title: Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis.
abstract: LKB1, originally considered a tumor suppressor, plays an important role in hepatocyte proliferation and liver regeneration. Mice lacking the methionine adenosyltransferase (MAT) gene MAT1A exhibit a chronic reduction in hepatic S-adenosylmethionine (SAMe) levels, basal activation of LKB1, and spontaneous development of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). These results are relevant for human health because patients with liver cirrhosis, who are at risk to develop HCC, have a marked reduction in hepatic MAT1A expression and SAMe synthesis. In this study, we isolated a cell line (SAMe-deficient [SAMe-D]) from MAT1A knockout (MAT1A-KO) mouse HCC to examine the role of LKB1 in the development of liver tumors derived from metabolic disorders. We found that LKB1 is required for cell survival in SAMe-D cells. LKB1 regulates Akt-mediated survival independent of phosphoinositide 3-kinase, adenosine monophosphate protein-activated kinase (AMPK), and mammalian target of rapamycin complex (mTORC2). In addition, LKB1 controls the apoptotic response through phosphorylation and retention of p53 in the cytoplasm and the regulation of herpesvirus-associated ubiquitin-specific protease (HAUSP) and Hu antigen R (HuR) nucleocytoplasmic shuttling. We identified HAUSP as a target of HuR. Finally, we observed cytoplasmic staining of p53 and p-LKB1(Ser428) in a NASH-HCC animal model (from MAT1A-KO mice) and in liver biopsies obtained from human HCC derived from both alcoholic steatohepatitis and NASH.
  
  
  CONCLUSIONS
  The SAMe-D cell line is a relevant model of HCC derived from NASH disease in which LKB1 is the principal conductor of a new regulatory mechanism and could be a practical tool for uncovering new therapeutic strategies.
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Bizkaia, Spain. mlmartinez@cicbiogune.es
authors.forename: Nuria
authors.initials: N
authors.lastname: Martínez-López
authors.forename: Marta
authors.initials: M
authors.lastname: Varela-Rey
authors.forename: David
authors.initials: D
authors.lastname: Fernández-Ramos
authors.forename: Ashwin
authors.initials: A
authors.lastname: Woodhoo
authors.forename: Mercedes
authors.initials: M
authors.lastname: Vázquez-Chantada
authors.forename: Nieves
authors.initials: N
authors.lastname: Embade
authors.forename: Luis
authors.initials: L
authors.lastname: Espinosa-Hevia
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Bustamante
authors.forename: Luis A
authors.initials: LA
authors.lastname: Parada
authors.forename: Manuel S
authors.initials: MS
authors.lastname: Rodriguez
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.forename: Maria L
authors.initials: ML
authors.lastname: Martínez-Chantar
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism; D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division; D004789:Enzyme Activation; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008716:Methionine Adenosyltransferase / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification
chemical_list: D012334:RNA, Neoplasm; C506577:MAT1A protein, human; C490703:Mat1a protein, mouse; D008716:Methionine Adenosyltransferase; D019870:1-Phosphatidylinositol 4-Kinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases
references.citation: Am J Hum Genet. 1998 Dec;63(6):1641-50
references.pmid: 9837816
references.citation: Methods Enzymol. 1979;58:536-44
references.pmid: 423789
references.citation: Dev Cell. 2006 Dec;11(6):859-71
references.pmid: 17141160
references.citation: FASEB J. 2002 Aug;16(10):1292-4
references.pmid: 12060674
references.citation: Annu Rev Nutr. 2008;28:273-93
references.pmid: 18331185
references.citation: Dev Cell. 2007 Apr;12(4):487-502
references.pmid: 17419990
references.citation: Gastroenterology. 2010 May;138(5):1943-53
references.pmid: 20102719
references.citation: Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5954-8
references.pmid: 8327466
references.citation: Carcinogenesis. 2002 Apr;23(4):541-7
references.pmid: 11960904
references.citation: Hepatology. 2009 Feb;49(2):608-17
references.pmid: 19177591
references.citation: RNA Biol. 2005 Jan;2(1):11-3
references.pmid: 17132932
references.citation: J Natl Cancer Inst. 1994 May 4;86(9):681-7
references.pmid: 8158699
references.citation: Science. 2005 Feb 18;307(5712):1098-101
references.pmid: 15718470
references.citation: Cancer Res. 2008 Sep 15;68(18):7270-7
references.pmid: 18794113
references.citation: FEBS J. 2007 Aug;274(16):4256-70
references.pmid: 17651432
references.citation: Hepatology. 2009 Jul;50(1):216-29
references.pmid: 19437488
references.citation: J Biol Chem. 2003 Sep 5;278(36):33637-44
references.pmid: 12807916
references.citation: J Biol Chem. 2004 May 14;279(20):20571-5
references.pmid: 14985341
references.citation: Cancer Res. 2002 Oct 15;62(20):5689-97
references.pmid: 12384526
references.citation: EMBO J. 2000 May 15;19(10):2340-50
references.pmid: 10811625
references.citation: Methods Mol Biol. 2008;463:191-202
references.pmid: 18951170
references.citation: Cell Mol Life Sci. 2001 Feb;58(2):266-77
references.pmid: 11289308
references.citation: J Huazhong Univ Sci Technolog Med Sci. 2005;25(1):45-7
references.pmid: 15934306
references.citation: Oncogene. 2005 Jan 13;24(3):502-11
references.pmid: 15543229
references.citation: EMBO J. 2007 Feb 21;26(4):976-86
references.pmid: 17290220
references.citation: Nat Genet. 2002 Aug;31(4):339-46
references.pmid: 12149612
references.citation: Proc Natl Acad Sci U S A. 1995 May 9;92(10):4407-11
references.pmid: 7753819
references.citation: Cancer Res. 1988 Dec 1;48(23):6863-71
references.pmid: 2846163
references.citation: Nature. 1999 Sep 2;401(6748):86-90
references.pmid: 10485711
references.citation: Cell Death Differ. 2007 Jul;14(7):1350-60
references.pmid: 17380154
references.citation: Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7262-6
references.pmid: 1353891
references.citation: Proc Natl Acad Sci U S A. 2001 May 8;98(10):5560-5
references.pmid: 11320206
references.citation: J Biol Chem. 2007 Jul 13;282(28):20351-64
references.pmid: 17519230
references.citation: J Biol Chem. 2002 Jun 14;277(24):21843-50
references.pmid: 11923280
references.citation: Gastroenterology. 2006 Jul;131(1):223-32
references.pmid: 16831604
references.citation: Cancer Res. 2006 Nov 15;66(22):10701-8
references.pmid: 17108107
references.citation: Nature. 2000 Nov 16;408(6810):307-10
references.pmid: 11099028
references.citation: Int J Biochem Cell Biol. 2009 May;41(5):969-76
references.pmid: 19027869
references.citation: Genes Dev. 1999 Nov 15;13(22):2905-27
references.pmid: 10579998
references.citation: Hepatology. 2007 May;45(5):1306-12
references.pmid: 17464973