title: BCL9-2 promotes early stages of intestinal tumor progression.
abstract: OBJECTIVE
  The roles of the 2 BCL9 and 2 Pygopus genes in Wnt to β-catenin signaling are not clear in vertebrates. We examined their expression and function in normal and tumor intestinal epithelia in mice and humans.
  
  
  METHODS
  Specific antibodies were generated to characterize the BCL9 and Pygopus proteins in normal intestine and in colon tumors. Targets of BCL9 and Pygopus in colon cancer cells were analyzed using small interfering RNA analysis. Transgenic mice were created that overexpressed BCL9-2 in intestine; these were crossed with APCMin/+ mice to create BCL9-2;APCMin/+ mice.
  
  
  RESULTS
  BCL9 and Pygopus2 were expressed in all normal intestinal and colon cancer cells. BCL9-2 was detectable only in the villi, not in the crypts of normal intestine. BCL9-2 was up-regulated in adenomas and in almost all colon tumors, with a concomitant increase of Pygopus2, whereas levels of BCL9 were similar between normal and cancer cells. Transgenic overexpression of BCL9-2 in the intestine of BCL9-2; APCMin/+ mice increased formation of adenomas that progressed to invasive tumors, resulting in reduced survival time. Using small interfering RNA analysis, we found that BCL9s and Pygopus are not targets of Wnt in colon cancer cells, but Wnt signaling correlated with levels of BCL9-2. BCL9-2 regulated expression of β-catenin-dependent and -independent target genes that have been associated with early stages of intestinal tumorigenesis.
  
  
  CONCLUSIONS
  BCL9-2 promotes early phases of intestinal tumor progression in humans and in transgenic mice. BCL9-2 increases the expression of a subset of canonical Wnt target genes but also regulates genes that are required for early stages of tumor progression.
authors.affiliation: Max Delbrueck Center for Molecular Medicine, Berlin, Germany. brembeck@med.uni-goettingen.de
authors.forename: Felix H
authors.initials: FH
authors.lastname: Brembeck
authors.forename: Maria
authors.initials: M
authors.lastname: Wiese
authors.forename: Nathalie
authors.initials: N
authors.lastname: Zatula
authors.forename: Tamara
authors.initials: T
authors.lastname: Grigoryan
authors.forename: Yiyang
authors.initials: Y
authors.lastname: Dai
authors.forename: Johannes
authors.initials: J
authors.lastname: Fritzmann
authors.forename: Walter
authors.initials: W
authors.lastname: Birchmeier
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000236:Adenoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D018938:Caco-2 Cells; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D017930:Genes, Reporter; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007422:Intestines / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D053539:Keratin-19 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C495498:BCL9L protein, human; C568071:BCL9L protein, mouse; C495270:CTNNB1 protein, human; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D053539:Keratin-19; C453402:PYGO1 protein, human; C453401:PYGO2 protein, human; C521908:Pygo1 protein, mouse; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C495570:pygopus 2 protein, mouse