Role of VHL, HIF1A and SDH on the expression of miR-210: Implications for tumoral pseudo-hypoxic fate

The hypoxia-inducible factor 1a (HIF-1a) and its microRNA target, miR-210, are candidate tumor-drivers of metabolic reprogramming in cancer. Neuroendocrine neoplasms such as paragangliomas (PGLs) are particularly appealing for understanding the cancer metabolic adjustments because of their associations with deregulations of metabolic enzymes, such as succinate dehydrogenase (SDH), and the von Hippel Lindau (VHL) gene involved in HIF-1α stabilization. However, the role of miR-210 in the pathogenesis of SDH-related tumors remains an unmet challenge. Herein is described an in vivo genetic analysis of the role of VHL, HIF1A and SDH on miR-210 by using knockout murine models, siRNA gene silencing, and analyses of human tumors. HIF-1a knockout abolished hypoxia-induced miR-210 expression in vivo but did not alter its constitutive expression in paraganglia. Normoxic miR-210 levels substantially increased by complete, but not partial, VHL silencing in paraganglia of knockout VHL-mice and by over-expression of p76del-mutated pVHL. Similarly, VHLmutated PGLs, not those with decreased VHL-gene/mRNA dosage, over-expressed miR-210 and accumulate HIF-1a in most tumor cells. Ablation of SDH activity in SDHD-null cell lines or reduction of the SDHD or SDHB protein levels elicited by siRNA-induced gene silencing did not induce miR-210 whereas the presence of SDH mutations in PGLs and tumor-derived cell lines was associated with mild increase of miR-210 and the presence of a heterogeneous, HIF-1a-positive and HIF-1a-negative, tumor cell population. Thus, activation of HIF-1a is likely an early event in VHLdefective PGLs directly linked to VHL mutations, but it is a late event favored but not directly triggered by SDHx mutations. This combined analysis provides insights into the mechanisms of HIF-1a/miR-210 regulation in normal and tumor tissues potentially useful for understanding the pathogenesis of cancer and other diseases sharing similar underpinnings.Instituto de Salud Carlos III FIS PI11/929Red Temática de Investigación Cooperativa en Cáncer RD12/0036/0015 Instituto de Salud Carlos III (ISCIII)Ministerio de Economía y Competitividad y Fondo Europeo de Desarrollo RegionalFondo Europeo de Desarrollo Regional (FEDER) (CIBERONC

Fatal sclerosing mesenteritis: a 7-year-old male autopsy case report

Sclerosing Mesenteritis (SM) is a rare diagnosis, particularly in pediatric patients, and is typically non-fatal when appropriately treated. Although molecular and immunohistochemical alterations have been described, no pathognomonic signature has been identified for this entity. This report presents a case of a seven-year-old boy who suffered sudden cardiorespiratory arrest. Upon autopsy, he was found to have multicentric SM on the upper mesentery, which led to bowel wall thinning and abdominal bleeding with bacterial translocation. We performed comprehensive morphological, immunohistochemical, and molecular analyses. SM is an atypical disorder with diverse clinical manifestations, including a rare but potentially fatal course. Early diagnosis is critical, given its potential severity. To our knowledge, this is the first case report of pediatric mortality linked to SM. Our findings emphasize the importance of increased awareness and early detection of SM in pediatric patients

Increased Inflammation Delays Wound Healing in Mice Deficient in Collagenase-2 (MMP-8)

Matrix metalloproteinases (MMPs) have been implicated in numerous tissue-remodeling processes. The finding that mice deficient in collagenase-2 (MMP-8) are more susceptible to develop skin cancer, prompted us to investigate the role of this protease in cutaneous wound healing. We have observed a significant delay in wound closure in MMP8-/- mice and an altered inflammatory response in their wounds, with a delay of neutrophil infiltration during the first days and a persistent inflammation at later time points. These changes were accompanied by alterations in the TGF-beta1 signaling pathway and by an apoptosis defect in MMP8-/- mice. The delay in wound healing observed in MMP8-/- mice was rescued by bone marrow transplantation from wild-type mice. Analysis of other MMPs showed that MMP8-/- mice had a significant increase in the expression of MMP-9, suggesting that both proteases might act coordinately in this process. This possibility was further supported by the novel finding that MMP-8 and MMP-9 form specific complexes in vivo. Taken together, these data indicate that MMP-8 participates in wound repair by contributing to the resolution of inflammation and open the possibility to develop new strategies for treating wound healing defects