Targeting tumor invasion: the roles of MDA-9/Syntenin

Abstract

Introduction: Melanoma differentiation-associated gene - 9 (MDA-9)/Syntenin has become an increasingly popular focus for investigation in numerous cancertypes. Originally implicated in melanoma metastasis, it has diverse cellular roles and is consistently identified as a regulator of tumor invasion and angiogenesis. As a potential target for inhibiting some of the most lethal aspects of cancer progression, further insight into the function of MDA-9/Syntenin is mandatory.

Areas covered: Recent literature and seminal articles were reviewed to summarize the latest collective understanding of MDA-9/Syntenin's role in normal and cancerous settings. Insights into its participation in developmental processes are included, as is the functional significance of the N- and C-terminals and PDZ domains of MDA-9/Syntenin. Current reports highlight the clinical significance of MDA-9/Syntenin expression level in a variety of cancers, often correlating directly with reduced patient survival. Also presented are assessments of roles of MDA-9/Syntenin in cancer progression as well as its functions as an intracellular adapter molecule.

Expert opinion: Multiple studies demonstrate the importance of MDA-9/Syntenin in tumor invasion and progression. Through the use of novel drug design approaches, this protein may provide a worthwhile therapeutic target. As many conventional therapies do not address, or even enhance, tumor invasion, an anti-invasive approach would be a worthwhile addition in cancer therapy.

Keywords: EGFR; PDZ; angiogenesis; breast cancer; c-Src; exosomes; glioblastoma; glioma; integrin; invasion; melanoma; melanoma differentiation-associated gene – 9; metastasis; small cell lung carcinoma; syndecan binding protein; syntenin; urothelial cell carcinoma; uveal melanoma.

Figure 1. MDA-9/Syntenin domain structure

Recent studies have shed light on the various activities and functions of the domains comprising MDA-9/Syntenin. Domain structure is depicted and select activities listed beneath each. MDA-9: Melanoma differentiation-associated gene – 9.

Figure 2. MDA-9/Syntenin-Ubiquitin binding

The N-terminal of MDA-9/Syntenin has been shown to bind a unique site on ubiquitin (Ub) [29]. As described in this work, the dimerization of MDA-9/Syntenin enhances Ub binding. The possible ramification of this insight is another method by which MDA-9 can facilitate interactions, now between two Ub-bound proteins.

Figure 3. MDA-9/Syntenin invasion signaling

A summary of important signaling pathways affected by MDA-9/Syntenin that impact cancer progression, particularly motility, invasion and angiogenesis. ECM: Extracellular matrix; FAK: Focal adhesion kinase; GSK3β: Glycogen synthase kinase 3β; HIF-1α: Hypoxia inducible factor-1α; IGFBP-2: Insulin-like growth factor binding protein – 2; IKK: IκB-kinase; MDA-9: Melanoma differentiation-associated gene – 9; PKCα: Protein kinase C – α.