Antoinette Lemoine

Publications (55)320.39 Total impact

• Article: GSK3-mediated VDAC phosphorylation controls outer mitochondrial membrane permeability during lipid accumulation.

  Cecile Martel, Maya Allouche, Davide Degli Esposti, Elena Fanelli, Céline Boursier, Céline Henry, Joel Chopineau, Giuseppe Calamita, Guido Kroemer, Antoinette Lemoine, Catherine Brenner
  [show abstract] [hide abstract]
  ABSTRACT: Non-alcoholic steatosis is a liver pathology characterized by fat accumulation and severe metabolic alterations involving early mitochondrial impairment and late hepatocyte cell death. However, mitochondrial dysfunction mechanisms remain elusive. Using four models of non-alcoholic steatosis, i.e. livers from patients with fatty liver disease, ob/ob mice, mice fed a high fat diet and in vitro models of lipotoxicity, we show that outer mitochondrial membrane permeability is altered and identified a post-translational modification of VDAC, a membrane channel and NADH oxidase, as a cause of early mitochondrial dysfunction. Thus, in non-alcoholic steatosis, VDAC exhibits reduced threonine phosphorylation, which increases the influx of water and calcium into mitochondria, sensitizes the organelle to matrix swelling, depolarization and cytochrome c release without inducing cell death. This also amplifies VDAC enzymatic and channel activities regulation by calcium and modifies its interaction with proteic partners. Moreover, lipid accumulation triggers a rapid lack of VDAC phosphorylation by GSK3. Pharmacological and genetic manipulations proved GSK3 to be responsible for VDAC phosphorylation in normal cells. Notably, VDAC phosphorylation level correlated with steatosis severity in patients. In conclusion, VDAC acts as an early sensor of lipid toxicity and its GSK3-mediated phosphorylation status controls outer mitochondrial membrane permeabilization in hepatosteatosis. (HEPATOLOGY 2012.).
  Hepatology 07/2012; · 11.66 Impact Factor
• Source

  Available from: Davide Degli Esposti

  Chapter: Hepatocellular Carcinoma: Epidemiology and Etiology

  Davide Degli Esposti, Morando Soffritti, Antoinette Lemoine, Eva Tibaldi, Marco Manservigi
  03/2012; , ISBN: 978-953-51-0112-3
• Source

  Available from: Davide Degli Esposti

  Article: Mitochondrial roles and cytoprotection in chronic liver injury.

  Davide Degli Esposti, Jocelyne Hamelin, Nelly Bosselut, Raphaël Saffroy, Mylène Sebagh, Alban Pommier, Cécile Martel, Antoinette Lemoine
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  ABSTRACT: The liver is one of the richest organs in terms of number and density of mitochondria. Most chronic liver diseases are associated with the accumulation of damaged mitochondria. Hepatic mitochondria have unique features compared to other organs' mitochondria, since they are the hub that integrates hepatic metabolism of carbohydrates, lipids and proteins. Mitochondria are also essential in hepatocyte survival as mediator of apoptosis and necrosis. Hepatocytes have developed different mechanisms to keep mitochondrial integrity or to prevent the effects of mitochondrial lesions, in particular regulating organelle biogenesis and degradation. In this paper, we will focus on the role of mitochondria in liver physiology, such as hepatic metabolism, reactive oxygen species homeostasis and cell survival. We will also focus on chronic liver pathologies, especially those linked to alcohol, virus, drugs or metabolic syndrome and we will discuss how mitochondria could provide a promising therapeutic target in these contexts.
  Biochemistry research international. 01/2012; 2012:387626.
• Source

  Available from: Lionel Larue

  Article: Withaferin A induces apoptosis in human melanoma cells through generation of reactive oxygen species and down-regulation of Bcl-2.

