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Somatic Mutations of the ß-Catenin Gene Are Frequent in Mouse And

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Somatic Mutations of the ß-Catenin Gene Are Frequent in Mouse And Proc. Natl. Acad. Sci. USA Vol. 95, pp. 8847–8851, July 1998 Medical Sciences Somatic mutations of the b-catenin gene are frequent in mouse and human hepatocellular carcinomas ALIX DE LA COSTE*†,BE´ATRICE ROMAGNOLO*†,PIERRE BILLUART*, CLAIRE-ANGE´LIQUE RENARD‡, MARIE-ANNICK BUENDIA‡,OLIVIER SOUBRANE§,MONIQUE FABRE¶,JAMEL CHELLY*, CHERIF BELDJORD*, i AXEL KAHN*, AND CHRISTINE PERRET* *Institut National de la Sante´et de la Recherche Me´dicaleU129, Institut Cochin de Ge´ne´tiqueMole´culaire,Universite´Paris V Rene´Descartes, 24 rue du Faubourg Saint-Jacques, 75014 Paris, France; ‡Institut National de la Sante´et de la Recherche Me´dicaleU163, Institut Pasteur, 28 rue du Docteur Roux, 75015 Paris, France; §Hoˆpital Cochin, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; and ¶Hoˆpital du Kremlin Bieˆtre,78 rue du Ge´ne´ralLeclerc, 94275 Le Kremlin-Biceˆtre,France Edited by Walter Bodmer, University of Oxford, Oxford, United Kingdom, and approved May 12, 1998 (received for review March 2, 1998) ABSTRACT Hepatocellular carcinoma (HCC) is the ma- protooncogene (7, 8). Activation of the Wnt-1 pathway results jor primary malignant tumor in the human liver, but the in inhibition of glycogen synthase kinase-3b (GSK-3b), and a molecular changes leading to liver cell transformation remain lack of phosphorylation of b-catenin, which then will not be largely unknown. The Wnt-b-catenin pathway is activated in degraded by the ubiquitinyproteasome system, and thus accu- colon cancers and some melanoma cell lines, but has not yet mulate in the cell (2, 9). The APC protein appears to be a been investigated in HCC. We have examined the status of the negative regulator of cytoplasmic b-catenin, acting by an as yet b -catenin gene in different transgenic mouse lines of HCC unknown mechanism. The APC gene is the gene most com- obtained with the oncogenes c-myc or H-ras. Fifty percent of monly mutated in colorectal cancer, and it is inactivated early the hepatic tumors in these transgenic mice had activating in the initiation of colon cancer. These mutations are associ- b somatic mutations within the -catenin gene similar to those ated with a rise in the free intracellular b-catenin, which results found in colon cancers and melanomas. These alterations in in loss of control of normal b-catenin signaling. This event has the b-catenin gene (point mutations or deletions) lead to a b been demonstrated in 85% of colorectal cancers (10). The disregulation of the signaling function of -catenin and thus major initiating event in the remaining 15% of colorectal to carcinogenesis. We then analyzed human HCCs and found cancers with an intact APC gene involves mutations in the similar mutations in eight of 31 (26%) human liver tumors b-catenin gene, which then lead to accumulation of the protein tested and in HepG2 and HuH6 hepatoma cells. The mutations b in the cytosolic-nuclear compartment (11, 12). Similar activat- led to the accumulation of -catenin in the nucleus. Thus b b ing mutations of the -catenin gene recently were found in alterations in the -catenin gene frequently are selected for b during liver tumorigenesis and suggest that disregulation of melanoma cell lines (13), implying that -catenin acts as an the Wnt-b-catenin pathway is a major event in the develop- oncogene in cancers without any clear association with APC ment of HCC in humans and mice. mutations. We therefore have looked for such mutations in the b-catenin gene in different types of HCCs, first in transgenic mice and then in humans. Hepatocellular carcinoma (HCC) is the major primary malig- nant tumor of the liver. Epidemiological studies indicate that hepatitis B virus is a major causal agent of liver cancer, but MATERIALS AND METHODS other etiological factors also have been found (see ref. 1 for Tumor Samples. Transgenic mice were maintained in ac- review). However, the molecular mechanisms that contribute cordance with the Ministe`rede l’Agriculture et de la foreˆt to tumor progression in hepatocarcinogenesis remain un- guidelines for the care and use of laboratory animals. known. To identify genetic alterations that could be involved in tumor progression during hepatocarcinogenesis, we ana- The human hepatocellular samples were obtained from lyzed the status of the b-catenin gene. The protein b-catenin patients of various geographical origin who underwent sur- is involved in two major functions: cell adhesion and the gery. transmission of the proliferating signal of the WinglessyWnt Western Blot. Tissues were homogenized with a Polytron in 3 y pathway. Disregulation of this pathway has been implicated in 1 Laemli sample buffer (1:10 wt vol) (Sigma). Samples of m carcinogenesis (see refs. 2 and 3 for reviews). b-catenin usually extract containing approximately 50 g of total protein were y y is found in the