Abstract
To investigate the relationship between the expression of p21WAF1/ClP1protein and p53 status and the possible role of the two proteins in hepatocellular carcinomas (HCCs), we examined the expression of p21WAF1/CIP1and p53 immunohistochemically in 81 tumours from 65 patients with hepatocellular carcinoma. p21WAF1/CIP1protein was absent from 59 of 81 tumours (72.8%), and altered p53 expression was found in 43 (53.1%). p21WAF1/CIP1expression was significantly associated with p53 status (P= 0.0008); 38 of 59 tumours lacking p21WAF1/CIP1protein were accompanied by altered p53 expression. Further analyses showed that p21WAF1/CIP1expression was inversely correlated with p53 expression in hepatitis C virus (HCV)-related HCCs, but not in HBV-related hepatocellular carcinomas and hepatocellular carcinomas without viral infection. All 11 tumours with intrahepatic metastasis showed altered p21WAF1/CIP1or p53 expression. In contrast, no intrahepatic metastasis was found in any of the 17 tumours without abnormal expression of either of the two proteins. These results suggest that: (1) different modes of p21WAF1/CIP1regulation are involved in HCCs differing in their hepatitis viral infection status, and p21WAF1/CIP1expression appears to be predominantly related to altered p53 in HCV-related HCCs; (2) disruption of the p53–p21WAF1/CIP1cell- cycle-regulating pathway may contribute to malignant progression of HCC. © 2000 Cancer Research Campaign
Keywords: p21WAF1/CIP1, p53, hepatocellular carcinoma
Full Text
The Full Text of this article is available as a PDF (415.6 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Cote R. J., Dunn M. D., Chatterjee S. J., Stein J. P., Shi S. R., Tran Q. C., Hu S. X., Xu H. J., Groshen S., Taylor C. R. Elevated and absent pRb expression is associated with bladder cancer progression and has cooperative effects with p53. Cancer Res. 1998 Mar 15;58(6):1090–1094. [PubMed] [Google Scholar]
- Dulić V., Kaufmann W. K., Wilson S. J., Tlsty T. D., Lees E., Harper J. W., Elledge S. J., Reed S. I. p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell. 1994 Mar 25;76(6):1013–1023. doi: 10.1016/0092-8674(94)90379-4. [DOI] [PubMed] [Google Scholar]
- Esrig D., Elmajian D., Groshen S., Freeman J. A., Stein J. P., Chen S. C., Nichols P. W., Skinner D. G., Jones P. A., Cote R. J. Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med. 1994 Nov 10;331(19):1259–1264. doi: 10.1056/NEJM199411103311903. [DOI] [PubMed] [Google Scholar]
- Farmer G., Bargonetti J., Zhu H., Friedman P., Prywes R., Prives C. Wild-type p53 activates transcription in vitro. Nature. 1992 Jul 2;358(6381):83–86. doi: 10.1038/358083a0. [DOI] [PubMed] [Google Scholar]
- Finlay C. A., Hinds P. W., Tan T. H., Eliyahu D., Oren M., Levine A. J. Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with an altered half-life. Mol Cell Biol. 1988 Feb;8(2):531–539. doi: 10.1128/mcb.8.2.531. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Furutani M., Arii S., Tanaka H., Mise M., Niwano M., Harada T., Higashitsuji H., Imamura M., Fujita J. Decreased expression and rare somatic mutation of the CIP1/WAF1 gene in human hepatocellular carcinoma. Cancer Lett. 1997 Jan 1;111(1-2):191–197. doi: 10.1016/s0304-3835(96)04509-0. [DOI] [PubMed] [Google Scholar]
- Gu Y., Turck C. W., Morgan D. O. Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit. Nature. 1993 Dec 16;366(6456):707–710. doi: 10.1038/366707a0. [DOI] [PubMed] [Google Scholar]
