Research progress on ADAM28 in malignant tumors

Abstract

A disintegrin and metalloproteinase (ADAM) 28 belongs to the zinc-dependent metalloproteinase superfamily and has a signal sequence at its N-terminus that can direct the protein into the secretory pathway. ADAM28 is a multifunctional protein that has been shown to play a role in regulating numerous biological processes, including cell adhesion, cell fusion, membrane protein shedding, protein hydrolysis, and signaling pathway modulation. ADAM28 is highly expressed in numerous malignant tumors and plays a pivotal role in the proliferation, metastasis and drug resistance of these tumors by acting on substrates such as IGFBP-3, vWF and CTGF, thereby promoting PSGL-1/P-selectin-mediated cell adhesion. Consequently, inhibiting ADAM28 could impede tumor proliferation, metastasis and drug resistance, which suggests that ADAM28 may serve as a prognostic indicator of and potential therapeutic target for malignant tumors. In this article, the structure and function of ADAM28 and its correlation with the onset and progression of human malignant tumors are primarily examined. Additionally, the potential applications of ADAM28 in tumor research are investigated to offer a theoretical foundation and reference for the clinical diagnosis and treatment of malignant tumors.

Keywords: ADAM28; Apoptosis; Cell proliferation; Connective tissue growth factor; Drug resistance; Insulin-like growth factor-binding protein-3; Von Willebrand factor.

Fig. 1

Comparison of the domain structures of the ADAM, ADAM28 isoforms. The transmembrane ADAM28 (ADAM28m) is composed of structural domains such as the prodomain (Pro), metalloproteinase domain (MP), disintegrin domain (Dis), cysteine-rich domain (Cys), EGF-like domain (EGF), transmembrane domain (TM), and cytoplasmic tail (Cyt). Secreted form of ADAM28 (ADAM28s) shares the similar structure except that the EGF-like, transmembrane and cytoplasmic portions are missing. Domains are not drawn to scale

Fig. 2

Functional roles of ADAM28 in cancer cell proliferation, invasion and metastasis. A ADAM28 reactivates IGF-1 by cleaving IGFBP-3 in the IGF-1/IGFBP-3 complex, stimulate cell proliferation. B ADAM28 selectively degrades CTGF in the complex of CTGF and vascular endothelial growth factor, thereby releasing biologically active VEGF and promoting the formation of tumor angiogenesis. C ADAM28 may play an invasive role through SOX4-mediated EMT. D The catalytic site in the metalloproteinase domain of ADAM has a high degree of sequence homology with MMPs. ADAM28 promotes invasion by degrading ECM components. E ADAM28 can promote P-selectin/glycoprotein ligand complex (PSGL-1/P-selectin)-mediated tumor cell rolling adhesion to endothelial cells and subsequent transendothelial migration into the interstitial space. F ADAM28 can cleave vWF, leading to protein degradation of vWF in the human body and inhibiting its effect of promoting cell apoptosis