Decreased Levels of Microfibril-Associated Glycoprotein (MAGP)-1 in Patients with Colon Cancer and Obesity Are Associated with Changes in Extracellular Matrix Remodelling

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.

C60 Fullerene Clusters Stabilize the Biologically Inactive Form of Topotecan

“…This phenomenon can be explained by the so-called nonspecific resistance to a wide range of antitumor antibiotics, even if they have typical contrasting mechanisms of action. 35,36 Nevertheless, in both series of experiments, the principal results are similar, viz.…”

“…As noted above, the doxorubicin-resistant HCT-116 (−/−) cell line had little tolerance to the action of TPT/TPT-C 60 fullerene because these compounds could be partially excreted outside the cells. This phenomenon can be explained by the so-called nonspecific resistance to a wide range of antitumor antibiotics, even if they have typical contrasting mechanisms of action. , Nevertheless, in both series of experiments, the principal results are similar, viz. C 60 fullerene itself has no effect on the cell lines studied, The inhibition of proliferation for TPT alone and that in mixture with C 60 fullerene are identical within the margin of error. …”

Microfibrillar-associated protein 2 is a prognostic marker that correlates with the immune microenvironment in glioma

“…MFAP2 is a key ECM glycoprotein and protein component of ECM microfibrils. Changes in MFAP2 expression regulate ECM remodeling ( Gomez de Segura et al, 2021 ). By interacting with EGFL7, MFAP2 promotes its deposition into fibers in the endothelial ECM, thus playing a key role in vascular development ( Villain et al, 2018 ).…”

The role of microfibrillar‐associated protein 2 in cancer

“…There is a high affinity between the growth factor binding region near the MFAP2 N-terminus and the transforming growth factor-β (TGF-β) superfamily members; the mutual effect between MFAP2 and the active TGF-β form has biological consequences ( 16 ). Numerous studies have shown abnormal MFAP2 levels and its effects on prognosis in different cancers ( Table 1 ), highlighting its significance in tumor progression, particularly during epithelial-mesenchymal transformation (EMT), because of its association with TGF-β ( 24 , 31 , 32 ). Changes in the MFAP2 level regulate ECM remodeling, playing an important role in tumorigenesis ( 32 ).…”

“…Numerous studies have shown abnormal MFAP2 levels and its effects on prognosis in different cancers ( Table 1 ), highlighting its significance in tumor progression, particularly during epithelial-mesenchymal transformation (EMT), because of its association with TGF-β ( 24 , 31 , 32 ). Changes in the MFAP2 level regulate ECM remodeling, playing an important role in tumorigenesis ( 32 ). In addition, MFAP2 is important in tumor cell apoptosis, proliferation, angiogenesis, invasion, and prognosis ( 18 , 20 , 23 , 24 ).…”