Amedeo Columbano

MicroRNAs (miRNAs) are evolutionarily conserved small noncoding RNAs involved in the regulation of gene expression and protein translation. Many studies have shown that they play a crucial role in driving organ and tissue differentiation during embryogenesis and in the fine-tuning of fundamental biological processes, such as proliferation and apoptosis. Growing evidence indicates that their deregulation plays an important role in cancer onset and progression as well, where they act as oncogenes or oncosuppressors. In this review, we highlight the most recent findings regarding the role of miRNAs in hepatocellular carcinoma (HCC) by analyzing the possible mechanisms by which they contribute to this neoplasm. Moreover, we discuss the possible role of circulating miRNAs as biomarkers, a field that needs urgent improvement in the clinical surveillance of HCC, and the fascinating possibility of using them as therapeutic targets or drugs themselves.

Epigenome-wide association studies (EWAS) are designed to characterise population-level epigenetic differences across the genome and link them to disease. Most commonly, they assess DNA-methylation status at cytosine-guanine dinucleotide (CpG) sites, using platforms such as the Illumina 450k array that profile a subset of CpGs genome wide. An important challenge in the context of EWAS is determining a significance threshold for declaring a CpG site as differentially methylated, taking multiple testing into account. We used a permutation method to estimate a significance threshold specifically for the 450k array and a simulation extrapolation approach to estimate a genome-wide threshold. These methods were applied to five different EWAS datasets derived from a variety of populations and tissue types. We obtained an estimate of α=2.4×10-7 for the 450k array, and a genome-wide estimate of α=3.6×10-8. We further demonstrate the importance of these results by showing that previously recommended sample sizes for EWAS should be adjusted upwards, requiring samples between ∼10% and ∼20% larger in order to maintain type-1 errors at the desired level.

The term apoptosis was proposed to define a type of cell death morphologically, biochemically, and molecularly distinct from necrosis, which plays a fundamental regulatory function in the control of the overall size of cell populations, being complementary but opposite to cell proliferation [Kerr et al. (1972): Br J Cancer 26:239-257]. This view has led to the appreciation that apoptosis is an integral part of normal biological processes and may impact on disease states. Introduction of the concept of apoptosis has raised great interest and many studies have been aimed to the identification of genes responsible for the induction of cell death. Indeed, over the past few years, many genes whose expression is associated with cell death have been described, and the molecular mechanisms underlying cell death have been, in some circumstances, clearly established. However, it is now evident that extension of the conclusions achieved by studies performed with highly selected in vitro systems (simple systems), to in vivo conditions (complex systems), has generated a certain degree of confusion. This is in part due to the indiscriminate use of the term apoptosis and to the uncertainty whether apoptosis is always different from necrosis, and, if this is the case, to the lack of well established criteria to discriminate the two processes; in addition, it still remains to be established whether both types of cell death, although different, could be induced simultaneously by the same agent, depending on the cell type and the experimental condition used. The distinction between apoptosis and necrosis, is not simply a problem of terminology; if necrosis and apoptosis are different from a mechanistic point of view, and if necrosis is merely the passive result of cellular injury (still to be shown), it becomes critical to discriminate between the two processes, in order to understand how to modulate apoptosis in view of its potential therapeutic use. This review will summarize existing informations and discuss some of the conflicting issues related to cell death in the liver.