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Clinical Cancer Research Vol. 7, 1293-1298, May 2001
© 2001 American Association for Cancer Research

Molecular Oncology

Tumor-Suppressor Effect of Interferon Regulatory Factor-1 in Human Hepatocellular Carcinoma1

Yoshinori Moriyama, Shuhei Nishiguchi, Akihiro Tamori2, Noritoshi Koh, Yoshihisa Yano, Shoji Kubo, Kazuhiro Hirohashi and Shuzo Otani

Second Department of Biochemistry [Y. M., Y. Y., S. O.], Third Department of Internal Medicine [Y. M., S. N., A. T., N. K.], and Second Department of Surgery [S. K., K. H.], Osaka City University Medical School, Osaka 545-8585, Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
IFN regulatory factor-1 (IRF-1) regulates the IFN system, inhibits cell growth, and has tumor-suppressor activities. p21 is a universal cyclin-dependent kinase inhibitor, the induction of which depends on both p53 and IRF-1 in mouse embryonic fibroblasts. The expression of p21 in hepatocellular carcinomas (HCCs) is regulated by wild-type p53. We examined the expressions of IRF-1 and p21 in 32 HCCs by quantitative reverse transcription-PCR and the mutation p53 gene in 32 HCCs by single-strand conformation polymorphism and direct sequencing. The expression of IRF-1 mRNA in 15 of 32 HCCs was lower than that in adjacent noncancerous tissue. IRF-1 mRNA expression was reduced in 0 of 3 specimens of well-differentiated HCC, 9 of 21 (42%) specimens of moderately differentiated HCC, and 6 of 8 (75%) specimens of poorly differentiated HCC. IRF-1 mRNA expression was significantly lower in tumors with portal thrombus than in those without portal thrombus (P = 0.003). p53 mutations were detected in 7 of 32 HCCs. p21 expression was reduced in 6 of the 7 (86%) HCCs with p53 mutations. In contrast, p21 expression was reduced in 13 of 25 (52%) HCCs with wild-type p53. IRF-1 expression was reduced in 7 of 13 (53%) HCCs with both wild-type p53 and reduced expression of p21. These results suggest that IRF-1 may be a tumor-suppressor gene for HCC and that IRF-1 is related to p21 expression in HCC with wild-type p53.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
HCC3 is one of the most common malignancies worldwide, with an estimated annual incidence of 1 million cases (1 , 2) . HCC is usually associated with pathological liver damage, such as chronic hepatitis and cirrhosis caused by hepatitis B virus (3 , 4) or HCV (5, 6, 7) . Although hepatitis virus proteins play an important role in experimental hepatocarcinogenesis (8 , 9) , the molecular mechanisms of human hepatocarcinogenesis remained to be defined. p53 is one of the most important tumor-suppressor genes and is inactivated in many kinds of human cancers (10) . p21, a universal cyclin-dependent kinase inhibitor (11) , is regulated by wild-type p53 (12, 13, 14) . Recent studies show that expression of p21 is regulated by a p53-independent pathway (15) .