  Eleonore Mayola, Cindy Gallerne, Davide Degli Esposti, Cecile Martel, Shazib Pervaiz, Lionel Larue, Brigitte Debuire, Antoinette Lemoine, Catherine Brenner, Christophe Lemaire
  [show abstract] [hide abstract]
  ABSTRACT: A high resistance and heterogeneous response to conventional anti-cancer chemotherapies characterize malignant cutaneous melanoma, the most aggressive and deadly form of skin cancer. Withaferin A (WFA), a withanolide derived from the medicinal plant Withania somnifera, has been reported for its anti-tumorigenic activity against various cancer cells. For the first time, we examined the death-inducing potential of WFA against a panel of four different human melanoma cells and investigated the cellular mechanisms involved. WFA induces apoptotic cell death with various IC50 ranging from 1.8 to 6.1 μM. The susceptibility of cells toward WFA-induced apoptosis correlated with low Bcl-2/Bax and Bcl-2/Bim ratios. In all cell lines, the apoptotic process triggered by WFA involves the mitochondrial pathway and was associated with Bcl-2 down regulation, Bax mitochondrial translocation, cytochrome c release into the cytosol, transmembrane potential (ΔΨm) dissipation, caspase 9 and caspase 3 activation and DNA fragmentation. WFA cytotoxicity requires early reactive oxygen species (ROS) production and glutathione depletion, the inhibition of ROS increase by the antioxidant N-acetylcysteine resulting in complete suppression of mitochondrial and nuclear events. Altogether, these results support the therapeutic potential of WFA against human melanoma.
  Apoptosis 06/2011; 16(10):1014-27. · 4.07 Impact Factor
• Article: Association between a polymorphism in the promoter of a glutamate receptor subunit gene (GRIN2A) and alcoholism.

  Marie-Charlotte Domart, Amine Benyamina, Antoinette Lemoine, Catherine Bourgain, Lisa Blecha, Brigitte Debuire, Michel Reynaud, Raphaël Saffroy
  [show abstract] [hide abstract]
  ABSTRACT: A variable (GT)(n) repeat in the 5'-regulatory region of N-methyl-D-aspartate GRIN2A subtype has recently been identified and associated with psychiatric disorders. In this study, we examined the association of this polymorphism with alcohol dependence. Subject-control analysis included 206 alcohol-dependent and 168 control subjects. Average observed repeat numbers and genotype distributions were significantly different (P-value = 0.001) in alcohol-dependent subjects versus control subjects. Short alleles were significantly less frequent among alcohol-dependent subjects (odds ratio = 0.58, P-value = 7 × 10(-4)). These results could be replicated in an independent sample of 116 alcohol-dependent subjects. For the first time, a significant association was identified between this polymorphism and alcoholism.
  Addiction Biology 04/2011; 17(4):783-5. · 4.83 Impact Factor
• Article: Ischaemic preconditioning of the graft in adult living related right lobe liver transplantation: impact on ischaemia-reperfusion injury and clinical relevance.

  Paola Andreani, Emir Hoti, Sofia de la Serna, Davide degli Esposti, Mylène Sebagh, Antoinette Lemoine, Philippe Ichai, Fauzi Saliba, Denis Castaing, Daniel Azoulay
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  ABSTRACT: Ischaemic preconditioning (IPC) of the right liver graft in the donor has not been studied in adult-to-adult living related liver transplantation (LRLT). To assess the IPC effect of the graft on ischaemia reperfusion injury in the recipient and compare recipient and donor outcomes with and without preconditioned grafts. Alternate patients were transplanted with right lobe grafts that were (n = 22; Group (Precond)) or were not (n = 22; Group (Control)) subjected to IPC in the living donor. Liver ischaemia-reperfusion injury, liver/kidney function, morbidity/mortality rates and outcomes were compared. Univariate and multivariate analyses were performed to identify factors predictive of the aspartate aminotransferase (AST) peak and minimum prothrombin time. Both groups had similar length of hospital stay, morbidity/mortality, primary non-function and acute rejection rates. Post-operative AST (P = 0.8) and alanine aminotransferase (ALT) peaks (P = 0.6) were similar in both groups (307 +/- 189 and 437 +/- 302 vs. 290 +/- 146 and 496 +/- 343, respectively). In univariate analysis, only pre-operative AST and warm ischemia time (WIT) were significantly associated with post-operative AST peak (in recipients). In multivariate analysis, the graft/recipient weight ratio (P = 0.003) and pre-operative bilirubin concentration (P = 0.004) were significantly predictive of minimum prothrombin time post-transplantation. Graft IPC in the living related donor is not associated with any benefit for the recipient or the donor and its clinical value remains uncertain.
  HPB 09/2010; 12(7):439-46. · 1.60 Impact Factor
• Source

  Available from: Christophe Lemaire

  Article: The fourth isoform of the adenine nucleotide translocator inhibits mitochondrial apoptosis in cancer cells.

