression level. In addition, suspended melanoma cells were more sensitive to chemoagents, which correlated with syndecan-2 overexpression, PI3K and ERK activations, serum level, and the presence of glycosaminoglycans.In conclusion, we showed upregulation of syndecan-2 in anoikis-resistant melanoma cells enhanced chemosensitivity through PI3K and ERK activation. This observation would support and refine the strategy of adjuvant chemotherapy to overcome metastatic melanoma.
Highlights
Melanoma is aggressive skin cancer with high morbidity, high mortality, and poor prognosis for its highly invasive characteristics
We had shown that melanoma cells remained survived under cell detachment, which was similar to the initial steps of tumor metastasis
We found that syndecan-2 expression level as well the kinase phosphorylation levels increased upon anchorage independency
Summary
Melanoma is aggressive skin cancer with high morbidity, high mortality, and poor prognosis for its highly invasive characteristics. Metastasis of tumor cells could be divided into several stages and characteristics distinct from their original tissue sources, including transformation to escape from primary tumors, intravasation into circulation system, dissemination in anchorage-independent / prolonged survival, and lodging at the secondary site for successive angiogenesis process [5,6,7]. Detachment of tumor cells from extracellular matrix and survival under anchorage-independency was recognized as initial step of tumor metastasis [8]. Detachment of normal cells causes cell apoptosis through anoikis signaling [9, 10], while the anoikis resistance of tumor cells ensured their survival and metastasis [11]. Many studies had focused on the change of protein expression for malignant melanoma cells under anchorage-independency [2, 15]. The understanding how these changes were contributive to alternative phenotypes of tumor cells was limited
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