- Hall P. A., Ray A., Lemoine N. R., Midgley C. A., Krausz T., Lane D. P. p53 immunostaining as a marker of malignant disease in diagnostic cytopathology. Lancet. 1991 Aug 24;338(8765):513–513. doi: 10.1016/0140-6736(91)90586-e. [DOI] [PubMed] [Google Scholar]
- Harper J. W., Adami G. R., Wei N., Keyomarsi K., Elledge S. J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805–816. doi: 10.1016/0092-8674(93)90499-g. [DOI] [PubMed] [Google Scholar]
- Hui A. M., Kanai Y., Sakamoto M., Tsuda H., Hirohashi S. Reduced p21(WAF1/CIP1) expression and p53 mutation in hepatocellular carcinomas. Hepatology. 1997 Mar;25(3):575–579. doi: 10.1002/hep.510250314. [DOI] [PubMed] [Google Scholar]
- Hui A. M., Li X., Makuuchi M., Takayama T., Kubota K. Over-expression and lack of retinoblastoma protein are associated with tumor progression and metastasis in hepatocellular carcinoma. Int J Cancer. 1999 Dec 22;84(6):604–608. doi: 10.1002/(sici)1097-0215(19991222)84:6<604::aid-ijc11>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
- Hui A. M., Makuuchi M., Li X. Cell cycle regulators and human hepatocarcinogenesis. Hepatogastroenterology. 1998 Sep-Oct;45(23):1635–1642. [PubMed] [Google Scholar]
- Hui A. M., Makuuchi M. Molecular basis of multistep hepatocarcinogenesis: genetic and epigenetic events. Scand J Gastroenterol. 1999 Aug;34(8):737–742. doi: 10.1080/003655299750025642. [DOI] [PubMed] [Google Scholar]
- Hui A. M., Sakamoto M., Kanai Y., Ino Y., Gotoh M., Yokota J., Hirohashi S. Inactivation of p16INK4 in hepatocellular carcinoma. Hepatology. 1996 Sep;24(3):575–579. doi: 10.1002/hep.510240319. [DOI] [PubMed] [Google Scholar]
- Hui A. M., Sun L., Kanai Y., Sakamoto M., Hirohashi S. Reduced p27Kip1 expression in hepatocellular carcinomas. Cancer Lett. 1998 Oct 23;132(1-2):67–73. doi: 10.1016/s0304-3835(98)00164-5. [DOI] [PubMed] [Google Scholar]
- Hunter T., Pines J. Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell. 1994 Nov 18;79(4):573–582. doi: 10.1016/0092-8674(94)90543-6. [DOI] [PubMed] [Google Scholar]
- Iggo R., Gatter K., Bartek J., Lane D., Harris A. L. Increased expression of mutant forms of p53 oncogene in primary lung cancer. Lancet. 1990 Mar 24;335(8691):675–679. doi: 10.1016/0140-6736(90)90801-b. [DOI] [PubMed] [Google Scholar]
- Jiang H., Lin J., Su Z. Z., Herlyn M., Kerbel R. S., Weissman B. E., Welch D. R., Fisher P. B. The melanoma differentiation-associated gene mda-6, which encodes the cyclin-dependent kinase inhibitor p21, is differentially expressed during growth, differentiation and progression in human melanoma cells. Oncogene. 1995 May 4;10(9):1855–1864. [PubMed] [Google Scholar]
- Loda M., Cukor B., Tam S. W., Lavin P., Fiorentino M., Draetta G. F., Jessup J. M., Pagano M. Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med. 1997 Feb;3(2):231–234. doi: 10.1038/nm0297-231. [DOI] [PubMed] [Google Scholar]
- Maki C. G., Howley P. M. Ubiquitination of p53 and p21 is differentially affected by ionizing and UV radiation. Mol Cell Biol. 1997 Jan;17(1):355–363. doi: 10.1128/mcb.17.1.355. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Michieli P., Chedid M., Lin D., Pierce J. H., Mercer W. E., Givol D. Induction of WAF1/CIP1 by a p53-independent pathway. Cancer Res. 1994 Jul 1;54(13):3391–3395. [PubMed] [Google Scholar]
- Naka T., Toyota N., Kaneko T., Kaibara N. Protein expression of p53, p21WAF1, and Rb as prognostic indicators in patients with surgically treated hepatocellular carcinoma. Anticancer Res. 1998 Jan-Feb;18(1B):555–564. [PubMed] [Google Scholar]
- Ng I. O., Lai E. C., Chan A. S., So M. K. Overexpression of p53 in hepatocellular carcinomas: a clinicopathological and prognostic correlation. J Gastroenterol Hepatol. 1995 May-Jun;10(3):250–255. doi: 10.1111/j.1440-1746.1995.tb01089.x. [DOI] [PubMed] [Google Scholar]