  Cindy Gallerne, Zahia Touat, Zhi Xiong Chen, Cécile Martel, Eleonore Mayola, Ossama Sharaf el dein, Nelly Buron, Morgane Le Bras, Etienne Jacotot, Annie Borgne-Sanchez, Antoinette Lemoine, Christophe Lemaire, Shazib Pervaiz, Catherine Brenner
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  ABSTRACT: The adenine nucleotide translocator (ANT) is a mitochondrial bi-functional protein, which catalyzes the exchange of ADP and ATP between cytosol and mitochondria and participates in many models of mitochondrial apoptosis. The human adenine nucleotide translocator sub-family is composed of four isoforms, namely ANT1-4, encoded by four nuclear genes, whose expression is highly regulated. Previous studies have revealed that ANT1 and 3 induce mitochondrial apoptosis, whereas ANT2 is anti-apoptotic. However, the role of the recently identified isoform ANT4 in the apoptotic pathway has not yet been elucidated. Here, we investigated the effects of stable heterologous expression of the ANT4 on proliferation, mitochondrial respiration and cell death in human cancer cells, using ANT3 as a control of pro-apoptotic isoform. As expected, ANT3 enhanced mitochondria-mediated apoptosis in response to lonidamine, a mitochondriotoxic chemotherapeutic drug, and staurosporine, a protein kinase inhibitor. Our results also indicate that the pro-apoptotic effect of ANT3 was accompanied by decreased rate of cell proliferation, alteration in the mitochondrial network topology, and decreased reactive oxygen species production. Of note, we demonstrate for the first time that ANT4 enhanced cell growth without impacting mitochondrial network or respiration. Moreover, ANT4 differentially regulated the intracellular levels of hydrogen peroxide without affecting superoxide anion levels. Finally, stable ANT4 overexpression protected cancer cells from lonidamine and staurosporine apoptosis in a manner independent of Bcl-2 expression. These data highlight a hitherto undefined cytoprotective activity of ANT4, and provide a novel dichotomy in the human ANT isoform sub-family with ANT1 and 3 isoforms functioning as pro-apoptotic while ANT2 and 4 isoforms render cells resistant to death inducing stimuli.
  The international journal of biochemistry & cell biology 05/2010; 42(5):623-9. · 4.89 Impact Factor
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  Available from: Michel Ducreux

  Article: Tumor marker evolution: comparison with imaging for assessment of response to chemotherapy in patients with colorectal liver metastases.

  Robbert J de Haas, Dennis A Wicherts, Eduardo Flores, Michel Ducreux, Francis Lévi, Bernard Paule, Daniel Azoulay, Denis Castaing, Antoinette Lemoine, René Adam
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  ABSTRACT: As the real clinical significance of carcinoembryonic antigen (CEA) and carbohydrate antigen 19.9 (CA19.9) evolution during preoperative chemotherapy for colorectal liver metastases (CLM) is still unknown, we explored the correlation between biological and radiological response to chemotherapy, and their comparative impact on outcome after hepatectomy. All patients resected for CLM at our hospital between 1990 and 2004 with the following eligibility criteria were included in the study: (1) preoperative chemotherapy, (2) complete resection of CLM, (3) no extrahepatic disease, and (4) elevated baseline tumor marker values. A 20% change of tumor marker levels while on chemotherapy was used to define biological response (decrease) or progression (increase). Correlation between biological and radiological response at computed tomography (CT) scan, and their impact on overall survival (OS) and progression-free survival (PFS) after hepatectomy were determined. Among 119 of 695 consecutive patients resected for CLM who fulfilled the inclusion criteria, serial CEA and CA19.9 were available in 113 and 68 patients, respectively. Of patients with radiological response or stabilization, 94% had similar biological evolution for CEA and 91% for CA19.9. In patients with radiological progression, similar biological evolution was observed in 95% of cases for CEA and in 64% for CA19.9. On multivariate analysis, radiological response (but not biological evolution) independently predicted OS. However, progression of CA19.9, but not radiological response, was an independent predictor of PFS. In patients with CLM and elevated tumor markers, biological response is as accurate as CT imaging to assess "clinical" response to chemotherapy. With regards to PFS, CA19.9 evolution has even better prognostic value than does radiological response. Assessment of tumor markers could be sufficient to evaluate chemotherapy response in a nonsurgical setting, limiting the need of repeat imaging.
  Annals of Surgical Oncology 04/2010; 17(4):1010-23. · 4.17 Impact Factor
• Source

  Available from: Davide Degli Esposti

  Article: Autophagy is induced by ischemic preconditioning in human livers formerly treated by chemotherapy to limit necrosis.

