The MDA-9/Syntenin/IGF1R/STAT3 Axis Directs Prostate Cancer Invasion

Although prostate cancer 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 prostate cancer progression. Using tissue samples from various Gleason stage prostate cancer patients with adjacent normal tissue, a series of normal prostate and prostate cancer 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 prostate cancer invasion. MDA-9/Syntenin physically interacted with insulin-like growth factor-1 receptor following treatment with insulin-like growth factor binding protein-2 (IGFBP2), regulating downstream signaling processes that enabled STAT3 phosphorylation. This activation enhanced expression of MMP2 and MMP9, two established enzymes that positively regulate invasion. In addition, MDA-9/syntenin-mediated upregulation of proangiogenic factors including IGFBP2, IL6, IL8, and VEGFA also facilitated migration of prostate cancer cells. Collectively, our results draw attention to MDA-9/Syntenin as a positive regulator of prostate cancer metastasis, and the potential application of targeting this molecule to inhibit invasion and metastasis in prostate cancer and potentially other cancers.Significance: This study provides new mechanistic insight into the proinvasive role of MDA-9/Syntenin in prostate cancer and has potential for therapeutic application to prevent prostate cancer metastasis. Cancer Res; 78(11); 2852–63. ©2018 AACR.

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