New and Notable This Week

This week’s selection of recently published papers from MDPI journals. IJMS Logo

Identification of Drivers from Cancer Genome Diversity in Hepatocellular Carcinoma

Atsushi Takai, Hien T. Dang and Xin W. Wang 

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

Abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers with a dismal outcome. The complicated molecular pathogenesis of HCC caused by tumor heterogeneity makes it difficult to identify druggable targets useful for treating HCC patients. One approach that has a potential for the improvement of patient prognosis is the identification of cancer driver genes that play a critical role in the development of HCC. Recent technological advances of high-throughput methods, such as gene expression profiles, DNA copy number alterations and somatic mutations, have expanded our understanding of the comprehensive genetic profiles of HCC. Integrative analysis of these omics profiles enables us to classify the molecular subgroups of HCC patients. As each subgroup classified according to genetic profiles has different clinical features, such as recurrence rate and prognosis, the tumor subclassification tools are useful in clinical practice. Furthermore, a global genetic analysis, including genome-wide RNAi functional screening, makes it possible to identify cancer vulnerable genes. Identification of common cancer driver genes in HCC leads to the development of an effective molecular target therapy.


For Open Access Article, see: Takai, A.; Dang, H.T.; Wang, X.W. Identification of Drivers from Cancer Genome Diversity in Hepatocellular CarcinomaInt. J. Mol. Sci. 201415, 11142-11160.



Modelling Proteasome and Proteasome Regulator Activities

Juliane Liepe 1,, Herman-Georg Holzhütter 2, Peter M. Kloetzel 2, Michael P. H. Stumpf 1,3 and Michele Mishto 2,4,

 1Theoretical Systems Biology, Division of Molecular Biosciences, Imperial College London, London SW7 2AZ, UK, 2Institute of Biochemistry, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany, 3Centre for Integrative Systems Biology and Bioinformatics, Imperial College London, London SW7 2AZ, UK, 4Interdepartmental Center for Cancer Research “Giorgio Prodi”, University of Bologna, 40126 Bologna, Italy

Abstract: Proteasomes are key proteases involved in a variety of processes ranging from the clearance of damaged proteins to the presentation of antigens to CD8+ T-lymphocytes. Which cleavage sites are used within the target proteins and how fast these proteins are degraded have a profound impact on immune system function and many cellular metabolic processes. The regulation of proteasome activity involves different mechanisms, such as the substitution of the catalytic subunits, the binding of regulatory complexes to proteasome gates and the proteasome conformational modifications triggered by the target protein itself. Mathematical models are invaluable in the analysis; and potentially allow us to predict the complex interactions of proteasome regulatory mechanisms and the final outcomes of the protein degradation rate and MHC class I epitope generation. The pioneering attempts that have been made to mathematically model proteasome activity, cleavage preference variation and their modification by one of the regulatory mechanisms are reviewed here. Slide2

For Open Access Article, see: Liepe, J.; Holzhütter, H.-G.; Kloetzel, P.M.; Stumpf, M.P.H.; Mishto, M. Modelling Proteasome and Proteasome Regulator ActivitiesBiomolecules 2014,4, 585-599.



Roles of Sphingolipid Metabolism in Pancreatic β Cell Dysfunction Induced by Lipotoxicity

Julien Véret 1, Lara Bellini 1, Paola Giussani 2, Carl Ng 3, Christophe Magnan 1 and Hervé Le Stunff 1

1University Paris Diderot, Sorbonne Paris City, Unit of Functional and Adaptative Biology UMR 8251 CNRS, 75205 Paris Cedex 13, France, 2Department of Medical Biotechnology and Translational Medicine, University of Milan, LITA Segrate, Via Fratelli Cervi 93, 20090 Segrate (MI), Italy, 3School of Biology and Environmental Science and UCD Earth Institute, University College Dublin, Belfield, Dublin 4, Ireland

Abstract: Pancreatic β cells secrete insulin in order to maintain glucose homeostasis. However, various environmental stresses such as obesity have been shown to induce loss of secretory responsiveness in pancreatic β cells and pancreatic β cell apoptosis which can favor the development of type 2 diabetes (T2D). Indeed, elevated levels of free fatty acids (FFAs) have been shown to induce β cell apoptosis. Importantly, the chronic adverse effects of FFAs on β cell function and viability are potentiated in the presence of hyperglycaemia, a phenomenon that has been termed gluco-lipotoxicity. The molecular mechanisms underlying the pathogenesis of gluco-lipotoxicity in pancreatic β cells are not completely understood. Recent studies have shown that sphingolipid metabolism plays a key role in gluco-lipotoxicity induced apoptosis and loss of function of pancreatic β cells. The present review focuses on how the two main sphingolipid mediators, ceramides and sphingoid base-1-phosphates, regulate the deleterious effects of gluco-lipotoxicity on pancreatic β cells. The review highlights the role of a sphingolipid biostat on the dysregulation of β cell fate and function induced by gluco-lipotoxicity, offering the possibility of new therapeutic targets to prevent the onset of T2D.


For Open Access Article, see: Véret, J.; Bellini, L.; Giussani, P.; Ng, C.; Magnan, C.; Stunff, H.L. Roles of Sphingolipid Metabolism in Pancreatic β Cell Dysfunction Induced by LipotoxicityJ. Clin. Med. 20143, 646-662.