BNIP3 supports melanoma cell migration and vasculogenic mimicry by orchestrating the actin cytoskeleton

BNIP3 is an atypical BH3-only member of the BCL-2 family of proteins with reported pro-death as well as pro-autophagic and cytoprotective functions, depending on the type of stress and cellular context. In line with this, the role of BNIP3 in cancer is highly controversial and increased BNIP3 levels in cancer patients have been linked with both good as well as poor prognosis. In this study, using small hairpin RNA (shRNA) lentiviral transduction to stably knockdown BNIP3 (BNIP3-shRNA) expression levels in melanoma cells, we show that BNIP3 supports cancer cell survival and long-term clonogenic growth. Although BNIP3-shRNA increased mitochondrial mass and baseline levels of reactive oxygen species production, which are features associated with aggressive cancer cell behavior, it also prevented cell migration and completely abolished the ability to form a tubular-like network on matrigel, a hallmark of vasculogenic mimicry (VM). We found that this attenuated aggressive behavior of these melanoma cells was underscored by severe changes in cell morphology and remodeling of the actin cytoskeleton associated with loss of BNIP3. Indeed, BNIP3-silenced melanoma cells displayed enhanced formation of actin stress fibers and membrane ruffles, while lamellopodial protrusions and filopodia, tight junctions and adherens junctions were reduced. Moreover, loss of BNIP3 resulted in re-organization of focal adhesion sites associated with increased levels of phosphorylated focal adhesion kinase. Remarkably, BNIP3 silencing led to a drop of the protein levels of the integrin-associated protein CD47 and its downstream signaling effectors Rac1 and Cdc42. These observations underscore that BNIP3 is required to maintain steady-state levels of intracellular complexes orchestrating the plasticity of the actin cytoskeleton, which is integral to cell migration and other vital processes stimulating cancer progression. All together these results unveil an unprecedented pro-tumorigenic role of BNIP3 driving melanoma cell's aggressive features, like migration and VM

C1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation

Complement C1q is the activator of the classical pathway. However, it is now recognized that C1q can exert functions unrelated to complement activation. Here we show that C1q, but not C4, is expressed in the stroma and vascular endothelium of several human malignant tumours. Compared with wild-type (WT) or C3- or C5-deficient mice, C1q-deficient (C1qa(-/-)) mice bearing a syngeneic B16 melanoma exhibit a slower tumour growth and prolonged survival. This effect is not attributable to differences in the tumour-infiltrating immune cells. Tumours developing in WT mice display early deposition of C1q, higher vascular density and an increase in the number of lung metastases compared with C1qa(-/-) mice. Bone marrow (BM) chimeras between C1qa(-/-) and WT mice identify non-BM-derived cells as the main local source of C1q that can promote cancer cell adhesion, migration and proliferation. Together these findings support a role for locally synthesized C1q in promoting tumour growth

Associations between neck circumference and adipocytokines among adolescents

Neck circumference (NC) was recently introduced as a predictor of cardiovascular disease (CVD) risk factor. Adipocytokines may have a key role in the development of CVD. Aims: The purpose of this study was to examine the associations between NC and adipocytokines, such as adiponectin and leptin in Portuguese adolescents.info:eu-repo/semantics/publishedVersio

Prognostic Implications of the Complement Protein C1q in Gliomas

The contribution of the complement system in the pathophysiology of brain cancers has been recently considered in light of its well-known involvement in carcinogenesis. Complement system represents an important component of the inflammatory response, which acts as a functional bridge between the innate and adaptive immune response. C1q, the first recognition subcomponent of the complement classical pathway, has recently been shown to be involved in a range of pathophysiological functions that are not dependent on complement activation. C1q is expressed in the microenvironment of various types of human tumors, including melanoma, prostate, mesothelioma, and ovarian cancers, where it can exert a protective or a harmful effect on cancer progression. Despite local synthesis of C1q in the central nervous system, the involvement of C1q in glioma pathogenesis has been poorly investigated. We, therefore, performed a bioinformatics analysis, using Oncomine dataset and UALCAN database in order to assess whether the expression of the genes encoding for the three chains of C1q (C1qA, C1qB, and C1qC) could serve as a potential prognostic marker for gliomas. The obtained results were then validated using an independent glioma cohort from the Chinese Glioma Genome Atlas datasets. Our bioinformatics analysis, coupled with immunohistochemistry and fluorescence microscopy, appears to suggest a positive correlation between higher levels of C1q expression and unfavorable prognosis in a diverse grade of gliomas

Fruit, vegetable consumption and blood pressure in healthy adolescents: A longitudinal analysis from the LabMed study

