AbstractsBiology & Animal Science

Role of the NADPH Oxidase NOX4 in Liver Fibrosis and Hepatocarcinogenesis

by Eva Crosas Molist

Institution: Universitat de Barcelona
Year: 2015
Keywords: Malalties del fetge; Enfermedades del higado; Liver diseases; Càncer de fetge; Càncer de higado; Liver cancer; NADPH oxidasa; NADPH oxidase; Factor de crecimiento transformante beta; Factor de creixement transformant beta; Transforming growth factor beta (TGF-β); Ciències de la Salut
Record ID: 1126471
Full text PDF: http://hdl.handle.net/10803/290850


Reactive oxygen species (ROS) are short-lived, highly electrophilic molecules generated by the partial reduction of oxygen to form superoxide, hydrogen peroxide and hydroxyl radical as well as other secondary metabolites. For years, ROS have been considered as damaging molecules; however, in the last 20 years it has been proved that low levels of ROS can provoke transient and reversible modifications, leading to the regulation of signalling pathways. Within the cell there are numerous potential sources of ROS. They can be produced as by-products of enzymatic processes, which is considered the case of mitochondrial ROS, but they can also be produced as primary species, which is the case of ROS from the NADPH oxidase (NOX) family of enzymes that has emerged in the last years as an important source of ROS in signal transduction. NOX-derived ROS have been implicated in regulation of cytoskeletal remodelling, gene expression, proliferation, differentiation, migration and cell death. The NOX family is composed of seven members, NOX1-5 and two dual oxidases (DUOX1-2), which share analogies in structure and catalytic function, since all of them are transmembrane flavoproteins that mediate the reduction of oxygen using NADPH as an electron donor. However, important differences in regulation and cellular functions are observed among them. It has been reported that NOX1, NOX2 and NOX4 are expressed in the liver. Indeed, previous works from our group demonstrated that different NOX isoforms play different functions, sometimes even opposite roles, in hepatocytes. In this work we analyse the role of the NADPH oxidase NOX4 in different physiological and pathological situations of the liver such as liver regeneration, liver fibrosis and hepatocarcinogenesis. First, we describe the role of NOX4 during liver fibrosis. We show that Nox4 expression is up-regulated during liver fibrosis in two different mice models, and it is required for TGF-ß­induced transdifferentiation of hepatic stellate cells (HSC) to myofibroblasts, as well as for hepatocyte apoptosis. Secondly, we analyse the relevance of the autocrine activation of the Transforming Growth Factor-beta (TGF-ß) pathway during hepatocarcinogenesis and its relation with NOX4. We show that high levels of autocrine TGF-ß provoke loss of epithelial characteristics, gain of mesenchymal features and resistance to TGF-ß suppressor effects, in different human hepatocellular carcinoma (HCC) cells. Surprisingly, there is an inverse correlation between autocrine TGF-ß and NOX4 expression in HCC cell lines. Another important point in this work is the study of the role of NOX4 in the proliferative capacity of hepatocytes, as well as in their tumorigenic capacity. Results show that NOX4 is a negative regulator of proliferation in both untransformed hepatocytes and liver tumour cells. Moreover, its expression is down-regulated during liver regeneration after partial hepatectomy in mice. Furthermore, Nox4 expression is also down-regulated during Diethylnitrosamine (DEN)­induced liver…