title: Upregulation of T-cell factor-4 isoform-responsive target genes in hepatocellular carcinoma.
abstract: BACKGROUND
  The Wnt/β-catenin signalling pathway regulates genes involved in cell proliferation, survival, migration and invasion through regulation by T-cell factor (TCF)-4 transcription factor proteins. However, the role of TCF-4 isoforms generated by alternative splicing events in hepatocellular carcinoma (HCC) is unknown.
  
  
  OBJECTIVE
  Here, we investigated TCF-4 isoforms (TCF-4J and K)-responsive target genes that are important in hepatic oncogenesis and tumour development.
  
  
  METHODS
  Gene expression microarray was performed on HCC cells overexpressing TCF-4J and K isoforms. Expression level of selected target genes was evaluated and correlations were made between their expression level and that of TCF-4 isoform in 47 pairs of human HCC tumours.
  
  
  RESULTS
  Comparison by gene expression microarray revealed that 447 genes were upregulated and 343 downregulated more than 2.0-fold in TCF-4J compared with TCF-4K expressing cells. We validated expression of 18 selected target genes involved in Wnt/β-catenin, insulin/IGF-1/IRS1 and Notch signalling pathways in 47 pairs of human HCCs and adjacent uninvolved liver tissues. It was observed that 13 genes (CLDN2, STK17B, SPP1, AXIN2, WISP2, MMP7, IRS1, ANXA1, CAMK2N1, ASPH, GPR56, CD24 and JAG1) activated by TCF-4J isoform in HCC cells, were also upregulated in HCC tumours compared with adjacent peritumour tissue; more importantly, 10 genes exhibited a significant correlation with the TCF-4J expression level in tumour.
  
  
  CONCLUSIONS
  TCF-4 isoforms (TCF-4J and K) activated different downstream target genes in HCC. The biological consequence of TCF-4J isoform expression was upregulation of genes associated with tripartite Wnt/β-catenin, insulin/IGF-1/IRS1 and Notch signal transduction pathway activation, which contribute to the pathogenesis of HCC.
authors: Warren Alpert Medical School, Brown University, Providence, RI, USA.
authors: Yoshito
authors: Y
authors: Tomimaru
authors: Hironori
authors: H
authors: Koga
authors: Hirohisa
authors: H
authors: Yano
authors: Suzanne
authors: S
authors: de la Monte
authors: Jack R
authors: JR
authors: Wands
authors: Miran
authors: M
authors: Kim
mesh_terms: D017398:Alternative Splicing / Q000502:physiology; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism*; D046228:Microarray Analysis; D020033:Protein Isoforms / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058118:Transcription Factor 7-Like 2 Protein / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: D020033:Protein Isoforms; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein
keywords: HCC; TCF-4; Wnt; target genes
references: In Vitro. 1984 Jun;20(6):493-504
references: 6086498
references: Nat Med. 2006 Apr;12(4):410-6
references: 16532004
references: Cancer Metastasis Rev. 2012 Dec;31(3-4):429-40
references: 22699312
references: Oncogene. 2006 Jul 20;25(31):4361-9
references: 16532032
references: Epigenetics. 2009 Jul 1;4(5):307-312
references: 28001119
references: Methods Mol Biol. 2008;468:111-28
references: 19099250
references: Hepatology. 2010 Jul;52(1):164-73
references: 20578260
references: J Clin Invest. 1996 Sep 15;98(6):1313-23
references: 8823296
references: Exp Cell Res. 2003 Oct 15;290(1):93-107
references: 14516791
references: Hepatology. 2004 Jul;40(1):167-76
references: 15239100
references: Hepatology. 2006 May;43(5):891-902
references: 16628664
references: Front Biosci. 2006 May 01;11:1901-15
references: 16368566
references: Gastroenterology. 2007 Jun;132(7):2557-76
references: 17570226
references: Carcinogenesis. 2008 Jul;29(7):1299-305
references: 18515282
references: J Hepatol. 2008 May;48(5):780-91
references: 18313787
references: Gastroenterology. 2008 Jul;135(1):244-256.e1
references: 18466772
references: Am J Pathol. 1994 Sep;145(3):610-23
references: 8080043
references: Nat Genet. 2000 Mar;24(3):245-50
references: 10700176
references: Cancer Res. 2007 Feb 1;67(3):901-10
references: 17283120
references: Cancer Cell. 2005 Jul;8(1):13-23
references: 16023595
references: Cell. 2006 Nov 3;127(3):469-80
references: 17081971
references: J Biol Chem. 2002 Oct 11;277(41):38239-44
references: 12154096
references: Semin Cancer Biol. 2011 Feb;21(1):44-58
references: 21182948
references: J Biol Chem. 2010 Jan 15;285(3):1928-38
references: 19843521
references: Biochem Biophys Res Commun. 2004 Feb 20;314(4):1001-7
references: 14751232
references: Adv Exp Med Biol. 2010;706:98-108
references: 21618829
references: Oncogene. 2006 Dec 4;25(57):7531-7
references: 17143297
references: Br J Cancer. 2011 Aug 9;105(4):542-51
references: 21772333
references: Hepatology. 2007 Jan;45(1):42-52
references: 17187432
references: Nat Med. 2003 Apr;9(4):416-23
references: 12640447
references: Curr Pharm Biotechnol. 2011 Nov;12(11):1900-8
references: 21470134
references: J Biol Chem. 2008 Apr 25;283(17):11565-74
references: 18305109
references: Cancer Res. 2008 Aug 15;68(16):6779-88
references: 18701503
references: Br J Cancer. 2008 Jul 8;99(1):143-50
references: 18577996
references: Int J Oncol. 2009 Oct;35(4):861-6
references: 19724923
references: Nat Cell Biol. 2010 May;12(5):468-76
references: 20418870
references: Cancer Res. 2009 Sep 15;69(18):7385-92
references: 19723656
references: Cancer Invest. 2011 Feb;29(2):107-12
references: 21329006
references: Hepatology. 2009 Jun;49(6):1935-43
references: 19475691
references: Cancer Sci. 2011 Aug;102(8):1522-31
references: 21564420
references: J Hepatol. 2011 Jan;54(1):89-97
references: 20970216
references: Proc Natl Acad Sci U S A. 2009 Apr 14;106(15):6315-20
references: 19325125
references: Cancer Res. 2001 Jul 15;61(14):5619-29
references: 11454716
references: Hepatology. 1993 Aug;18(2):320-7
references: 8393423
references: Mol Cancer. 2004 May 13;3:15
references: 15140260
references: J Hepatol. 2011 Feb;54(2):288-99
references: 21055837
references: Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13092-7
references: 17670948
references: Anticancer Res. 2007 Nov-Dec;27(6A):3729-34
references: 17970035
references: Hepatology. 2006 Aug;44(2):446-57
references: 16871543
references: Exp Cell Res. 2011 Apr 15;317(7):920-31
references: 21256126
references: J Hepatol. 2006 May;44(5):971-83
references: 16564107
references: Br J Cancer. 2009 Aug 4;101(3):483-91
references: 19638987
references: Int J Cancer. 2010 Mar 1;126(5):1109-20
references: 19653274
references: Mol Cell Biol. 2002 Feb;22(4):1172-83
references: 11809808
references: J Gastroenterol Hepatol. 2013 Jan;28(1):179-87
references: 22988930
references: Brain Res Bull. 2012 Jan 4;87(1):30-6
references: 21985983
references: PLoS One. 2012;7(6):e39981
references: 22768190