Epigenetic repression of ROR2 has a Wnt-mediated, pro-tumourigenic role in colon cancer

Background: Wnt factors control cell differentiation through semi-independent molecular cascades known as the beta-catenin-dependent (canonical) and -independent (non-canonical) Wnt signalling pathways. Genetic and epigenetic alteration of components of the canonical Wnt signalling pathway is one of the primary mechanisms underlying colon cancer. Despite increasing evidence of the role of the non-canonical pathways in tumourigenesis, however, the underlying molecular mechanisms are poorly understood. Results: Here we report that the receptor tyrosine kinase-like orphan receptor 2 (ROR2), a transmembrane receptor for Wnt factors that activates non-canonical pathways, is frequently repressed by aberrant promoter hypermethylation in human colon cancer cell lines and primary tumours. By restoring ROR2 activity in colon cancer cells harbouring ROR2 promoter hypermethylation, we show that the role of ROR2 in colon cancer cells is mediated, at least in part, by canonical Wnt and that its epigenetic-dependent loss can be pro-tumourigenic. Conclusions: Our data show the importance of epigenetic alterations of ROR2 in colon cancer, highlighting the close interconnection between canonical and non-canonical Wnt signalling pathways in this type of tumour

Hyalectanase Activities by the ADAMTS Metalloproteases

The hyalectan family is composed of the proteoglycans aggrecan, versican, brevican and neurocan. Hyalectans, also known as lecticans, are components of the extracellular matrix of different tissues and play essential roles in key biological processes including skeletal development, and they are related to the correct maintenance of the vascular and central nervous system. For instance, hyalectans participate in the organization of structures such as perineural nets and in the regulation of neurite outgrowth or brain recovery following a traumatic injury. The ADAMTS (A Disintegrin and Metalloprotease domains, with thrombospondin motifs) family consists of 19 secreted metalloproteases. These enzymes also perform important roles in the structural organization and function of the extracellular matrix through interactions with other matrix components or as a consequence of their catalytic activity. In this regard, some of their preferred substrates are the hyalectans. In fact, ADAMTSs cleave hyalectans not only as a mechanism for clearance or turnover of proteoglycans but also to generate bioactive fragments which display specific functions. In this article we review some of the physiological and pathological effects derived from cleavages of hyalectans mediated by ADAMTSs

Lung Inflammatory Phenotype in Mice Deficient in Fibulin-2 and ADAMTS-12

Interaction between extracellular matrix (ECM) components plays an important role in the regulation of cellular behavior and hence in tissue function. Consequently, characterization of new interactions within ECM opens the possibility of studying not only the functional but also the pathological consequences derived from those interactions. We have previously described the interaction between fibulin2 and ADAMTS-12 in vitro and the effects of that interaction using cellular models of cancer. Now, we generate a mouse deficient in both ECM components and evaluate functional consequences of their absence using different cancer and inflammation murine models. The main findings indicate that mice deficient in both fibulin2 and ADAMTS12 markedly increase the development of lung tumors following intraperitoneal urethane injections. Moreover, inflammatory phenotype is exacerbated in the lung after LPS treatment as can be inferred from the accumulation of active immune cells in lung parenchyma. Overall, our results suggest that protective effects in cancer or inflammation shown by fibulin2 and ADAMTS12 as interactive partners in vitro are also shown in a more realistic in vivo context

Biocompatibility and Antioxidant Capabilities of Carbon Dots Obtained from Tomato (<i>Solanum lycopersicum</i>)

Since their discovery in 2004, carbon dots have attracted strong interest in the scientific community due to their characteristic properties, particularly their luminescence and their ease of synthesis and derivatization. Carbon dots can be obtained from different carbon sources, including natural products, resulting in a so-called ’green synthesis’. In this work, we obtain carbon dots from tomato juice in order to obtain nanoparticles with the antioxidant capabilities of the natural antioxidants present in that fruit. The obtained material is characterized regarding nanoparticle size distribution, morphology, surface functional groups and optic properties. Antioxidant properties are also evaluated through the DPPH method and their cytotoxicity is checked against human dermal fibroblast and A549 cell-lines. The results indicate that carbon dots obtained from tomato have a higher antioxidant power than other already-published antioxidant carbon dots. The bandgap of the synthesized materials was also estimated and coherent with the literature values. Moreover, carbon dots obtained from tomato juice are barely toxic for healthy cells up to 72 h, while they induce a certain cytotoxicity in A549 lung carcinoma cells

The molecular interaction of ADAMTS-1 and fibulin-1 and its potential contribution to breast cancer biology

Aim: Fibulins and ADAMTSs are two families of extracellular matrix proteins implicated in key functional and pathological processes. The fact that the fibulin-1 and ADAMTS-1 proteins interact raises new questions about the roles of these extracellular matrix proteins in modulating tumor progression. Herein, we described the functional implications of the interaction between fibulin-1 and ADAMTS-1 on the behavior of breast cancer cell lines.Methods: Fibulin-1 and ADAMTS-1 were exogenously expressed in MCF-7 and MDA-MB-231 cell lines to assay the effect of their interaction in cellular properties.Results: ADAMTS-1 expression exacerbates tumor effects in terms of proliferation, invasion and mammosphere formation. In contrast, the simultaneous expression of ADAMTS-1 and fibulin-1 impairs these effects. The analysis of the expression of both proteins in human breast cancer tissue arrays provides new insights into the complex roles of fibulin-1 and ADAMTS-1 in this type of tumor.Conclusion: Our results suggests that the interaction between ADAMTS-1 and fibulin-1 induces a pronounced anti-tumoral effect

Identification of relevant genetic alterations in cancer using topological data analysis

Rare cancer mutations are often missed using recurrence-based statistical approaches, but are usually accompanied by changes in expression. Here the authors leverage this information to uncover several elusive candidate cancer-associated genes using topological data analysis

Epigenetic repression of ROR2 has a Wnt-mediated, pro-tumourigenic role in colon cancer

Abstract Background Wnt factors control cell differentiation through semi-independent molecular cascades known as the β-catenin-dependent (canonical) and -independent (non-canonical) Wnt signalling pathways. Genetic and epigenetic alteration of components of the canonical Wnt signalling pathway is one of the primary mechanisms underlying colon cancer. Despite increasing evidence of the role of the non-canonical pathways in tumourigenesis, however, the underlying molecular mechanisms are poorly understood. Results Here we report that the receptor tyrosine kinase-like orphan receptor 2 (ROR2), a transmembrane receptor for Wnt factors that activates non-canonical pathways, is frequently repressed by aberrant promoter hypermethylation in human colon cancer cell lines and primary tumours. By restoring ROR2 activity in colon cancer cells harbouring ROR2 promoter hypermethylation, we show that the role of ROR2 in colon cancer cells is mediated, at least in part, by canonical Wnt and that its epigenetic-dependent loss can be pro-tumourigenic. Conclusions Our data show the importance of epigenetic alterations of ROR2 in colon cancer, highlighting the close interconnection between canonical and non-canonical Wnt signalling pathways in this type of tumour.</p