Christèle Desbois-Mouthon
University of Paris
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Featured researches published by Christèle Desbois-Mouthon.
Liver International | 2015
Hamza Chettouh; Marie Lequoy; Laetitia Fartoux; Corinne Vigouroux; Christèle Desbois-Mouthon
Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and is one of the leading causes of cancer‐related death. The risk factors for HCC include cirrhosis, chronic viral hepatitis, heavy alcohol intake and metabolic diseases such as obesity, type 2 diabetes and metabolic syndrome. Insulin resistance is a common denominator of all of these conditions and is tethered to hyperinsulinaemia. Here, we give an overview of the recent advances linking hyperinsulinaemia to HCC development and progression. In particular, we summarise the underlying causes of hyperinsulinaemia in the setting of chronic liver diseases. We present epidemiological evidence linking metabolic diseases to HCC risk and HCC‐related mortality, as well as the pathogenic cellular and molecular mechanisms explaining this relation. A better understanding of the mechanisms by which insulin participates in HCC biology might ultimately provide novel opportunities for prevention and treatment.
Free Radical Biology and Medicine | 2015
Thanh Huong Nguyen Ho-Bouldoires; Audrey Clapéron; Martine Mergey; Dominique Wendum; Christèle Desbois-Mouthon; Sylvana Tahraoui; Laetitia Fartoux; Hamza Chettouh; Fatiha Merabtene; Olivier Scatton; Matthias Gaestel; Françoise Praz; C. Housset; Laura Fouassier
The development and progression of liver cancer are characterized by increased levels of reactive oxygen species (ROS). ROS-induced oxidative stress impairs cell proliferation and ultimately leads to cell death. Although liver cancer cells are especially resistant to oxidative stress, mechanisms of such resistance remain understudied. We identified the MAPK-activated protein kinase 2 (MK2)/heat shock protein 27 (Hsp27) signaling pathway mediating defenses against oxidative stress. In addition to MK2 and Hsp27 overexpression in primary liver tumors compared to adjacent nontumorous tissues, the MK2/Hsp27 pathway is activated by hydrogen peroxide-induced oxidative stress in hepatobiliary cancer cells. MK2 inactivation or inhibition of MK2 or Hsp27 expression increases caspase-3 and PARP cleavage and DNA breaks and therefore cell death. Interestingly, MK2/Hsp27 inhibition decreases antioxidant defenses such as heme oxygenase 1 through downregulation of the transcription factor nuclear factor erythroid-derived 2-like 2. Moreover, MK2/Hsp27 inhibition decreases both phosphorylation of epidermal growth factor receptor (EGFR) and expression of its ligand, heparin-binding EGF-like growth factor. A new identified partner of MK2, the scaffold PDZ protein EBP50, could facilitate these effects through MK2/Hsp27 pathway regulation. These findings demonstrate that the MK2/Hsp27 pathway actively participates in resistance to oxidative stress and may contribute to liver cancer progression.
Hepatology | 2017
Lucille Morzyglod; Michèle Caüzac; Lucie Popineau; Pierre-Damien Denechaud; Lluis Fajas; Bruno Ragazzon; Véronique Fauveau; Julien Planchais; Mireille Vasseur-Cognet; Laetitia Fartoux; Olivier Scatton; Olivier Rosmorduc; Sandra Guilmeau; Catherine Postic; Chantal Desdouets; Christèle Desbois-Mouthon; Anne-Françoise Burnol
Metabolic diseases such as obesity and type 2 diabetes are recognized as independent risk factors for hepatocellular carcinoma (HCC). Hyperinsulinemia, a hallmark of these pathologies, is suspected to be involved in HCC development. The molecular adapter growth factor receptor binding protein 14 (Grb14) is an inhibitor of insulin receptor catalytic activity, highly expressed in the liver. To study its involvement in hepatocyte proliferation, we specifically inhibited its liver expression using a short hairpin RNA strategy in mice. Enhanced insulin signaling upon Grb14 inhibition was accompanied by a transient induction of S‐phase entrance by quiescent hepatocytes, indicating that Grb14 is a potent repressor of cell division. The proliferation of Grb14‐deficient hepatocytes was cell‐autonomous as it was also observed in primary cell cultures. Combined Grb14 down‐regulation and insulin signaling blockade using pharmacological approaches as well as genetic mouse models demonstrated that Grb14 inhibition–mediated hepatocyte division involved insulin receptor activation and was mediated by the mechanistic target of rapamycin complex 1–S6K pathway and the transcription factor E2F1. In order to determine a potential dysregulation in GRB14 gene expression in human pathophysiology, a collection of 85 human HCCs was investigated. This revealed a highly significant and frequent decrease in GRB14 expression in hepatic tumors when compared to adjacent nontumoral parenchyma, with 60% of the tumors exhibiting a reduced Grb14 mRNA level. Conclusion: Our study establishes Grb14 as a physiological repressor of insulin mitogenic action in the liver and further supports that dysregulation of insulin signaling is associated with HCC. (Hepatology 2017;65:1352‐1368).
