Identification of the leukocyte cell-derived chemotaxin 2 as a direct target gene of beta-catenin in the liver.
To clarify molecular mechanisms underlying liver carcinogenesis induced by aberrant activation of Wnt pathway, we isolated the target genes of beta-catenin from mice exhibiting constitutive activated beta-catenin in the liver. Adenovirus-mediated expression of oncogenic beta-catenin was used to isolate early targets of beta-catenin in the liver. Suppression subtractive hybridization was used to identify the leukocyte cell-derived chemotaxin 2 (LECT2) gene as a direct target of beta-catenin. Northern blot and immunohistochemical analyses demonstrated that LECT2 expression is specifically induced in different mouse models that express activated beta-catenin in the liver. LECT2 expression was not activated in livers in which hepatocyte proliferation was induced by a beta-catenin-independent signal. We characterized by mutagenesis the LEF/TCF site, which is crucial for LECT2 activation by beta-catenin. We further characterized the chemotactic property of LECT2 for human neutrophils. Finally, we have shown an up-regulation of LECT2 in human liver tumors that expressed aberrant activation of beta-catenin signaling; these tumors constituted a subset of hepatocellular carcinomas (HCC) and most of the hepatoblastomas that were studied. In conclusion, our results show that LECT2, which encodes a protein with chemotactic properties for human neutrophils, is a direct target gene of Wnt/beta-catenin signaling in the liver. Since HCC develops mainly in patients with chronic hepatitis or cirrhosis induced by viral or inflammatory factors, understanding the role of LECT2 in liver carcinogenesis is of interest and may lead to new therapeutic perspectives.
Ovejero
Christine
C
Institut Cochin, Département GDPM, Paris, France.
Cavard
Catherine
C
Périanin
Axel
A
Hakvoort
Theodorus
T
Vermeulen
Jacqueline
J
Godard
Cécile
C
Fabre
Monique
M
Chafey
Philippe
P
Suzuki
Kazuo
K
Romagnolo
Béatrice
B
Yamagoe
Satoshi
S
Perret
Christine
C
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002460:Cell Line; D002633:Chemotaxis; D003598:Cytoskeletal Proteins / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000494:pharmacology / Q000502:physiology; D008113:Liver Neoplasms / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D009693:Nucleic Acid Hybridization / Q000379:methods; D015398:Signal Transduction; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000502:physiology*; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation; D051176:beta Catenin
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C103468:LECT2 protein, human; C491213:Lect2 protein, mouse; D009419:Nerve Tissue Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C090743:Tcf4 protein, mouse; C544895:Tcf7l2 protein, mouse; D015534:Trans-Activators; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin