MDA-9/Syntenin/SDCBP: new insights into a unique multifunctional scaffold protein

Abstract

Tumor metastasis comprises a series of coordinated events that culminate in dissemination of cancer cells to distant sites within the body representing the greatest challenge impeding effective therapy of cancer and the leading cause of cancer-associated morbidity. Cancer cells exploit multiple genes and pathways to colonize to distant organs. These pathways are integrated and regulated at different levels by cellular- and extracellular-associated factors. Defining the genes and pathways that govern metastasis can provide new targets for therapeutic intervention. Melanoma differentiation associated gene-9 (mda-9) (also known as Syntenin-1 and SDCBP (Syndecan binding protein)) was identified by subtraction hybridization as a novel gene displaying differential temporal expression during differentiation of melanoma. MDA-9/Syntenin is an established Syndecan binding protein that functions as an adaptor protein. Expression of MDA-9/Syntenin is elevated at an RNA and protein level in a wide-range of cancers including melanoma, glioblastoma, neuroblastoma, and prostate, breast and liver cancer. Expression is increased significantly in metastatic cancer cells as compared with non-metastatic cancer cells or normal cells, which make it an attractive target in treating cancer metastasis. In this review, we focus on the role and regulation of mda-9 in cancer progression and metastasis.

Keywords: Cancer; Metastasis; PDZ domain; Syntenin; mda-9.

Figure 1:

Protein structure of MDA-9/Syntenin: MDA-9/Syntenin protein is composed of 298-amino acids and contains four domains as shown in this figure. PDZ1 and PDZ2 domains are the signaling domains and the predominant binding domains for interacting protein partners. These two domains are surrounded by the NTD (N-terminal domain) and CTD (C-terminal domain).

Figure 2:

Clinical relevance of MDA-9/Syntenin in a wide spectrum of cancers: Expression analysis in patient’s samples and in vivo studies in animal models signify the role of MDA-9/Syntenin in cancer progression, risk of metastasis and overall survival (Figure adapted from Das SK et al, Advances in Cancer Research, Volume 144, 2019, Pages 137–191).

Figure 3:

Role of MDA-9/Syntenin in different steps of metastasis: MDA-9/Syntenin regulates adhesion of cancer cells by regulating FAK/SRC signaling, MMPs, and EGFR, migration and invasion by Syndecans, β-Catenin, and MMPs and EMT mostly by E-Cadherin, ZO-1, and Snail. Multiple factors are regulated by MDA-9/Syntenin in angiogenesis, i.e., VEGFA, IGFBP2, and IL8.

Figure 4:

MDA-9/Syntenin interacts with a broad spectrum of protein partners and regulates diverse signaling cascades: Following interaction with FAK/SRC complex MDA-9/Syntenin regulates p38MAPK, ultimately regulating MMPs. MDA-9/Syntenin also regulates VEGFA and MMPs via regulating STAT3. MDA-9/Syntenin interacts with EGFR which deregulates the GSK3β/β-Catenin pathway. Also, it interacts with ILK complex regulating IGFBP2 mediated by HIF1α. In addition, MDA-9/Syntenin regulates the TGFβ pathway.