Nature Communications | 2018
Paul J. Meakin; Anna Mezzapesa; Eva Benabou; Mary E. Haas; Bernadette Bonardo; Michel Grino; Jean-Michel Brunel; Christèle Desbois-Mouthon; Sudha B. Biddinger; Roland Govers; Michael L.J. Ashford; Franck Peiretti
Insulin receptor (IR) plays a key role in the control of glucose homeostasis; however, the regulation of its cellular expression remains poorly understood. Here we show that the amount of biologically active IR is regulated by the cleavage of its ectodomain, by the β-site amyloid precursor protein cleaving enzyme 1 (BACE1), in a glucose concentration-dependent manner. In vivo studies demonstrate that BACE1 regulates the amount of IR and insulin signaling in the liver. During diabetes, BACE1-dependent cleavage of IR is increased and the amount of IR in the liver is reduced, whereas infusion of a BACE1 inhibitor partially restores liver IR. We suggest the potential use of BACE1 inhibitors to enhance insulin signaling during diabetes. Additionally, we show that plasma levels of cleaved IR reflect IR isoform A expression levels in liver tumors, which prompts us to propose that the measurement of circulating cleaved IR may assist hepatic cancer detection and management.A soluble form of insulin receptor in human plasma has been previously reported. Here the authors demonstrate that insulin receptor is cleaved by BACE1 that can regulate biological active insulin receptor levels in a glucose concentration-dependent manner, both in physiological and diabetic conditions.
Clinical Cancer Research | 2018
Javier Vaquero; Cindy Lobe; Sylvana Tahraoui; Audrey Clapéron; Martine Mergey; Fatiha Merabtene; Dominique Wendum; Cédric Coulouarn; C. Housset; Christèle Desbois-Mouthon; Françoise Praz; Laura Fouassier
Purpose: Cholangiocarcinoma (CCA) is a desmoplastic tumor of the biliary tree in which epidermal growth factor receptor (EGFR) is overexpressed and contributes to cancer progression. Although EGFR has been envisaged as a target for therapy, treatment with tyrosine kinase inhibitors (TKI) such as erlotinib did not provide therapeutic benefit in patients with CCA, emphasizing the need to investigate resistance mechanisms against EGFR inhibition. Experimental Design: Resistant CCA cells to EGFR inhibition were obtained upon long-time exposure of cells with erlotinib. Cell signaling, viability, migration, and spheroid growth were determined in vitro, and tumor growth was evaluated in CCA xenograft models. Results: Erlotinib-resistant CCA cells displayed metastasis-associated signatures that correlated with a marked change in cell plasticity associated with an epithelial–mesenchymal transition (EMT) and a cancer stem cell (CSC)–like phenotype. Resistant cells exhibited an upregulation of insulin receptor (IR) and insulin-like growth factor (IGF) 1 receptor (IGF1R), along with an increase in IGF2 expression. IR/IGF1R inhibition reduced EMT and CSC-like traits in resistant cells. In vivo, tumors developed from resistant CCA cells were larger and exhibited a more prominent stromal compartment, enriched in cancer-associated fibroblasts (CAF). Pharmacological coinhibition of EGFR and IR/IGF1R reduced tumor growth and stromal compartment in resistant tumors. Modeling of CCA-CAF crosstalk showed that IGF2 expressed by fibroblasts boosted IR/IGF1R signaling in resistant cells. Furthermore, IR/IGF1R signaling positively regulated fibroblast proliferation and activation. Conclusions: To escape EGFR-TKI treatment, CCA tumor cells develop an adaptive mechanism by undergoing an IR/IGF1R-dependent phenotypic switch, involving a contribution of stromal cells. Clin Cancer Res; 24(17); 4282–96. ©2018 AACR.
Histopathology | 2017
Marie Lequoy; Christèle Desbois-Mouthon; Dominique Wendum; Vandana Gupta; Jean-Luc Blachon; Olivier Scatton; Sylvie Dumont; Mireille M. Bonnemaire; Fabien Schmidlin; Olivier Rosmorduc; Laetitia Fartoux
To investigate the status of somatostatin receptors (SSTRs) in resected hepatocellular carcinoma (HCC).
Journal of Hepatology | 2015
Javier Vaquero; Audrey Clapéron; Martine Mergey; Christèle Desbois-Mouthon; Françoise Praz; Laura Fouassier
Cancer Genomics & Proteomics | 2017
Claire Goumard; Christèle Desbois-Mouthon; Dominique Wendum; Claire Calmel; Fatiha Merabtene; Olivier Scatton; Françoise Praz
Journal of Experimental & Clinical Cancer Research | 2016
Corina Buta; Eva Benabou; Marie Lequoy; Hélène Regnault; Dominique Wendum; Fatiha Meratbene; Hamza Chettouh; Lynda Aoudjehane; Filomena Conti; Y. Chrétien; Olivier Scatton; Olivier Rosmorduc; Françoise Praz; Laetitia Fartoux; Christèle Desbois-Mouthon
Journal of Hepatology | 2018
E. Benabou; Z. Salame; Dominique Wendum; M. Lequoy; S. Tahraoui; Fatiha Merabtene; C. Yves; Olivier Scatton; Olivier Rosmorduc; Laura Fouassier; Laetitia Fartoux; Françoise Praz; Christèle Desbois-Mouthon