  Davide Degli Esposti, Marie-Charlotte Domart, Mylène Sebagh, Francis Harper, Gérard Pierron, Catherine Brenner, Antoinette Lemoine
  [show abstract] [hide abstract]
  ABSTRACT: The effectiveness of ischemic preconditioning (IP) against hepatic ischemia/reperfusion injury during human liver surgery is linked to decreased apoptotic cell death as well as preservation of the ATP content in liver tissue. Overproduction of Bcl-2 is reported in preconditioned organs. In human liver biopsies exhibiting steatosis and/or vascular injuries (mainly peliosis) induced by chemotherapy, we find that the expression of Bcl-2 in centrolobular and peliotic areas colocalizes with the autophagy protein Beclin 1 in IP livers. Increased expression of phosphorylated Bcl-2 in preconditioned livers is associated with decreased immunoprecipitation of Beclin 1 and increased expression of LC3-II. The increased number of autophagic vacuoles seen by electron microscopy confirmed that IP could trigger autophagy in chemotherapy-injured livers, probably to reduce the pro-inflammatory necrotic cell death of hepatocytes or endothelial cells and to increase ATP levels. Indeed, necrosis is less frequent (p = 0.04) in IP livers than in the others although no change in apoptosis as assessed by TUNEL assay or caspase-3, -8 and -9 expressions is observed. In conclusion, Bcl-2 and Beclin 1 could be major targets in the regulation of cell death during ischemia/reperfusion injury modulating autophagy to switch on/off necrosis and/or apoptosis.
  Autophagy 01/2010; 6(1):172-4. · 7.45 Impact Factor
• Article: Association between MTHFR 677C-T polymorphism and alcohol dependence according to Lesch and Babor typology.

  Amine Benyamina, Raphaël Saffroy, Lisa Blecha, Patrick Pham, Laurent Karila, Brigitte Debuire, Antoinette Lemoine, Michel Reynaud
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  ABSTRACT: Prior studies have associated 677C-T Methylenetetrahydrofolate reductase (MTHFR) gene polymorphism with decreased enzymatic activity and modified homocysteine regulation. This study determines and compares MTHFR 677C-T distribution and examines its consequences on homocysteine metabolism and alcohol dependence in alcoholic patients classified according to the Babor and Lesch typologies. MTHFR TT genotype was more prevalent in AD patients with milder alcohol dependence (Babor type A) and with Lesch type 3, associated with depression. MTHFR TT was also associated with hyperhomocysteinemia. Determining MTHFR 677C-T genotype, folate and vitamin B12 levels could assist physicians in identifying type 3 patients and improve addictions management.
  Addiction Biology 08/2009; 14(4):503-5. · 4.83 Impact Factor
• Article: Concurrent induction of necrosis, apoptosis, and autophagy in ischemic preconditioned human livers formerly treated by chemotherapy.

