Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation - PubMed (original) (raw)

Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation

J T Nhieu et al. Am J Pathol. 1999 Sep.

Abstract

Inappropriate activation of the Wnt pathway resulting from beta-catenin gene alterations has recently been implicated in the development of hepatocellular carcinoma (HCC). To explore the in vivo effects of mutated beta-catenin, HCC specimens from 32 patients carrying one or several tumors were screened for somatic mutations in exon 3 of the beta-catenin gene, and the expression and subcellular localization of beta-catenin was studied by immunohistochemistry. Missense mutations or interstitial deletions in beta-catenin exon 3 were detected in 12 of 35 (34%) HCC samples. After immunostaining, most tumors exhibited increased membranous and/or cytoplasmic expression of beta-catenin compared with adjacent nontumoral liver. Strong nuclear accumulation of beta-catenin was observed either focally or uniformly in 15 of 35 (43%) tumor specimens, but not in cirrhotic nodules or dysplastic liver cells in adjacent liver. Aberrant nuclear expression of beta-catenin was significantly associated with the presence of mutations in the beta-catenin gene (P < 0.005). Moreover, nuclear beta-catenin staining correlated significantly with increased Ki-67 proliferative index in tumor (P < 0.001) and seemed to be associated with poor outcome in patients with HCC. In conclusion, our data indicate that activation of the Wnt/beta-catenin pathway in HCC results mainly from somatic mutations in the beta-catenin gene and may promote tumor progression by stimulating tumor cell proliferation.

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Figures

Figure 1.

Figure 1.

Oncogenic mutations of one β-catenin allele in HCC. A: Genomic PCR of β-catenin intron 2 to exon 4 sequences showing the normal PCR product (1.1 kbp) in tumors carrying wild-type (lanes 1 and 3) or point mutated β-catenin (lane 4, Patient 1) and a smaller product (0.5 kbp) corresponding to the deleted allele in Patient 12 (lane 2). B: Sequence analysis showing three point mutations in tumor from Patient 7. C: Sequence analysis of the tumorous (T) and nontumorous (NT) liver from Patient 11 showing an interstitial deletion spanning 553 bp of exon 3, intron 3, and exon 4. The dinucleotide CA was present at both ends of the deletion. D: Summary of amino acid substitutions found in 10 different tumors.

Figure 2.

Figure 2.

A, B, C, and E: β-catenin immunolocalization. A: In nontumoral liver, a thin membranous signal delineates the hepatocytes, and bile ductules show strong membranous and pale cytoplasmic staining. B: Overexpression of β-catenin in the cytoplasm and in most nuclei in a HCC case harboring a mutation in β-catenin exon 3. C: Tumoral invasion of a portal vein with strong cytoplasmic and nuclear β-catenin staining. E: Heterogeneous tumor showing strong cytoplasmic and nuclear β-catenin staining in most cells in some areas (left and right sides), and milder staining with only few positive nuclei in another area (center). D and F: MIB-1 (Ki-67) immunostaining. D: A serial section of the portal tumoral invasion shown in C, showing a high proliferative index. F: A serial section of the heterogeneous tumor in E, showing colocalization of MIB-1 and β-catenin stainings. Original magnifications, ×250 (A, B) and ×100 (C-F).

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References

    1. Murray CJL, Lopez AD: Mortality by cause for eight regions of the world: global burden of disease study. Lancet 1997, 349:1269-1276 - PubMed
    1. Nagai H, Buendia MA: Oncogenes, tumor suppressors, and co-factors in hepatocellular carcinoma. Koshy R Caselman W eds. Hepatitis B Virus. 1998, :pp 182-218 Imperial College Press, London
    1. Nagai H, Pineau P, Tiollais P, Buendia MA, Dejean A: Comprehensive allelotyping of human hepatocellular carcinoma. Oncogene 1997, 14:2927-2933 - PubMed
    1. Murakami Y, Hayashi K, Hirohashi S, Sekiya T: Aberrations of the tumor suppressor p53 and retinoblastoma genes in human hepatocellular carcinomas. Cancer Res 1991, 51:5520-5525 - PubMed
    1. Hsu HC, Peng SY, Lai PL, Sheu JC, Chen DS, Lin LI, Slagle BL, Butel JS: Allelotype and loss of heterozygosity of p53 in primary and recurrent hepatocellular carcinomas. Cancer 1994, 73:42-47 - PubMed

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