Abstract
Accumulating evidence has demonstrated that aberration of the p53 tumour-suppressor gene is one of the pivotal genetic events in hepatocellular carcinogenesis. Recent reports suggest that the product of hepatitis B virus (HBV) interacts with p53 and that the hepatitis C virus (HCV) core protein reduces p53 expression. A novel p73 gene, which is related to p53, has recently been identified and mapped to chromosome 1p36.3, which is a locus of multiple tumour-suppressor genes for many cancers, including hepatocellular carcinoma (HCC) and neuroblastoma. Here, we investigated mRNA expression, allelotype and mutation of p73 in 48 HCCs obtained from untreated patients. Reverse transcriptase polymerase chain reaction (RT-PCR) revealed that p73 mRNA was expressed ubiquitously at low levels in all the tumour tissues, as well as in the adjacent normal liver tissues. The frequency of p73 loss of heterozygosity was observed in 20% of HCCs, but PCR-single strand conformation polymorphism (SSCP) analysis showed no mutations in the 48 tumours except for three types of polymorphisms. These results suggest that p73 may play a role in hepatocellular carcinogenesis in a different manner from a Knudson two-hit model. The regulatory mechanism of interaction between p73 and hepatitis viruses remains to be determined. © 1999 Cancer Research Campaign
Keywords: p73, hepatocellular carcinoma, p53, mutation, mRNA expression, 1p36
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- Bressac B., Kew M., Wands J., Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature. 1991 Apr 4;350(6317):429–431. doi: 10.1038/350429a0. [DOI] [PubMed] [Google Scholar]
- Buetow K. H., Murray J. C., Israel J. L., London W. T., Smith M., Kew M., Blanquet V., Brechot C., Redeker A., Govindarajah S. Loss of heterozygosity suggests tumor suppressor gene responsible for primary hepatocellular carcinoma. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8852–8856. doi: 10.1073/pnas.86.22.8852. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
- Coursaget P., Depril N., Chabaud M., Nandi R., Mayelo V., LeCann P., Yvonnet B. High prevalence of mutations at codon 249 of the p53 gene in hepatocellular carcinomas from Senegal. Br J Cancer. 1993 Jun;67(6):1395–1397. doi: 10.1038/bjc.1993.258. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ding S. F., Habib N. A., Dooley J., Wood C., Bowles L., Delhanty J. D. Loss of constitutional heterozygosity on chromosome 5q in hepatocellular carcinoma without cirrhosis. Br J Cancer. 1991 Dec;64(6):1083–1087. doi: 10.1038/bjc.1991.468. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fujimori M., Tokino T., Hino O., Kitagawa T., Imamura T., Okamoto E., Mitsunobu M., Ishikawa T., Nakagama H., Harada H. Allelotype study of primary hepatocellular carcinoma. Cancer Res. 1991 Jan 1;51(1):89–93. [PubMed] [Google Scholar]
- Henkler F., Waseem N., Golding M. H., Alison M. R., Koshy R. Mutant p53 but not hepatitis B virus X protein is present in hepatitis B virus-related human hepatocellular carcinoma. Cancer Res. 1995 Dec 15;55(24):6084–6091. [PubMed] [Google Scholar]
- Honda K., Sbisà E., Tullo A., Papeo P. A., Saccone C., Poole S., Pignatelli M., Mitry R. R., Ding S., Isla A. p53 mutation is a poor prognostic indicator for survival in patients with hepatocellular carcinoma undergoing surgical tumour ablation. Br J Cancer. 1998 Mar;77(5):776–782. doi: 10.1038/bjc.1998.126. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hsu I. C., Metcalf R. A., Sun T., Welsh J. A., Wang N. J., Harris C. C. Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature. 1991 Apr 4;350(6317):427–428. doi: 10.1038/350427a0. [DOI] [PubMed] [Google Scholar]
- Jost C. A., Marin M. C., Kaelin W. G., Jr p73 is a simian [correction of human] p53-related protein that can induce apoptosis. Nature. 1997 Sep 11;389(6647):191–194. doi: 10.1038/38298. [DOI] [PubMed] [Google Scholar]
- Kaghad M., Bonnet H., Yang A., Creancier L., Biscan J. C., Valent A., Minty A., Chalon P., Lelias J. M., Dumont X. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell. 1997 Aug 22;90(4):809–819. doi: 10.1016/s0092-8674(00)80540-1. [DOI] [PubMed] [Google Scholar]
- Kazachkov Y., Khaoustov V., Yoffe B., Solomon H., Klintmalm G. B., Tabor E. p53 abnormalities in hepatocellular carcinoma from United States patients: analysis of all 11 exons. Carcinogenesis. 1996 Oct;17(10):2207–2212. doi: 10.1093/carcin/17.10.2207. [DOI] [PubMed] [Google Scholar]