  Marie-Charlotte Domart, Davide Degli Esposti, Mylène Sebagh, Natalia Olaya, Francis Harper, Gérard Pierron, Brigitte Franc, Kenneth K Tanabe, Brigitte Debuire, Daniel Azoulay, Catherine Brenner, Antoinette Lemoine
  [show abstract] [hide abstract]
  ABSTRACT: Liver pathology induced by chemotherapy (steatosis or vascular injury) is known to increase the liver's sensitivity to ischemia/ reperfusion (I/R) injury, thereby increasing morbidity and mortality after liver resection. Our aim was to assess whether ischemic preconditioning (IP) reduces I/R injury to livers with chemotherapy-induced pathology. We analyzed a series of livers from patients treated with chemotherapy for colorectal cancer who underwent IP (n=30) or not (n=31) before hepatectomy. All but one of the livers exhibited chemotherapy-induced steatosis and/ or peliosis before the I/R insult. Necrosis was less frequent (p=0.038) in livers with IP than in the others. IP had no influence on apoptosis as assessed by terminal transferase uridyl nick-end labeling (TUNEL) assay or caspase-3, -8 and -9 expression. IP induced a twofold increase in B-cell leukemia/ lymphoma 2 (Bcl-2; p<0.05), which was localized to hepatocytes of centrolobular and peliotic areas and colocalized with the autophagy protein beclin-1 in livers with IP, suggesting their coordinated role in autophagy. Increased expression of the phosphorylated Bcl-2 was observed in preconditioned livers and was associated with a decreased immunoprecipitation of beclin-1 and the increased expression of light chain 3 type II (LC3-II). The increased number of autophagic vacuoles seen by electron microscopy confirmed an association of autophagy in chemotherapy-injured livers following IP. However, the differences in protein expression were not reflected in postresection liver-injury tests or measure of patient morbidity. IP is associated with a reduction in necrosis of hepatocytes already damaged by chemotherapy and an activation of autophagy. Bcl-2 and beclin-1 could be major targets in the regulation of cell death during I/R injury.
  Journal of Hepatology 08/2009; 51(5):881-9. · 9.26 Impact Factor
• Article: BRIEF REPORT: Association between MTHFR 677C‐T polymorphism and alcohol dependence according to Lesch and Babor typology

  Amine Benyamina, Raphaël Saffroy, Lisa Blecha, Patrick Pham, Laurent Karila, Brigitte Debuire, Antoinette Lemoine, Michel Reynaud
  [show abstract] [hide abstract]
  ABSTRACT: Prior studies have associated 677C-T Methylenetetrahydrofolate reductase (MTHFR) gene polymorphism with decreased enzymatic activity and modified homocysteine regulation. This study determines and compares MTHFR 677C-T distribution and examines its consequences on homocysteine metabolism and alcohol dependence in alcoholic patients classified according to the Babor and Lesch typologies. MTHFR TT genotype was more prevalent in AD patients with milder alcohol dependence (Babor type A) and with Lesch type 3, associated with depression. MTHFR TT was also associated with hyperhomocysteinemia. Determining MTHFR 677C-T genotype, folate and vitamin B12 levels could assist physicians in identifying type 3 patients and improve addictions management.
  Addiction Biology 07/2009; 14(4):503 - 505. · 4.83 Impact Factor
• Source

  Available from: retroconference.org

  Article: Relationship between polymerase gamma (POLG) polymorphisms and antiretroviral therapy-induced lipodystrophy in HIV-1 infected patients: a case-control study.

  Franck Chiappini, Elina Teicher, Raphaël Saffroy, Brigitte Debuire, Daniel Vittecoq, Antoinette Lemoine
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  ABSTRACT: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) used for the treatment of HIV-1 inhibit the replication of mitochondrial DNA (mtDNA), which may contribute to severe mitochondrial toxicity including lipodystrophy, through the inhibition of polymerase gamma (POLG). Polymorphisms of POLG could explain the variation in mitochondrial toxicity in HIV-1-infected patients. We explored the relationship between selected polymorphisms of POLG and lipodystrophy related to NRTIs. We studied single nucleotide polymorphisms (SNP) at three amino acid residues (R1142, E1143 and R1146) and the CAG repeats of POLG in a case-control study including HIV-1 treated patients with lipodystrophy (n=69) and 2 controls (without lipodystrophy) per case matched by age, race and sex (n=138). Compared with matched controls, the polymorphisms in E1143 were significantly more frequent in case patients with lipodystrophy (aOR=4.7; p=0.048), and this was associated with a significant decrease of mtDNA in PBMC. In addition, among the parameters tested, the conditional logistic regression showed that the lipodystrophy has a strong link with E1143 polymorphisms, associated with D4T treatment (aOR=9.29, p=0.002). In conclusion, patients harbouring the changes of E1143 in the catalytic site of POLG exhibit a 4-fold increased risk to develop lipodystrophy than HIV-1 treated patients who do not have changes in E1143 and this risk can increase if the patient presenting the SNP received D4T. These could be due to decreased content of mtDNA in PBMC in these patients. Therefore, the toxicity of NRTIs leading to lipodystrophy in some HIV-1 infected patients could be explained in part by the occurrence of POLG polymorphisms.
  Current HIV research 04/2009; 7(2):244-53. · 1.98 Impact Factor
• Article: Protective effect against alcohol dependence of the thermolabile variant of MTHFR.

