Amphiregulin: An early trigger of liver regeneration in mice. [See comment]

Division of Hepatology and Gene Therapy, Cntro de Investigción Médica Aplicada, Facultad e Medicina,Universidad de Navarra, Pamplona, Spain.
Gastroenterology (Impact Factor: 16.72). 03/2005; 128(2):424-32. DOI: 10.1053/j.gastro.2004.11.006
Source: PubMed


Liver regeneration is a unique response directed to restore liver mass after resection or injury. The survival and proliferative signals triggered during this process are conveyed by a complex network of cytokines and growth factors acting in an orderly manner. Activation of the epidermal growth factor receptor is thought to play an important role in liver regeneration. Amphiregulin is a member of the epidermal growth factor family whose expression is not detectable in healthy liver. We have investigated the expression of amphiregulin in liver injury and its role during liver regeneration after partial hepatectomy.
Amphiregulin gene expression was examined in healthy and cirrhotic human and rat liver, in rodent liver regeneration after partial hepatectomy, and in primary hepatocytes. The proliferative effects and intracellular signaling of amphiregulin were studied in isolated hepatocytes. The in vivo role of amphiregulin in liver regeneration after partial hepatectomy was analyzed in amphiregulin-null mice.
Amphiregulin gene expression is detected in chronically injured human and rat liver and is rapidly induced after partial hepatectomy in rodents. Amphiregulin expression is induced in isolated hepatocytes by interleukin 1beta and prostaglandin E(2), but not by hepatocyte growth factor, interleukin 6, or tumor necrosis factor alpha. We show that amphiregulin behaves as a primary mitogen for isolated hepatocytes, acting through the epidermal growth factor receptor. Finally, amphiregulin-null mice display impaired proliferative responses after partial liver resection.
Our findings indicate that amphiregulin is an early-response growth factor that may contribute to the initial phases of liver regeneration.

