New mechanisms involving the EGFR and FGF15/19 systems in liver regeneration and carcinogenesis
© Berasain and Avila; licensee BioMed Central Ltd. 2014
Published: 19 June 2014
There are two important aspects regarding the signals and pathways activated during liver injury and regeneration. One is their extensive crosstalk, with frequent mutual influences on the expression and activities of the different growth factors and cytokines. The other is the common involvement of many of these mediators and pathways in the liver carcinogenic process, when the reparative reaction goes awry in the setting of chronic liver injury. This has been cogently demonstrated for the epidermal growth factor receptor (EGFR) signaling system. Normal hepatocytes express high levels of EGFR, EGFR activation contributes significantly to hepatocellular survival and proliferation during injury and regeneration, and also plays a fundamental role in the negative regulation of liver acute phase response triggered by inflammatory cytokines . Amphiregulin (AR) is one of the ligands of the EGFR which expression is markedly up-regulated during liver inflammation and injury (Figure 1). AR plays a non-redundant role among EGFR ligands in hepatocyte proliferation and survival in different models of liver injury and regeneration, including Fas activation, CCl4 administration, ischemia-reperfusion and PH . Interestingly, AR is also essential for the attenuation of the liver acute phase response, contributing to the repression of acute phase proteins such as α1-antichymotrypsin, also known as serpinA3 [4, 5]. Persistent AR up-regulation has been detected in chronic liver injury, and this growth factor plays an important role in hepatic fibrogenesis, a consequence of the dysregulated wound healing response occuring during chronic liver damage . Furthermore, AR mediates an autocrine stimulatory loop contributing to the neoplastic properties of hepatocellular carcinoma (HCC) cells through the stimulation of the EGFR . Importantly, AR contributes to the resistance of HCC cells to the growth inhibitory and pro-apoptotic actions of transforming growth factor β (TGFβ), conventional cytotoxic drugs like doxorubicin (Dox), and most importantly targeted anti-HCC agents like sorafenib (Figure 1). Regarding the mechanisms leading to AR up-regulation in HCC cells, we found that AR gene expression could be induced by FGF19, which in turn is frequently overexpressed in human HCC cells . This stimulatory effect of FGF19 on AR gene transcription was mediated thorugh the stimulation of β-catenin (b-cat) signaling. This is an example of the extensive crosstalk among different growth factors in liver injury and carcinogenesis alluded above.
Finally, we could also identify a novel pro-tumorigenic mechanism activated by the AR/EGFR signaling system in liver cancer development. As previously mentioned, AR plays a fundamental role in the negative control of the acute phase reaction, and in the down-regulation of acute phase proteins during liver regeneration, counteracting the effects of inflammatory cytokines like oncostatin M (OSM). One of the most dysregulated acute phase genes in AR deficient mice undergoing an acute phase was serpinA3, a serin-protease inhibitor secreted by hepatocytes during inflammation . We found that serpinA3 expression was markedly reduced in HCC cells due to an AR/EGFR autocrine loop (Figure 1), and importantly reduced serpinA3 expression was consistently found in human HCC tissues . Intriguingly, serpinA3 was also detected in the nucleus of hepatocytes, and restitution of the expression of this gene significantly blunted HCC cell proliferation and the growth of HCC xenografts in nude mice . Interestingly, from a mechanistically point of view, we could demonstrate that nuclear serpinA3 forms polymeric aggregates that tightly bind chromatin, inducing a condensed status that is not compatible with DNA synthesis and cell proliferation. These findings provide a mechanistic explanation to the early observations of reduced acute phase gene expression during liver regeneration, and identify serpinA3 as an important regulator of hepatocellular proliferation, which is lost during liver cancer development. Together, our observations provide novel insights into the mechanisms of liver repair and regeneration. We also identify new pro-regenerative agents with potential therapeutic application in an acute setting, as well as novel targets for antitumoral intervention.
- Michalopoulos GK: Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. Am J Pathol 2010, 176: 2–13. 10.2353/ajpath.2010.090675PubMed CentralPubMedView ArticleGoogle Scholar
- Fernández-Barrena MG, Monte MJ, Latasa MU, Uriarte I, Vicente E, Chang HC, Rodriguez-Ortigosa CM, Elferink RO, Berasain C, Marin JJ, Prieto J, Ávila MA: Lack of Abcc3 expression impairs bile-acid induced liver growth and delays hepatic tegeneration after partial hepatectomy in mice. J Hepatol 2012, 56: 367–373.PubMedView ArticleGoogle Scholar
- Uriarte I, Fernández-Barrena MG, Monte MJ, Latasa MU, Chang HCY, Carotti S, et al.: Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice. Gut 2013, 62: 899–910. 10.1136/gutjnl-2012-302945PubMedView ArticleGoogle Scholar
- Berasain C, Avila MA: The EGFR signaling system in the liver: from hepatoportection to hepatocarcinogenesis. J Gastroenterol 2014, 49: 9–23. 10.1007/s00535-013-0907-xPubMedView ArticleGoogle Scholar
- Berasain C, Avila MA: Amphiregulin. Semin Cell Dev Biol, in press.Google Scholar
- Santamaría M, Pardo-Saganta A, Alvarez-Asiain L, Di Scala M, Qian C, Prieto J, Avila MA: Nuclear α1-antichymotrypsin promotes chromatin condensation and inhibits proliferation of human hepatocellular carcinoma cells. Gastroenterology 2013, 144: 818–828. 10.1053/j.gastro.2012.12.029PubMedView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.