  Raphaël Saffroy, Amine Benyamina, Patrick Pham, Cathy Marill, Laurent Karila, Maâmar Reffas, Brigitte Debuire, Michel Reynaud, Antoinette Lemoine
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  ABSTRACT: Hyperhomocysteinemia is frequently observed in alcohol-dependent subjects, in particularly in those with marked withdrawal symptoms. The common C677T transition on the methylenetetrahydrofolate reductase (MTHFR) gene influences homocysteinemia. Our objective was to study the prevalence of the MTHFR C677T polymorphism in alcohol-dependent subjects and the influence of this polymorphism on symptoms associated with alcoholism. MTHFR C677T polymorphism was determined in 93 control subjects and 242 alcohol-dependent subjects. Serum homocysteine, folate and vitamin B12 levels together with hepatic biological parameters were determined in the control and alcohol-dependent subjects. Hyperhomocysteinemia is frequently observed in alcohol-dependent subjects, particularly in those with marked withdrawal symptoms. Alcohol-dependent subjects showed a significant decrease in MTHFR 677TT prevalence (9%, 21/242) compared to controls (18%, 17/93) (p<0.02). The relative risk estimated as an odds ratio for alcoholism in subjects with the TT genotype is 0.42 (odd ratio 95% confidence interval, 0.21-0.83). Moreover, drinkers with TT genotype presented lower values for markers of alcohol misuse (p<0.05), better liver function tests, a lower frequency of relapses and no marked withdrawal symptoms as assessed by the Lesch typology. MTHFR 677TT genotype could play a protective role against alcohol dependence. Moreover, when subjects with MTHFR 677TT genotype become dependent to alcohol, they seem to constitute a subgroup of alcoholic patients with a decreased risk for developing neurotoxic withdrawal symptoms and hepatic toxicity.
  Drug and Alcohol Dependence 08/2008; 96(1-2):30-6. · 3.38 Impact Factor
• Article: Generation and modulation of hepatocellular carcinoma circulating cells: a new experimental model.

  Olivier Scatton, Franck Chiappini, Xu-Hui Liu, Philippe Riou, Anthony Marconi, Brigitte Debuire, Daniel Azoulay, Antoinette Lemoine
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  ABSTRACT: To establish a new experimental model of human hepatocellular carcinoma by orthotopic implantation of tumoral cells with its subsequent removal, to generate and modulate circulating tumoral cells. Three human hepatoma cell lines (HepG2, PLC/PRF, and Mahlavu) were orthotopically implanted under the Glisson's capsule of the left lateral lobe of the liver in a total of 56 non-obese diabetic/severe combined immunodeficiency mice. Tumor removal was performed 30 d after injection, and a laparotomy without tumor removal was done in control mice. Generation of circulating cells was monitored by flow cytometry using fluorescein isothiocyanate-conjugated anti-HLA antibody. In 26 mice implanted with Mahlavu cells, 20 developed a unique tumor allowing a resection (77%), which was technically feasible in 80% of cases. The overall perioperative mortality was 30% (3/10) after resection; no mortality was observed in the control group. The circulating tumoral cells decreased dramatically after resection of the tumor as compared with control mice. This new model is feasible and may be an interesting useful tool to study the hepatocellular carcinoma metastatic process and is consistent with the human clinical practice.
  Journal of Surgical Research 05/2008; 150(2):183-9. · 2.25 Impact Factor
• Article: KIT mutations induce intracellular retention and activation of an immature form of the KIT protein in gastrointestinal stromal tumors.