- Noda A., Ning Y., Venable S. F., Pereira-Smith O. M., Smith J. R. Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res. 1994 Mar;211(1):90–98. doi: 10.1006/excr.1994.1063. [DOI] [PubMed] [Google Scholar]
- Ogawa M., Maeda K., Onoda N., Chung Y. S., Sowa M. Loss of p21WAF1/CIP1 expression correlates with disease progression in gastric carcinoma. Br J Cancer. 1997;75(11):1617–1620. doi: 10.1038/bjc.1997.276. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Qin L. F., Ng I. O., Fan S. T., Ng M. p21/WAF1, p53 and PCNA expression and p53 mutation status in hepatocellular carcinoma. Int J Cancer. 1998 Aug 21;79(4):424–428. doi: 10.1002/(sici)1097-0215(19980821)79:4<424::aid-ijc19>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
- Ray R. B., Steele R., Meyer K., Ray R. Hepatitis C virus core protein represses p21WAF1/Cip1/Sid1 promoter activity. Gene. 1998 Feb 27;208(2):331–336. doi: 10.1016/s0378-1119(98)00030-4. [DOI] [PubMed] [Google Scholar]
- Sarnow P., Ho Y. S., Williams J., Levine A. J. Adenovirus E1b-58kd tumor antigen and SV40 large tumor antigen are physically associated with the same 54 kd cellular protein in transformed cells. Cell. 1982 Feb;28(2):387–394. doi: 10.1016/0092-8674(82)90356-7. [DOI] [PubMed] [Google Scholar]
- Sheikh M. S., Rochefort H., Garcia M. Overexpression of p21WAF1/CIP1 induces growth arrest, giant cell formation and apoptosis in human breast carcinoma cell lines. Oncogene. 1995 Nov 2;11(9):1899–1905. [PubMed] [Google Scholar]
- Somasundaram K., El-Deiry W. S. Inhibition of p53-mediated transactivation and cell cycle arrest by E1A through its p300/CBP-interacting region. Oncogene. 1997 Mar 6;14(9):1047–1057. doi: 10.1038/sj.onc.1201002. [DOI] [PubMed] [Google Scholar]
- Steegenga W. T., van Laar T., Riteco N., Mandarino A., Shvarts A., van der Eb A. J., Jochemsen A. G. Adenovirus E1A proteins inhibit activation of transcription by p53. Mol Cell Biol. 1996 May;16(5):2101–2109. doi: 10.1128/mcb.16.5.2101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Waga S., Hannon G. J., Beach D., Stillman B. The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature. 1994 Jun 16;369(6481):574–578. doi: 10.1038/369574a0. [DOI] [PubMed] [Google Scholar]
- Xiong Y., Hannon G. J., Zhang H., Casso D., Kobayashi R., Beach D. p21 is a universal inhibitor of cyclin kinases. Nature. 1993 Dec 16;366(6456):701–704. doi: 10.1038/366701a0. [DOI] [PubMed] [Google Scholar]
- Yew P. R., Berk A. J. Inhibition of p53 transactivation required for transformation by adenovirus early 1B protein. Nature. 1992 May 7;357(6373):82–85. doi: 10.1038/357082a0. [DOI] [PubMed] [Google Scholar]
- Zhang W., Grasso L., McClain C. D., Gambel A. M., Cha Y., Travali S., Deisseroth A. B., Mercer W. E. p53-independent induction of WAF1/CIP1 in human leukemia cells is correlated with growth arrest accompanying monocyte/macrophage differentiation. Cancer Res. 1995 Feb 1;55(3):668–674. [PubMed] [Google Scholar]
- el-Deiry W. S., Harper J. W., O'Connor P. M., Velculescu V. E., Canman C. E., Jackman J., Pietenpol J. A., Burrell M., Hill D. E., Wang Y. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994 Mar 1;54(5):1169–1174. [PubMed] [Google Scholar]
- el-Deiry W. S., Tokino T., Velculescu V. E., Levy D. B., Parsons R., Trent J. M., Lin D., Mercer W. E., Kinzler K. W., Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993 Nov 19;75(4):817–825. doi: 10.1016/0092-8674(93)90500-p. [DOI] [PubMed] [Google Scholar]
