Abstract
Objective: The protein microfibril-associated glycoprotein (MAGP)-1 constitutes a crucial extracellular matrix protein. We aimed to determine its impact on visceral adipose tissue (VAT) remodelling during obesity-associated colon cancer (CC). Methods: Samples obtained from 79 subjects (29 normoponderal (NP) (17 with CC) and 50 patients with obesity (OB) (19 with CC)) were used in the study. Circulating concentrations of MAGP-1 and its gene expression levels (MFAP2) in VAT were analysed. The impact of inflammation-related factors and adipocyte-conditioned media (ACM) on MFAP2 mRNA levels in colon adenocarcinoma HT-29 cells were further analysed. The effects of MAGP-1 in the expression of genes involved in the extracellular matrix (ECM) remodelling and tumorigenesis in HT-29 cells was also explored. Results: Obesity (p < 0.01) and CC (p < 0.001) significantly decreased MFAP2 gene expression levels in VAT whereas an opposite trend in TGFB1 mRNA levels was observed. Increased mRNA levels of MFAP2 after the stimulation of HT-29 cells with lipopolysaccharide (LPS) (p < 0.01) and interleukin (IL)-4 (p < 0.01) together with a downregulation (p < 0.05) after hypoxia mimicked by CoCl2 treatment was observed. MAGP-1 treatment significantly enhanced the mRNA levels of the ECM-remodelling genes collagen type 6 α3 chain (COL6A3) (p < 0.05), decorin (DCN) (p < 0.01), osteopontin (SPP1) (p < 0.05) and TGFB1 (p < 0.05). Furthermore, MAGP-1 significantly reduced (p < 0.05) the gene expression levels of prostaglandin-endoperoxide synthase 2 (COX2/PTGS2), a key gene controlling cell proliferation, growth and adhesion in CC. Interestingly, a significant decrease (p < 0.01) in the mRNA levels of MFAP2 in HT-29 cells preincubated with ACM from volunteers with obesity compared with control media was observed. Conclusion: The decreased levels of MAGP-1 in patients with obesity and CC together with its capacity to modulate key genes involved in ECM remodelling and tumorigenesis suggest MAGP-1 as a link between AT excess and obesity-associated CC development.
Highlights
Colon cancer (CC) is the second leading cause of death in developed societies [1]
We found that obesity (p = 0.006) and CC (p = 0.012) increased plasma levels of chitinase 3-like 1 (YKL-40), a marker that contributes to chronic inflammation and oncogenic transformation
We found that obesity increased (p = 0.038) plasma levels of vascular endothelial growth factor A (VEGFA)
Summary
Colon cancer (CC) is the second leading cause of death in developed societies [1]. More than one-half of all causes of deaths related to cancer are attributable to modifiable risk factors including smoking, alcohol consumption, lack of physical activity and excess body weight with, 8% of all cancer deaths being associated to obesity [2]. Growing evidence indicates that obesity promotes CC by the tumour-promoting effects of systemically dysregulated adipokines and metabolic mediators, and by local progression enhancement through chronic low-grade inflammation [4,5,8,9] and the extracellular matrix (ECM) remodelling impairment of the AT [9,10,11] In this sense, the ECM of the AT is recognized as a dynamic regulator of cellular processes providing structural support to the surrounding cells and, playing a crucial role in the biological function of different organs [12,13]. Since MAGP-1 is reported as an important ECM component of the AT with a role in cancer progression, we hypothesized that dysregulated levels of MAGP-1 in obesity may function as a link between AT excess and CC development. The impact of the adipocyte-conditioned medium (ACM) obtained from patients with obesity on the expression of MFAP2 in HT-29 cells was further analyzed
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