- Knudson A. G., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. doi: 10.1073/pnas.68.4.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kress S., Jahn U. R., Buchmann A., Bannasch P., Schwarz M. p53 Mutations in human hepatocellular carcinomas from Germany. Cancer Res. 1992 Jun 1;52(11):3220–3223. [PubMed] [Google Scholar]
- Kuroki T., Fujiwara Y., Tsuchiya E., Nakamori S., Imaoka S., Kanematsu T., Nakamura Y. Accumulation of genetic changes during development and progression of hepatocellular carcinoma: loss of heterozygosity of chromosome arm 1p occurs at an early stage of hepatocarcinogenesis. Genes Chromosomes Cancer. 1995 Jul;13(3):163–167. doi: 10.1002/gcc.2870130305. [DOI] [PubMed] [Google Scholar]
- Levine A. J., Momand J., Finlay C. A. The p53 tumour suppressor gene. Nature. 1991 Jun 6;351(6326):453–456. doi: 10.1038/351453a0. [DOI] [PubMed] [Google Scholar]
- Lunn R. M., Zhang Y. J., Wang L. Y., Chen C. J., Lee P. H., Lee C. S., Tsai W. Y., Santella R. M. p53 mutations, chronic hepatitis B virus infection, and aflatoxin exposure in hepatocellular carcinoma in Taiwan. Cancer Res. 1997 Aug 15;57(16):3471–3477. [PubMed] [Google Scholar]
- Murakami Y., Hayashi K., Sekiya T. Detection of aberrations of the p53 alleles and the gene transcript in human tumor cell lines by single-strand conformation polymorphism analysis. Cancer Res. 1991 Jul 1;51(13):3356–3361. [PubMed] [Google Scholar]
- Möröy T., Marchio A., Etiemble J., Trépo C., Tiollais P., Buendia M. A. Rearrangement and enhanced expression of c-myc in hepatocellular carcinoma of hepatitis virus infected woodchucks. Nature. 1986 Nov 20;324(6094):276–279. doi: 10.1038/324276a0. [DOI] [PubMed] [Google Scholar]
- Nagai H., Pineau P., Tiollais P., Buendia M. A., Dejean A. Comprehensive allelotyping of human hepatocellular carcinoma. Oncogene. 1997 Jun 19;14(24):2927–2933. doi: 10.1038/sj.onc.1201136. [DOI] [PubMed] [Google Scholar]
- Nishida N., Fukuda Y., Kokuryu H., Toguchida J., Yandell D. W., Ikenega M., Imura H., Ishizaki K. Role and mutational heterogeneity of the p53 gene in hepatocellular carcinoma. Cancer Res. 1993 Jan 15;53(2):368–372. [PubMed] [Google Scholar]
- Piao Z., Kim H., Jeon B. K., Lee W. J., Park C. Relationship between loss of heterozygosity of tumor suppressor genes and histologic differentiation in hepatocellular carcinoma. Cancer. 1997 Sep 1;80(5):865–872. [PubMed] [Google Scholar]
- Ray R. B., Steele R., Meyer K., Ray R. Transcriptional repression of p53 promoter by hepatitis C virus core protein. J Biol Chem. 1997 Apr 25;272(17):10983–10986. doi: 10.1074/jbc.272.17.10983. [DOI] [PubMed] [Google Scholar]
- Simon D., Knowles B. B., Weith A. Abnormalities of chromosome 1 and loss of heterozygosity on 1p in primary hepatomas. Oncogene. 1991 May;6(5):765–770. [PubMed] [Google Scholar]
- Teramoto T., Satonaka K., Kitazawa S., Fujimori T., Hayashi K., Maeda S. p53 gene abnormalities are closely related to hepatoviral infections and occur at a late stage of hepatocarcinogenesis. Cancer Res. 1994 Jan 1;54(1):231–235. [PubMed] [Google Scholar]
- Tsuda H., Zhang W. D., Shimosato Y., Yokota J., Terada M., Sugimura T., Miyamura T., Hirohashi S. Allele loss on chromosome 16 associated with progression of human hepatocellular carcinoma. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6791–6794. doi: 10.1073/pnas.87.17.6791. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vesey D. A., Hayward N. K., Cooksley W. G. p53 gene in hepatocellular carcinomas from Australia. Cancer Detect Prev. 1994;18(2):123–130. [PubMed] [Google Scholar]
- Vogelstein B., Fearon E. R., Hamilton S. R., Kern S. E., Preisinger A. C., Leppert M., Nakamura Y., White R., Smits A. M., Bos J. L. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988 Sep 1;319(9):525–532. doi: 10.1056/NEJM198809013190901. [DOI] [PubMed] [Google Scholar]
- Wang X. W., Gibson M. K., Vermeulen W., Yeh H., Forrester K., Stürzbecher H. W., Hoeijmakers J. H., Harris C. C. Abrogation of p53-induced apoptosis by the hepatitis B virus X gene. Cancer Res. 1995 Dec 15;55(24):6012–6016. [PubMed] [Google Scholar]
- Yeh S. H., Chen P. J., Chen H. L., Lai M. Y., Wang C. C., Chen D. S. Frequent genetic alterations at the distal region of chromosome 1p in human hepatocellular carcinomas. Cancer Res. 1994 Aug 1;54(15):4188–4192. [PubMed] [Google Scholar]