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    • "This process has been extensively studied in rodents which underwent surgical removal of approximately two thirds of the original liver mass (partial hepatectomy, PH; Higgins and Anderson, 1931). Extracellular signals, especially those mediated by the cytokines TNF-α, IL-1, or IL-6 (Jia, 2011), hepatocyte growth factor (Ping et al., 2006), or amphiregulin (Berasain et al., 2005), are required for priming residual liver cells to induce dedifferentiation and sensitization toward mitogens (Taub, 2004; Fausto et al., 2006; Michalopoulos, 2007). Mitogenic signals as well as removal of anti-mitogenic signals initiate cell cycle progression in partially dedifferentiated hepatocytes by altering expression of genes encoding transcription factors as STAT-3, AP-1, NFkB, forkhead box proteins, or the zinc finger transcriptional repressor Snail (Costa et al., 2003; Sekiya and Suzuki, 2011). "
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    ABSTRACT: Purpose: The cyclin-dependent kinase (Cdk) inhibitor p27Kip1 may be involved in regulating re-entry of residual hepatocytes into the cell cycle upon loss of liver tissue by partial hepatectomy (PH). As yet, changes in Kip1 expression during the initial period following PH are not well-characterized. We investigated immediate changes in Kip1 mRNA and protein levels as well as changes in Kip1 phosphorylation in liver tissue within the relevant time window between surgery and the onset of DNA synthesis at 10–12 h. Methods: We used real-time PCR, quantitative Western blotting, and immune histochemistry on tissue samples of adult rats obtained during or between 2 and 10 h after surgical removal of two thirds of the liver to analyze Kip1 mRNA or protein levels, respectively, or to quantify nuclear expression of Kip1. Results: Kip1 mRNA was down-regulated within 4 h after PH by 60% and remained unchanged thereafter up to 10 h. With a lag phase of 2–3 h, Kip1-protein was down-regulated to a level of 40% of the control. The level of Thr187-phosphorylated Kip1 started to increase at 4 h and reached a maximum level at 8–10 h after PH. Kip1 immunoreactivity was observed in 30% of the hepatocytes before PH. Within 6–8 h after PH, more than half of the hepatocytes lost nuclear Kip1 signals. Kip1-specific micro-RNAs (miRNA221, miRNA222) were not changed upon PH. Conclusions: A portion of hepatocytes in adult rats constitutively express Kip1 and down-regulate Kip1 immediately upon PH. This response involves transcriptional processes (loss of Kip1 mRNA) as well as accelerated degradation of existing protein (increase in pThr187-phosphorylation mediating polyubiquitinylation and proteasomal degradation of Kip1). Kip1 down-regulation occurs precisely within the intervall between surgery and onset of DNA synthesis which supports the hypothesis that it mediates activation of G0/0S-phase Cdk/cyclin-complexes and re-entry of hepatocytes into the cell cycle.
    Full-text · Article · Jun 2013 · Frontiers in Physiology
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    • "In vivo, this priming stage is required since hepatocytes exhibit only a minimal response to transforming growth factor alpha (TGF-α), epidermal growth factor (EGF), or hepatocyte growth factor (HGF) without it. In contrast, these factors are potent mitogens in vitro [5] [6] [7] [8]. In primary culture, hepatocytes replicate their DNA synchronously after addition of EGFR ligands, suggesting that isolation of hepatocytes from the liver induces priming [6] [9] [10] and for review [11] [12] [13]. "
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    ABSTRACT: Unraveling the molecular clues of liver proliferation has become conceivable thanks to the model of two-third hepatectomy. The synchronicity and the well-scheduled aspect of this process allow scientists to slowly decipher this mystery. During this phenomenon, quiescent hepatocytes of the remnant lobes are able to reenter into the cell cycle initiating the G1-S progression synchronously before completing the cell cycle. The major role played by this step of the cell cycle has been emphasized by loss-of-function studies showing a delay or a lack of coordination in the hepatocytes G1-S progression. Two growth factor receptors, c-Met and EGFR, tightly drive this transition. Due to the level of complexity surrounding EGFR signaling, involving numerous ligands, highly controlled regulations and multiple downstream pathways, we chose to focus on the EGFR pathway for this paper. We will first describe the EGFR pathway in its integrity and then address its essential role in the G1/S phase transition for hepatocyte proliferation. Recently, other levels of control have been discovered to monitor this pathway, which will lead us to discuss regulations of the EGFR pathway and highlight the potential effect of misregulations in pathologies.
    Full-text · Article · Sep 2012
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    • "The similarities in cyst AREG levels between non-mucinous and benign mucinous cysts may be related to the physiologic expression of AREG as part of a reparative process in combination with a smaller cellular mass of mucin producing cells. Recent studies have determined that AREG serves an important role in tissue repair after damage in the gastrointestinal tract [22,23]. "
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    ABSTRACT: Accurate tests to diagnose adenocarcinoma and high-grade dysplasia among mucinous pancreatic cysts are clinically needed. This study evaluated the diagnostic utility of amphiregulin (AREG) as a pancreatic cyst fluid biomarker to differentiate non-mucinous, benign mucinous, and malignant mucinous cysts. A single-center retrospective study to evaluate AREG levels in pancreatic cyst fluid by ELISA from 33 patients with a histological gold standard was performed. Among the cyst fluid samples, the median (IQR) AREG levels for non-mucinous (n = 6), benign mucinous (n = 15), and cancerous cysts (n = 15) were 85 pg/ml (47-168), 63 pg/ml (30-847), and 986 pg/ml (417-3160), respectively. A significant difference between benign mucinous and malignant mucinous cysts was observed (p = 0.025). AREG levels greater than 300 pg/ml possessed a diagnostic accuracy for cancer or high-grade dysplasia of 78% (sensitivity 83%, specificity 73%). Cyst fluid AREG levels are significantly higher in cancerous and high-grade dysplastic cysts compared to benign mucinous cysts. Thus AREG exhibits potential clinical utility in the evaluation of pancreatic cysts.
    Full-text · Article · Feb 2012 · BMC Gastroenterology
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