lateral cell membrane, as part of the E-cad- resolved on 7.5% (wt vol) SDS PAGE and transferred to herinycatenin adherens complex, and in the cytoplasm and nitrocellulose filters. The membranes were blocked with 5% nucleus where it acts as a mediator of WinglessyWnt- (wtyvol) milk powder in Tris-buffered saline containing 0.05% dependent signal transduction (2, 4). Signal transduction via (volyvol) Tween 20 (Sigma). b-catenin protein was detected by b-catenin involves its posttranslational stabilization and pas- using a rabbit polyclonal anti-b-catenin (M. Mareels, Univer- sage into the nucleus where it interacts with transcription sity Hospital, Gent, Belgium; dilution 1:10,000). Blots were factors of the T cell factorylymphoid enhancer factor family to standardized by staining with ponceau red staining. Immuno- activate target genes involved in cell growth control and staining was performed with peroxidase-coupled anti-rabbit apoptosis (3, 5, 6). The amount of free cytoplasmic b-catenin IgG (Amersham) (dilution 1:10,000) and ECL (Amersham). seems to be regulated by the opposing actions of the adeno- matous polyposis coli (APC) suppressor gene and the Wnt-1 This paper was submitted directly (Track II) to the Proceedings office. Abbreviations: HCC, hepatocellular carcinoma; APC, adenomatous b b The publication costs of this article were defrayed in part by page charge polyposis coli; GSK-3 , glycogen synthase kinase-3 ; RT-PCR, re- verse transcription–PCR; DGGE, denaturing gradient gel electro- payment. This article must therefore be hereby marked ‘‘advertisement’’ in phoresis; L-PK, L-type pyruvate kinase. accordance with 18 U.S.C. §1734 solely to indicate this fact. †A.d.L.C. and B.R. contributed equally to this work. i © 1998 by The National Academy of Sciences 0027-8424y98y958847-5$2.00y0 To whom reprint requests should be addressed. e-mail: perret@icgm. PNAS is available online at http:yywww.pnas.org. cochin.inserm.fr. 8847 Downloaded by guest on September 24, 2021 8848 Medical Sciences: de La Coste et al. Proc. Natl. Acad. Sci. USA 95 (1998) Reverse Transcription–PCR (RT-PCR) Amplification of a missense mutation of the serine or threonine residues therein b-Catenin mRNA. Total RNAs were isolated from frozen results in the accumulation of truncated or normal-sized samples of mouse and human HCCs. The corresponding b-catenin and then in activation of b-catenin-mediated signal normal RNAs were obtained from histologically normal tissue (11, 13, 15–17). We used immunoblotting to evaluate the status surrounding the tumor. Total RNAs were reverse-transcribed of b-catenin in hepatic tumors developed in several transgenic to obtain the cDNA that was amplified by RT-PCR. The mouse models. The L-type pyruvate kinase (L-PK)yc-myc and sequences of the primers were chosen to amplify both the the L-PKyH-ras transgenic mice express the oncogene c-myc human and the mouse b-catenin cDNAs (21, 22). Five pairs of and H-ras in the liver under the control of the rat L-PK primers (F1-R1, F2-R2, F3-R3, F4-R4, and F5-R5) were regulatory regions, resulting in the development of multifocal designed to amplify overlapping PCR products, which covered HCCs (18, 19). Similarly, WHVyc-myc mice express a trans- the whole b-catenin ORF. The sequences of primers used to gene carrying the c-myc oncogene under the control of the amplify b-catenin were: F1, 59-GCGTGGACAATGGCTAC- woodchuck hepatitis virus (WHV) regulatory sequences and TCAAG-39; R1, 59-TATTAACTACCACCTGGTCCTC-39; also develop liver tumors (20). Isolated hepatic tumor nodules F2, 59-ACGCGGAACTTGCCACACGTGC-39; R2, 59-TTC- and samples of adjacent nontumoral tissues were collected AGCACTCTGCTTGTGGTC-39; F3, 59-ATCAAGAGAGC- from transgenic mice and analyzed by Western blotting using AAGCTCATCAT-39; R3, 59-TGAAGGCGAACGGCATT- an anti-b-catenin antibody (21). In addition to the 92-kDa CTGGG-39; F4, 59-GCTCTTCGTCATCTGACCAGCC-39; full-length b-catenin, several truncated b-catenins were R4, 59-GAGCAAGTTCACAGAGGACCCC-39; F5, 59-GG- present in 12 of 20 tumor samples taken from L-PKyc-myc ACTCAATACCATTCCATTGT-39; and R5, 59-TTACAGG- transgenic mice (Fig. 1A). b-catenin was detected at increased TCAGTATCAAACCAG-39. levels in three other tumor samples (Fig. 1A, lanes 9–12). The PCR fragments were separated by electrophoresis on Different tumor nodules taken from a single mouse synthesize 1.5% (wtyvol) nusieve agarose gels, transferred to a nylon different forms of b-catenin (Fig. 1A, lanes 9–10), indicating membrane, and hybridized with internal oligonucleotide that these multiple nodules had a distinct clonal origin. probes. All deleted PCR products then were sequenced. We identified the molecular abnormalities involved in the Mutation Analysis. Denaturing gradient gel electrophoresis production of truncated b-catenin by analyzing the entire (DGGE) analysis was carried out on PCR products corre- coding region of the b-catenin mRNA by using a RT-PCR sponding to exon 2 of the the mouse b-catenin gene and exon strategy (Fig.
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