  Séverine Tabone-Eglinger, Frédéric Subra, Hiba El Sayadi, Laurent Alberti, Eric Tabone, Jean-Philippe Michot, Nathalie Théou-Anton, Antoinette Lemoine, Jean-Yves Blay, Jean-François Emile
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  ABSTRACT: Gastrointestinal stromal tumors (GIST) are frequently associated with gain-of-function mutations of KIT, which can be inhibited by imatinib both in vitro and in vivo. The survival of patients with GIST, following imatinib therapy, has been correlated with the nature of mutations but not with KIT expression. Subcellular localization, activation, and trafficking of the mature and the immature forms of KIT were investigated in GIST samples and in NIH3T3 cells infected with two different GIST-type exon 11-mutated human KIT cDNA. Paranuclear dot expression of KIT was more frequent in GISTs with homozygous KIT mutations than in those with heterozygous (P = 0.01) or no mutations (P < 0.01). Activation of the immature 125 kDa form of KIT was detected in most GISTs with KIT mutations but not in GISTs without KIT mutations. In NIH3T3 cells, mutant KIT was mainly retained within endoplasmic reticulum and Golgi compartments in an immature constitutively phosphorylated form, whereas the wild-type KIT was expressed at the plasma membrane, in a mature nonphosphorylated form. Imatinib-induced inhibition of the phosphorylation of immature and mature mutant KIT proteins resulted in the restoration of KIT expression at the cell surface. These results show that GIST-type KIT mutations induce an activation-dependent alteration of normal maturation and trafficking, resulting in the intracellular retention of the activated kinase within the cell. These observations likely account for the absence of correlation between response to imatinib and KIT expression using immunohistochemistry and may deserve to be investigated in other tyrosine kinase-activated tumors.
  Clinical Cancer Research 04/2008; 14(8):2285-94. · 7.74 Impact Factor
• Article: Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis.

  Kenneth K Tanabe, Antoinette Lemoine, Dianne M Finkelstein, Hiroshi Kawasaki, Tsutomu Fujii, Raymond T Chung, Gregory Y Lauwers, Yakup Kulu, Alona Muzikansky, Darshini Kuruppu, Michael Lanuti, Jonathan M Goodwin, Daniel Azoulay, Bryan C Fuchs
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  ABSTRACT: Overexpression of epidermal growth factor (EGF) in the liver induces transformation to hepatocellular carcinoma in animal models. Polymorphisms in the EGF gene modulate EGF levels. To assess the relationship among human EGF gene single-nucleotide polymorphism, EGF expression, and risk of hepatocellular carcinoma. Molecular mechanisms linking the 61*G allele polymorphism to EGF expression were examined in human hepatocellular carcinoma cell lines and human liver tissue. A case-control study involving 207 patients with cirrhosis was conducted at the Massachusetts General Hospital (1999-2006) and a validation case-control study involving 121 patients with cirrhosis was conducted at Hôpital Paul Brousse (1993-2006). Restriction fragment-length polymorphism was used to determine the EGF gene polymorphism genotype. Logistic regression analysis was used to assess the association between the EGF polymorphism and hepatocellular carcinoma risk. Mechanisms by which the EGF gene polymorphism modulates EGF levels and associations among EGF gene polymorphism, EGF levels, and hepatocellular carcinoma. Transcripts from the EGF 61*G allele exhibited more than a 2-fold longer half-life than those from the 61*A allele, and EGF secretion was 2.3-fold higher in G/G hepatocellular carcinoma cell lines than A/A cell lines. Serum EGF levels were 1.8-fold higher in G/G patients than A/A patients, and liver EGF levels were 2.4-fold higher in G/G patients than A/A patients. Among the 207 patients with cirrhosis in the Massachusetts study population, 59 also had hepatocellular carcinoma. Analysis of the distribution of allelic frequencies revealed that there was a 4-fold odds of hepatocellular carcinoma in G/G patients compared with A/A patients in the Massachusetts study population (odds ratio, 4.0; 95% confidence interval [CI], 1.6-9.6; P = .002). Logistic regression analysis demonstrated that the number of copies of G was significantly associated with hepatocellular carcinoma after adjusting for age, sex, race, etiology, and severity of cirrhosis (G/G or A/G vs A/A; hazard ratio, 3.49; 95% CI, 1.29-9.44; P = .01). The significant association was validated in the French patients with alcoholic cirrhosis and hepatocellular carcinoma. The EGF gene polymorphism genotype is associated with risk for development of hepatocellular carcinoma in liver cirrhosis through modulation of EGF levels.
  JAMA The Journal of the American Medical Association 02/2008; 299(1):53-60. · 30.03 Impact Factor
• Source

  Available from: Jean-François Emile

  Article: Frequent EGFR Positivity and Overexpression in High-Grade Areas of Human MPNSTs.

