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.