Background and aims: The associations between fruit and vegetable consumption and high blood pressure among adults are well studied. Nonetheless, data on the influence of a low consumption of fruit and vegetables on cardiovascular disease risk, particularly blood pressure, among healthy adolescents are scarce. Therefore, we aim to analyse the associations between fruit and/or vegetable intake and blood pressure over a two-year period in healthy adolescents.Methods and results: As part of a cohort, 606 adolescents from the LabMed Physical Activity study were evaluated in 2011 (baseline) and 2013 (follow-up). Blood pressure was measured according to standardized procedures and fruit and vegetable consumption was assessed with a food frequency questionnaire. Anthropometric variables, socioeconomic status, pubertal stage and lifestyle determinants were gathered and used as confounders. Prospective associations between fruit and/or vegetable intake and blood pressure were examined using generalized linear models. Girls who consumed more fruit at baseline had a significant decrease in diastolic blood pressure at follow-up [unstandardized beta: -0.005 mmHg (95% CI: -0.01; -0.0002) (p = 0.038)].Conclusion: In apparently healthy adolescents, fruit intake may already start to have an effect in blood pressure. Girls who consumed more fruit exhibited lower levels of diastolic blood pressure. (C) 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.This study was supported by the Research Centre on Physical Activity Health and Leisure (CIAFEL) of the Faculty of Sport, University of Porto and by FCT grant BD88984/2012 (J. Oliveira-Santos); The Research Centre on Physical Activity Health and Leisure (CIAFEL) is supported by UID/DTP/00617/2013 (FCT); the author C. Agostinis-Sobrinho was given Doctoral scholarship from the Brazilian government by CAPES (Coordination of Improvement of Higher Education Personnel) (Proc: 9588-13-2).The authors gratefully acknowledged the participation of all adolescents and their parents, teachers and schools of the LabMed Study. They also acknowledge the cooperation of volunteer's subjects and the Research Centre in Physical Activity, Health and Leisure (University of Porto) for the sponsoring the LabMed Study

PARL deficiency in mouse causes Complex III defects, coenzyme Q depletion, and Leigh-like syndrome

The mitochondrial intramembrane rhomboid protease PARL has been implicated in diverse functions in vitro, but its physiological role in vivo remains unclear. Here we show that ablation in mouse causes a necrotizing encephalomyelopathy similar to Leigh syndrome, a mitochondrial disease characterized by disrupted energy production. Mice with conditional PARL deficiency in the nervous system, but not in muscle, develop a similar phenotype as germline KOs, demonstrating the vital role of PARL in neurological homeostasis. Genetic modification of two major PARL substrates, PINK1 and PGAM5, do not modify this severe neurological phenotype. brain mitochondria are affected by progressive ultrastructural changes and by defects in Complex III (CIII) activity, coenzyme Q (CoQ) biosynthesis, and mitochondrial calcium metabolism. PARL is necessary for the stable expression of TTC19, which is required for CIII activity, and of COQ4, which is essential in CoQ biosynthesis. Thus, PARL plays a previously overlooked constitutive role in the maintenance of the respiratory chain in the nervous system, and its deficiency causes progressive mitochondrial dysfunction and structural abnormalities leading to neuronal necrosis and Leigh-like syndrome

THE CLINICOPATHOLOGICAL AND PROGNOSTIC SIGNIFICANCES OF C1Q EXPRESSION IN GLIOMAS: A BIOINFORMATICS ANALYSIS

Introduction. The complement system represents an important component of the inflammatory response and acts as a functional bridge between the innate and adaptive immune response. The contribution of the complement component C1q in the pathophysiology of brain cancers has been recently considered in light of its well-known involvement in carcinogenesis. Brain malignancies arise from cells of the CNS and are classified according to the tissue of phylogenetic origin. Gliomas represent the most common and aggressive form of brain tumours in adults. They derive from glial cells that help to support the functions of the other main brain cells type, the neurons (1). These are a heterogeneous group of diseases with multiple subtypes (1, 2). Glioblastoma multiforme (GBM) is the most common and fatal form of a primary brain tumour, accounting for approximately 60% of all glioma cases (3), whereas grade-II and -III gliomas are the second most common type of glioma in adults (~30%) (3). C1q molecule, together with other complement components, can be locally produced within the CNS by microglia and astrocytes, rendering it an attractive player in primary brain tumour development (4). The role of C1q in gliomas microenvironment is still poorly characterized and it is still quite puzzling whether it exerts a beneficial or a harmful activity for cancer progression. In the present study we performed a bioinformatics analysis aimed at investigating if C1q can serve as a potential prognostic marker for gliomas. Methods. The expression levels of C1qA, C1qB and C1qC genes in gliomas were analysed using Oncomine analysis. Available genomics data from The Cancer Genome Atlas project was used for Kaplan–Meier survival analysis to generate survival probability plots, using UALCAN analysis. Results. From the analysis performed on several data- sets using Oncomine, we showed a significantly higher mRNA expression levels for C1qA, C1qB and C1qC chains were detected in gliomas (different histotypes and grades) as compared to normal brain tissue (Fig. 1). We observed a positive correlation between the mRNA expression of C1qA, C1qB and C1qC mRNA poly- peptide chains and the unfavorable prognosis only in gliomas grade-II and -III, where the survival probability is indeed reduced (P <0.05) (Fig. 2). No correlation was observed in glioblastoma multiforme (Fig. 2). By immu- nohistochemical approaches we detected a high depo- sition of C1q in the tumor microenvironment of both in grade-II and -III gliomas and in GBMs examined (Fig. 3a glioma, 3b glioblastoma multiforme; 20x Magnification). Moreover, in double immunocytochemical experiments we demonstrated that CD68 positive infiltrating cells are actively synthesizing C1q in the tumor micro-envi- ronment. CD68 expression is characteristic of tumor- associated macrophages, whose enrichment in glioma has been associated with poor prognosis (5). Conclusion. In our study C1q expression was significantly correlated with poor survival probability in gliomas grade-II and -III while this is not the case for GBM. These data altogether underline how complex, multifaceted and still poorly understood is the role C1q can exert on tumor progression, and how the very same molecule can differentially affect the outcome depending on the biological context it comes to act