IRF-1 was identified originally as a regulator of the IFN system (16 , 17) . Malignant transformation induced by c-myc or fos-B can be suppressed by overexpression of the IRF-1 gene (18) . IRF-1 and p53 cooperate through two parallel, independent pathways in the induction of cell cycle arrest and p21 gene transcription (19) . Available evidence suggests that IRF-1 may function as a tumor-suppressor gene. Other studies propose that IRF-1 might induce apoptosis in a human squamous cervical carcinoma cell line (20) . In NIH3T3 cells, cell death attributable to apoptosis was caused by the combined activity of HER1 and IRF-1 (21) . In acute myeloid leukemia and myelodysplastic syndrome, point mutations or deletions of both the IRF-1 gene and exon skipping of IRF-1 mRNA have been detected frequently (22) . Loss of heterozygosity in IRF-1 appears to be critical for the development of human gastric cancers (23 , 24) . However, few studies have assessed the role of IRF-1 in HCC. In the present study, we examined the expressions of IRF-1 and p21 and analyzed the mutations of p53 to determine whether IRF-1 acts as a tumor-suppressor gene in human liver cancer.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Human Specimens.
Tissue samples were obtained from patients with histologically confirmed HCC who underwent hepatectomy. The subjects comprised 31 men and 1 woman, ages 47–76 years (mean, 60.2 years; Table 1Citation ). Serum obtained before surgery was tested for HBsAg (Auszyme II; Dainabot, Tokyo, Japan), HCVAb (Ortho HCVAb ELISA Test II; Ortho Diagnostic Systems, Tokyo, Japan), and AFP (RIA; Dainabot Radioisotope Laboratory, Tokyo, Japan). HBsAg was detected in 5 patients, and HCVAb was detected in 27 patients. No patient had received treatment (transcatheter arterial embolization, percutaneous ethanol injection, and others) before operation. Tissue samples were collected immediately after surgical resection and were separated macroscopically into carcinoma and noncancerous tissue. One portion of each specimen was frozen in liquid nitrogen and stored at -80°C. Total RNA and DNA were extracted from this portion by conventional methods. The remaining portions were fixed in 10% neutral formalin and embedded in paraffin for histological examination. Stained slides were reviewed by a pathologist to confirm tumor location and type. HCC tissue was classified histologically into four groups (well-differentiated, moderately differentiated, poorly differentiated, and undifferentiated) according to Edmondson and Steiner’s classification as modified by the Liver Cancer Study Group of Japan. This study was conducted in accordance with the Helsinki Declaration and the guidelines of the ethics committee of our institution. Informed consent was obtained from each patient.


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  		Table 1 IRF-1 expression and clinicopathological factors

 
RT-PCR Analysis.
First-strand cDNA was prepared from 100 ng of total cellular RNA using a random hexadeoxynucleotide primer (Takara Shuzo, Otsu, Japan) and Super Script RNase H- reverse transcriptase (Life Technologies, Inc., Gaithersburg, MD; Ref. 22 ). The PCR reaction was performed in a reaction mixture containing 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl2, 200 µM deoxynucleotide triphosphates, 1 mM 5' and 3' 32P-end-labeled PCR primers, 0.25 unit of TaqDNA polymerase (Takara Co. Ltd., Tokyo, Japan), and reverse transcriptase reaction product. The quantitative PCR cycle parameters, 95°C for 30 s, 55°C for 30 s, and 72°C for 60 s, for 24 cycles were performed for IRF-1; at 94°C for 30 s, 55°C for 60 s, and 72°C for 90 s, 20 cycles were performed for p21 and 18 cycles were performed for ß-actin (22 , 24) . Each PCR reaction mixture underwent electrophoresis in 5% polyacrylamide gel in 0.5x TBE buffer. The gels were dried and were subjected to autoradiography. The signal intensities were evaluated with an image analyzer (BAS 2000 II; Fujix, Tokyo, Japan).

Direct Sequencing for p53.
We directly sequenced exons 5–8 of the p53 genes, in which 98% of p53 mutations had occurred (25) , in 32 tumors. We performed SSCP analysis as described previously (26) . Next, we directly sequenced all of the cases that had band mobility. One hundred ng of genomic DNA were subjected to 35 PCR cycles (94°C, 55°C, and 72°C for 0.5, 0.5, and 1 min, respectively) with rTaq DNA polymerase (Takara Shuzo Co. Ltd., Tokyo, Japan). The PCR products were treated with exonuclease and alkaline phosphatase. Double-stranded DNA was sequenced by the dideoxy method with fluorescently labeled 2',3'-dideoxynucleoside 5'-triphosphates with each primer. Gel electrophoresis and DNA sequencing were performed with a DNA sequencing system (373A; Applied Biosystems, Tokyo, Japan).

Primers.
The primers used in this study are described in Table 2Citation .


