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Identification of the leukocyte cell‐derived chemotaxin 2 as a direct target gene of β‐catenin in the liver
Author(s) -
Ovejero Christine,
Cavard Catherine,
Périanin Axel,
Hakvoort Theodorus,
Vermeulen Jacqueline,
Godard Cécile,
Fabre Monique,
Chafey Philippe,
Suzuki Kazuo,
Romagnolo Béatrice,
Yamagoe Satoshi,
Perret Christine
Publication year - 2004
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20286
Subject(s) - wnt signaling pathway , carcinogenesis , beta catenin , catenin , cancer research , suppression subtractive hybridization , biology , signal transduction , gene , gene expression , microbiology and biotechnology , genetics , cdna library
To clarify molecular mechanisms underlying liver carcinogenesis induced by aberrant activation of Wnt pathway, we isolated the target genes of β‐catenin from mice exhibiting constitutive activated β‐catenin in the liver. Adenovirus‐mediated expression of oncogenic β‐catenin was used to isolate early targets of β‐catenin in the liver. Suppression subtractive hybridization was used to identify the leukocyte cell‐derived chemotaxin 2 (LECT2) gene as a direct target of β‐catenin. Northern blot and immunohistochemical analyses demonstrated that LECT2 expression is specifically induced in different mouse models that express activated β‐catenin in the liver. LECT2 expression was not activated in livers in which hepatocyte proliferation was induced by a β‐catenin–independent signal. We characterized by mutagenesis the LEF/TCF site, which is crucial for LECT2 activation by β‐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 β‐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/β‐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. (H EPATOLOGY 2004;40:167–176.)