Blanca Herrera

Complutense University of Madrid, Madrid, Madrid, Spain

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Publications (8)41.19 Total impact

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    ABSTRACT: Oval cells constitute an interesting hepatic cell population. They contribute to sustain liver regeneration during chronic liver damage, but in doing this they can be target of malignant conversion and become tumor-initiating cells and drive hepatocarcinogenesis. The molecular mechanisms beneath either their pro-regenerative or pro-tumorigenic potential are still poorly understood. In this study, we have investigated the role of the HGF/c-Met pathway in regulation of oval cell migratory and invasive properties. Our results show that HGF induces c-Met-dependent oval cell migration both in normal culture conditions and after in vitro wounding. HGF-triggered migration involves F-actin cytoskeleton reorganization, which is also evidenced by activation of Rac1. Furthermore, HGF causes ZO-1 translocation from cell-cell contact sites to cytoplasm and its concomitant activation by phosphorylation. However, no loss of expression of cell-cell adhesion proteins, including E-cadherin, ZO-1 and Occludin-1, is observed. Additionally, migration does not lead to cell dispersal but to a characteristic organized pattern in rows, in turn associated with Golgi compaction, providing strong evidence of a morphogenic collective migration. Besides migration, HGF increases oval cell invasion through extracellular matrix, process that requires PI3K activation and is at least partly mediated by expression and activation of metalloproteases. Altogether, our findings provide novel insights into the cellular and molecular mechanisms mediating the essential role of HGF/c-Met signaling during oval cell-mediated mouse liver regeneration. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 05/2015; 1853(10 Pt A). DOI:10.1016/j.bbamcr.2015.05.017 · 4.66 Impact Factor

  • Journal of Hepatology 04/2015; 62:S469-S470. DOI:10.1016/S0168-8278(15)30628-0 · 11.34 Impact Factor
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    Blanca Herrera · Steven Dooley · Katja Breitkopf-Heinlein ·
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    ABSTRACT: Bone morphogenetic proteins (BMP-2 to BMP-15) belong to the Transforming Growth Factor (TGF)-β superfamily and, besides their well-documented roles during embryogenesis and bone formation, some of them have recently been described to be involved in the pathogenesis of different organs, including the liver. The role of BMPs in liver damage responses including hepatocellular carcinoma (HCC) development has only begun to be addressed and strong evidence supports the concept of a pro-tumorigenic role of BMP signaling in HCC cells. BMP-9 (also termed Growth and Differentiation Factor (GDF)-2) represents the most recently discovered member of the BMP family. We have previously demonstrated that in HCC patient samples BMP-9 expression was positively associated with the tumor seize ("T stage") and that it enhanced cell migration and induced epithelial to mesenchymal transition (EMT) in HCC cells in vitro. In another study we recently found that BMP-9 promotes growth in HCC cells, but not in non-transformed hepatocytes. Published as well as unpublished results obtained with primary hepatocytes support the concept of a dual function of BMP-9 in the liver: while in primary, non-malignant cells BMP-9 stabilizes the epithelial phenotype and inhibits proliferation, in HCC cells it induces cell growth and the acquisition of a migratory phenotype. In this review article we summarize current knowledge about BMPs in liver diseases, with special focus on the role of BMP-9 in HCC development and progression, that may provide new clues for a better understanding of the contribution of BMP-signaling to chronic liver diseases.
    International Journal of Molecular Sciences 04/2014; 15(4):5199-220. DOI:10.3390/ijms15045199 · 2.86 Impact Factor

  • Journal of Hepatology 04/2013; 58:S127-S128. DOI:10.1016/S0168-8278(13)60305-0 · 11.34 Impact Factor

