Dermatopontin Influences the Development of Obesity-Associated Colon Cancer by Changes in the Expression of Extracellular Matrix Proteins

Abstract

Dysfunctional adipose tissue (AT) in the context of obesity leads to chronic inflammation together with an altered extracellular matrix (ECM) remodelling, favouring cancer development and progression. Recently, the influence of dermatopontin (DPT) in AT remodelling and inflammation has been proposed. We aimed to evaluate the role of DPT in the development of obesity-associated colon cancer (CC). Samples obtained from 73 subjects [26 lean (LN) and 47 with obesity (OB)] were used in a case-control study. Enrolled subjects were further subclassified according to the established diagnostic protocol for CC (42 without CC and 31 with CC). In vitro studies in the adenocarcinoma HT-29 cell line were performed to analyse the impact of pro- and anti-inflammatory mediators on the transcript levels of DPT as well as the effect of DPT on ECM remodelling and inflammation. Although obesity increased (p < 0.05) the circulating levels of DPT, its concentrations were significantly decreased (p < 0.05) in patients with CC. Gene expression levels of DPT in the colon from patients with CC were downregulated and, oppositely, a tendency towards increased mRNA levels in visceral AT was found. We further showed that DPT expression levels in HT-29 cells were enhanced (p < 0.05) by inflammatory factors (LPS, TNF-α and TGF-β), whereas the anti-inflammatory IL-4 decreased (p < 0.05) its expression levels. We also demonstrated that DPT upregulated (p < 0.05) the mRNA of key molecules involved in ECM remodelling (COL1A1, COL5A3, TNC and VEGFA) whereas decorin (DCN) expression was downregulated (p < 0.05) in HT-29 cells. Finally, we revealed that the adipocyte-conditioned medium obtained from volunteers with OB enhanced (p < 0.01) the expression of DPT in HT-29 and Caco-2 cells. The decreased circulating and expression levels of DPT in the colon together with the tendency towards increased levels in visceral AT in patients with CC and its influence on the expression of ECM proteins suggest a possible role of DPT in the OB-associated CC.

DNMT3a-dermatopontin axis suppresses breast cancer malignancy via inactivating YAP

“…Obesity-associated dysfunctional adipose tissue (AT) also secretes pro-oncogenic factors such as TNFα, IL-6, IL-1β and provides a carcinogenesis-promoting microenvironment for breast cancer development and progression; it is therefore a fundamental factor of postmenopausal breast cancer development [ 22 ]. Recently, the influence of DPT in AT remodeling and inflammation has been proposed [ 23 ]. A great variety of biological functions in both, physiological and pathological processes have been attributed to DPT due to its interaction with the transforming growth factor-β (TGF-β) and decorin together with its binding to integrin α3β1 and syndecan [ 9 , 10 , 24 ].…”

“…Recently, the influence of DPT in AT remodeling and inflammation has been proposed [23]. A great variety of biological functions in both, physiological and pathological processes have been attributed to DPT due to its interaction with the transforming growth factor-β (TGF-β) and decorin together with its binding to integrin α3β1 and syndecan [9,10,24].…”

Proteomic Analysis of Aqueous Humor Reveals Changes in Extracellular Matrix Pathways in Proliferative Diabetic Retinopathy Patients Treated with Intravitreal Ranibizumab

“…What's more, DPT protein, also known as tyrosine-rich acidic matrix protein (TRAMP), is predominantly found in the dermis of the skin and is an extensively distributed noncollagenous component of the ECM (Kim et al, 2019). It is involved in cell adhesion (Kramer et al, 2017), fibrosis (Wu et al, 2014), myogenesis (Kim et al, 2019), angiogenesis (Krishnaswamy et al, 2017), adipose tissue inflammation (Catalán et al, 2022), osteogenic proliferation and differentiation (Xi et al, 2018;Zhao et al, 2023), and tumor invasion and metastasis (Yamatoji et al, 2012). Combining DIA analysis and existing reports, we focused on the protein of DPT.…”

Extracellular Matrix and Cancer: An Intricate Affair

“…To get to the heart of the studies, Victoria Catalán and colleagues evaluate the role of dermatopontin (DPT) in obesity-associated colon cancer development [ 1 ]. The authors demonstrate that the circulating levels of DPT increase in obese patients; however, they significantly decrease during colon cancer development.…”