Identification of the leukocyte cell-derived chemotaxin 2 as a direct target gene of β-catenin in the liver
✍ Scribed by Christine Ovejero; Catherine Cavard; Axel Périanin; Theodorus Hakvoort; Jacqueline Vermeulen; Cécile Godard; Monique Fabre; Philippe Chafey; Kazuo Suzuki; Béatrice Romagnolo; Satoshi Yamagoe; Christine Perret
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 413 KB
- Volume
- 40
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
To clarify molecular mechanisms underlying liver carcinogenesis induced by aberrant activation of Wnt pathway, we isolated the target genes of -catenin from mice exhibiting constitutive activated -catenin in the liver. Adenovirus-mediated expression of oncogenic -catenin was used to isolate early targets of -catenin in the liver. Suppression subtractive hybridization was used to identify the leukocyte cell-derived chemotaxin 2 (LECT2) gene as a direct target of -catenin. Northern blot and immunohistochemical analyses demonstrated that LECT2 expression is specifically induced in different mouse models that express activated -catenin in the liver. LECT2 expression was not activated in livers in which hepatocyte proliferation was induced by a -catenin-independent signal. We characterized by mutagenesis the LEF/TCF site, which is crucial for LECT2 activation by -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 -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/-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. (HEPATOLOGY 2004;40:167-176.) H epatocellular carcinoma (HCC), the major primary liver cancer, is becoming increasingly common worldwide. 1 The prognosis for patients with HCC is rather poor. The molecular changes underlying HCC remain largely unknown despite the fact that major risk factors, such as chronic hepatitis B or C infection and exposure to hepatocarcinogens like aflatoxin B1, are well recognized. Several genetic changes have been implicated in at least 3 pathways of carcinogenesis, specifically, the p53, RB and Wnt/-catenin signaling pathways. 2 Deregulation of the Wnt pathway appears to be most frequent of these changes in human HCC; it occurs in about 30% to 40% of patients. 2,3 It also occurs in more than 90% of hepatoblastomas, which are rare embryonal liver tumors. 4 Mutations affecting 2 partners of the Wnt pathway have been found in liver cancers. One is a mutation that activates the -catenin gene. Such mutations occur mainly in hepatitis B-negative HCC 5 and in more than 50% of hepatoblastomas. 6,7 The other is a mutation that inactivates the axin 1, and, less commonly, the axin 2 gene. 5,8,9 Mutations that activate the Wnt pathway result in -catenin accumulation in the nucleus. This process, in association with LEF/TCF transcription factors, modulates the transcription of target genes. 10,11 It is now clear that the genetic program triggered by activation of -catenin signaling depends on the cellular context. The -catenin target genes c-myc and cyclin D1 are well