  • Journal of Hepatology 04/2013; 58:S120. DOI:10.1016/S0168-8278(13)60286-X · 11.34 Impact Factor
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    ABSTRACT: Liver progenitor cells rise as potential critical players in hepatic regeneration but also carcinogenesis. It is therefore mandatory to define the signals controlling their activation and expansion. Recently, by using a novel in vitro model of oval cell lines expressing a mutant tyrosine kinase-inactive form of c-Met we demonstrated that autocrine c-Met signalling plays an essential role in promoting oval cell survival. Here, we investigated the significance of the epidermal growth factor receptor (EGFR) signalling in oval cell proliferation and survival, as well as a potential functional crosstalk between the c-Met and the EGFR pathways. We found an autocrine activation of the EGFR-triggered pathway in Met(flx/flx) and Met(-/-) oval cells as judged by constitutive expression of the EGFR ligands, transforming growth factor-alpha (TGF-α) and heparin-binding EGF like growth factor (HB-EGF), and activation of EGFR. On the other hand, treatment with AG1478, a specific inhibitor of EGFR, effectively blocked endogenous and EGF-induced proliferation, while increased serum withdrawal and transforming growth factor-beta (TGF-β)-induced apoptosis. These results suggest that constitutively activated EGFR might promote oval cell proliferation and survival. We found that hepatocyte growth factor (HGF) does not transactivate EGFR nor EGF transactivates c-Met. Furthermore, treatment with AG1478 or EGFR gene silencing did not interfere with HGF-mediated activation of target signals, such as protein kinase B (AKT/PKB), and extracellular signal-regulated kinases 1/2 (ERK 1/2), nor did it have any effect on HGF-induced proliferative and antiapoptotic activities in Met(flx/flx) cells, showing that HGF does not require EGFR activation to mediate such responses. EGF induced proliferation and survival equally in Met(flx/flx) and Met(-/-) oval cells, proving that EGFR signalling does not depend on c-Met tyrosine kinase activity. Together, our results provide strong evidence that in normal, untransformed oval cells, c-Met and EGFR represent critical molecular players to control proliferation and survival that function independent of one another.
    Cellular Signalling 02/2012; 24(2):505-13. DOI:10.1016/j.cellsig.2011.09.031 · 4.32 Impact Factor
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    ABSTRACT: Most of the morphologic changes that are observed in apoptotic cells are caused by a set of cysteine proteases (caspases) that are activated during this process. In previous works from our group we found that treatment of rat fetal hepatocytes with transforming growth factor beta1 (TGF-beta1) is followed by apoptotic cell death. TGF-beta1 mediates radical oxygen species (ROS) production that precedes bcl-xL down-regulation, loss of mitochondrial transmembrane potential, release of cytochrome c, and activation of caspase-3 (Herrera et al., FASEB J 2001;15:741-751). In this work, we have analyzed how TGF-beta1 activates the caspase cascade and whether or not caspase activation precedes the oxidative stress induced by this factor. Our results show that TGF-beta1 activates at least caspase-3, -8, and -9 in rat fetal hepatocytes, which are not required for ROS production, glutathione depletion, bcl-xL down-regulation, and initial cytochrome c release. However, caspase activation mediates cleavage of Bid and Bcl-xL that could originate an amplification loop on the mitochondrial events. An interesting result is that transmembrane potential disruption occurs later than the initial cytochrome c release and is mostly blocked by the pan-caspase inhibitor Z-VAD.fmk, indicating that the decrease in mitochondrial transmembrane potential (Delta(Psi)m) may be a consequence of caspase activity rather than the mechanism by which TGF-beta induces cytochrome c efflux. Finally, although Z-VAD.fmk completely blocks nucleosomal DNA fragmentation, it only delays cell death, which suggests that activation of the apoptotic program by TGF-beta in fetal hepatocytes inevitably leads to death, with or without caspases.
    Hepatology 10/2001; 34(3):548-56. DOI:10.1053/jhep.2001.27447 · 11.06 Impact Factor
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    ABSTRACT: We have previously found that transforming growth factor-beta (TGF-beta) induces an increase in radical oxygen species (ROS) production that mediates its apoptotic effects in fetal hepatocytes. In this paper we show that TGF-beta activates p38 mitogen-activated protein kinase (p38MAPK) and ROS may be responsible for this activation. Activation of p38MAPK occurs late, coincident with the maximal production of ROS, it is inhibited by radical scavengers and it is accentuated by the presence of glutathione synthesis inhibitors. However, p38MAPK does not appear to be involved in any of the apoptotic events: loss of Bcl-x(L) levels, cytochrome c release, cleavage of caspase substrates and loss of cell viability.
    FEBS Letters 07/2001; 499(3):225-9. DOI:10.1016/S0014-5793(01)02554-6 · 3.17 Impact Factor