Research progress on the role of decorin in the development of oral mucosal carcinogenesis

Abstract

Decorin (DCN) is primarily found in the connective tissues of various parts of the body, including the lungs, kidneys, bone tissue, aorta, and tendons. It is an important component of the extracellular matrix (ECM) and belongs to the class I small leucine-rich proteoglycans family. DCN is increasingly attracting attention due to its significant role in tumors, fibrotic diseases, and the regulation of vascular formation. Moreover, its anti-tumor properties have positioned it as a promising biomarker in the fight against cancer. Numerous studies have confirmed that DCN can exert inhibitory effects in various solid tumors, particularly in oral squamous cell carcinoma (OSCC), by activating its downstream pathways through binding with the epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) receptor, or by stabilizing and enhancing the expression of the tumor suppressor gene p53 to mediate apoptosis in cancer cells that have undergone mutation. The occurrence of OSCC is a continuous and dynamic process, encompassing the transition from normal mucosa to oral potentially malignant disorders (OPMDs), and further progressing from OPMDs to the malignant transformation into OSCC. We have found that DCN may exhibit a bidirectional effect in the progression of oral mucosal carcinogenesis, showing a trend of initial elevation followed by a decline, which decreases with the differentiation of OSCC. In OPMDs, DCN exhibits high expression and may be associated with malignant transformation, possibly linked to the increased expression of P53 in OPMDs. In OSCC, the expression of DCN is reduced, which can impact OSCC angiogenesis, and inhibit tumor cell proliferation, migration, and invasion capabilities, serving as a potential marker for predicting adverse prognosis in OSCC patients. This article reviews the current research status of DCN, covering its molecular structure, properties, and involvement in the onset and progression of oral mucosal carcinogenesis. It elucidates DCN's role in this process and aims to offer insights for future investigations into its mechanism of action in oral mucosal carcinogenesis and its potential application in the early diagnosis and treatment of OSCC.

Keywords: Decorin (DCN); Oral erythroplakia (OEL); Oral leukoplakia (OLK); Oral lichen planus (OLP); Oral potentially malignant disorders (OPMDs); Oral squamous cell carcinoma (OSCC); Oral submucous fibrosis.

Figure 1. Structure of DCN: DCN consists of a core protein and a GAG side chain, which is linked to serine residues near the N-terminus. In domain I, the initial 16-amino acid-long signal peptide directs the core protein to the rough endoplasmic reticulum and is cleaved through a cotranslational pathway. In domain II, a 14-amino acid propeptide regulates the attachment of the GAG chain. The protein core is composed of LRRs rich in leucine residues, with cysteine-rich domains containing disulfide bonds on the sides. The central domain in domain III consists of 12 LRRs. Most DCN core protein ligands share an interface with the DCN core protein, which serves as a crucial hub for extracellular matrix, cell surface receptors, and growth factors. DCN exhibits high affinity binding sites for Col in LRRs 4-6 and low affinity sites at the C-terminus. The binding sites for TGF-β subtypes are LRR4 and LRR5 in domain II of the DCN core protein, while LRR7 domain interacts with EGFR and ErB4 to activate the MAPK pathway. DCN interacts with various growth factor signaling pathways. The carboxyl-terminal domains and binding sites for Fn and Col can be found in domain IV.

Figure 2. Cancer inhibitory effects of DCN. DCN induces EGFR phosphorylation, which triggers intracellular MAPK. This leads to enhanced expression of p21, resulting in cell cycle arrest and the release of Caspase 3, leading to cell apoptosis. Through Met receptor signaling, DCN downregulates β-catenin and MYC to inhibit tumor growth. It also suppresses angiogenesis by inhibiting HIF-1α and VEGFA. DCN-mediated VEGFR2 signaling inhibits angiogenesis and induces autophagy in endothelial cells by inhibiting mTOR and activating Beclin-1, LC3, and Peg3. Additionally, DCN stabilizes and increases p53 expression, thereby mediating cell cycle arrest and apoptosis.

Figure 3. Antifibrotic effects of DCN. DCN binds to TGF-β1 through its domain III, thereby inhibiting its binding to receptors and consequently suppressing fibrosis in tissues and organs.

Figure 4. Bidirectional regulation of angiogenesis by DCN. DCN can activate TSP-1 and TIMP-3 through Met, while inhibiting the expression of MMP-9 and MMP-2 to suppress angiogenesis; DCN participates in and enhances the degradation of VEGF-A through VEGFR2, thus inhibiting angiogenesis; Overexpression of DCN can upregulate the expression of VEGF-A through the IGF1R-AKT-VEGF signaling pathway to promote vascular formation.