  Séverine Tabone-Eglinger, Radislav Bahleda, Jean-François Côté, Philippe Terrier, Dominique Vidaud, Anne Cayre, Alain Beauchet, Nathalie Théou-Anton, Marie-José Terrier-Lacombe, Antoinette Lemoine, Frédérique Penault-Llorca, Axel Le Cesne, Jean-François Emile
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  ABSTRACT: Malignant peripheral nerve sheath tumours (MPNSTs) are highly malignant and resistant. Transformation might implicate up regulation of epidermal growth factor receptor (EGFR). Fifty-two MPNST samples were studied for EGFR, Ki-67, p53, and survivin expression by immunohistochemistry and for EGFR amplification by in situ hybridization. Results were correlated with clinical data. EGFR RNA was also quantified by RT-PCR in 20 other MPNSTs and 14 dermal neurofibromas. Half of the patients had a neurofibromatosis type 1 (NF1). EGFR expression, detected in 86% of MPNSTs, was more frequent in NF1 specimens and closely associated with high-grade and p53-positive areas. MPNSTs expressed more EGFR transcripts than neurofibromas. No amplification of EGFR locus was observed. NF1 status was the only prognostic factor in multivariate analysis, with median survivals of 18 and 43 months for patients with or without NF1. Finally, EGFR might become a new target for MPNSTs treatment, especially in NF1-associated MPNSTs.
  Sarcoma 02/2008; 2008:849156.
• Article: [Gene expression profiling in colon cancer].

  Alain Barrier, Pierre-Yves Boelle, Antoinette Lemoine, Antoine Flahault, Sandrine Dudoit, Michel Huguier
  [show abstract] [hide abstract]
  ABSTRACT: Identification of new prognostic factors for colon cancer with no lymph node involvement may improve the selection of patients for adjuvant chemotherapy. The aim of this study was to assess the possibility of using gene expression profiling for this purpose. Fifty patients operated on for stage II colon cancer were included. Twenty-five of these patients relapsed, while the other 25 remained disease-free for at least 5 years. MRNA was extracted from fresh-frozen biopsies and hybridized to the Affymetrix GeneChip HGU133A. One thousand six hundred random splits of the 50 patients into a training set and a validation set were considered. For each split, a prognostic combination was derived from the training set (selection of the 30 genes most differentially expressed between patients who recurred and those who did not, by linear discriminant analysis), and its prognostic performance was assessed with the validation set. On average, accuracy was 76%, sensitivity 85%, and specificity 68%. A total of 6,124 genes were included in at least one of the 1,600 predictive combinations, and 55 genes were included in more than 100 combinations. This study supports the possibility of predicting the prognosis of non-metastatic colon cancer by tumor gene expression profiling. It also shows the highly variable gene composition of predictive combinations.
  Bulletin de l'Académie nationale de médecine 07/2007; 191(6):1091-101; discussion 1102-3. · 0.25 Impact Factor
• Article: New perspectives and strategy research biomarkers for hepatocellular carcinoma.

  Raphaël Saffroy, Patrick Pham, Maâmar Reffas, Mohamed Takka, Antoinette Lemoine, Brigitte Debuire
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  ABSTRACT: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Cirrhosis caused by hepatitis B virus, hepatitis C virus or chronic alcohol intake is associated with major risk. Systematic screening for HCC of asymptomatic patients with cirrhosis is needed for earlier detection of small tumors requiring treatment (liver transplantation, surgical resection, percutaneous techniques). The recommended screening strategy among cirrhotic patients is based on regular liver ultrasonography associated with serum alpha-fetoprotein (AFP) assay. As the performance of AFP is not satisfactory, additional tumoral markers are proposed (des-gamma-carboxyprothrombin, glycosylated AFP-L3 fraction). Currently, diagnosis of HCC in cirrhotic patients includes non-invasive tests (imaging after contrast administration, AFP assay); diagnostic biopsy is performed when imaging is limited. After treatment, tumor recurrence is assessed by regular follow-up (AFP assay and imaging). Despite the lack of accurate markers, recent developments in genomic and proteomic approaches will allow the discovery of new biomarkers for primary tumors, as well as for recurrence. This review summarizes the current state of biomarkers for screening, diagnosis and follow-up of HCC, and highlights new perspectives in the field.
  Clinical Chemistry and Laboratory Medicine 02/2007; 45(9):1169-79. · 2.15 Impact Factor