The MDA-9/Syntenin/IGF-1R/STAT3 axis directs prostate cancer invasion

Although prostate cancer (PCa) is clinically manageable during several stages of progression, survival is severely compromised once cells invade and metastasize to distant organs. Comprehending the pathobiology of invasion is required for developing efficacious targeted therapies against metastasis. Based on bioinformatics data, we predicted an association of melanoma differentiation associated gene-9 (syntenin, or syndecan binding protein (SDCBP)) in PCa progression. Using tissue samples from various Gleason stage PCa patients with adjacent normal tissue, a series of normal prostate and PCa cell lines (with differing tumorigenic/metastatic properties), mda-9/syntenin manipulated variants (including loss-of-function and gain-of-function cell lines), and CRISPR/Cas9 stable MDA-9/syntenin knockout cells, we now confirm the relevance of and dependence on MDA-9/syntenin in PCa invasion. MDA-9/syntenin physically interacted with insulin-like growth factor-1 receptor (IGF-1R) following treatment with insulin-like growth factor binding protein-2 (IGFBP-2), regulating downstream signaling processes that enabled STAT3 phosphorylation. This activation enhanced expression of MMP-2 and MMP-9, two established enzymes that positively regulate invasion. Additionally, MDA-9/syntenin-mediated upregulation of pro-angiogenic factors including IGFBP-2, IL-6, IL-8, and VEGF-A also facilitated migration of PCa cells. Collectively, our results draw attention to MDA-9/syntenin as a positive regulator of PCa metastasis, and the potential application of targeting this molecule to inhibit invasion and metastasis in PCa and potentially other cancers.

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