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  		Table 2 Primers used in this study

 
Statistics.
The Student t test was used to analyze differences in age, HBsAg, HCVAb, formation of capsule, portal invasion, intrahepatic metastasis, infiltration to capsule, septal formation, cirrhosis, and histology. Tumor size and AFP were expressed as medians with 25th and 75th percentiles. The significance of differences between median values was evaluated by the Mann-Whitney U test. P < 0.05 was considered significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
IRF-1 mRNA Expression.
We examined the level of IRF-1 mRNA expression in 32 HCCs by RT-PCR. Relative IRF-1 expression values (units) were obtained by dividing the IRF-1:ß-actin ratio of tumor by that of normal tissue. In 15 of the 32 tumors, IRF-1 mRNA expression was 0.4 arbitrary unit or fewer (Fig. 1Citation and Table 3Citation ). Next, we examined the relationship between IRF-1 mRNA expression and clinicopathological findings. IRF-1 mRNA expression was reduced in 0 of the 3 specimens of well-differentiated HCC, 9 of the 21 (42%) specimens of moderately differentiated HCC, and 6 of the 8 (75%) specimens of poorly differentiated HCC (Fig. 2)Citation . The IRF-1 mRNA expression was significantly lower in tumors with portal thrombus than in those without portal thrombus. There was no relation between IRF-1 mRNA expression and tumor size (Table 1)Citation .



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  		Fig. 1. Examples of IRF-1 mRNA expression in HCC tumors and noncancerous tissues by RT-PCR analysis. IRF-1 mRNA expressions were reduced in cases 2 (0.23 unit), 15 (0.12 unit), and 24 (0.21 unit). The 379-bp bands were measured by an image analyzer. Relative IRF-1 expression values (units) were obtained by dividing the IRF-1:ß-actin ratio of tumor by that of normal tissue. T, HCC tumor tissue; N, normal liver tissue.

 

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  		Table 3 IRF-1 and p21waf1/cip1 mRNA expression and p53 statusin HCC

 


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  		Fig. 2. The reduced expressions of IRF-1 and p21 mRNA and the degree of histological differentiation of HCC. Although the differences were not significant, IRF-1 and p21 were less expressed in dedifferentiated HCC. %, the incidence of reduced expressions of IRF-1 and p21 mRNA in each differentiated tumor.

 
p21 mRNA Expression and p53 Mutation.
We analyzed the expression of p21 mRNA in these tumors. In 19 of the 32 tumors, p21 mRNA expression was reduced 0.4 arbitrary unit or fewer (Fig. 3Citation and Table 3Citation ). p21 mRNA expression was reduced in 1 of the 3 (33%) specimens of well-differentiated HCC, 12 of the 21 (57%) specimens of moderately differentiated HCC, and 6 of the 8 (75%) specimens of poorly differentiated HCC (Fig. 2)Citation . Seven of the 32 (22%) tumors had point mutations and amino acid changes. The detailed results are shown in Fig. 4Citation and Table 3Citation . All of the tumors with amino acid changes were moderately differentiated HCC.



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  		Fig. 3. Examples of p21 mRNA expression in HCC tumors and noncancerous tissues by RT-PCR analysis. p21 mRNA expressions were reduced in cases 2 (0.19 unit) and 12 (0.13 unit). T, HCC tumor tissue; N, normal liver tissue.

 


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  		Fig. 4. Example of p53 mutation status. a, PCR-SSCP analysis for mutation in exon 6. Apparent band mobility is shown. b, direct sequencing of p53. A point mutation is found at codon 220 (TAT to TGT, Tyr to Cys). T, HCC tumor tissue; N, normal liver tissue.

 
Relationship among IRF-1 and p21 mRNA Expressions, and p53 Mutations.
p53 mutations were detected in 7 of the 32 HCCs. Of these 7 tumors, p21 expression was reduced in 6 (86%). Among the 25 HCCs with wild-type p53, p21 expression was reduced in 13 (52%). IRF-1 expression was reduced in 7 of the 13 (53%) HCCs with wild-type p53 and reduced expression of p21. However, 6 HCCs with reduced p21 expression had wild-type p53 and normal IRF-1 expression (Table 3)Citation .


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, we found that expression of IRF-1 mRNA was lower in human HCC than in noncancerous liver tissue. In the hepatoma cell line PLC/PRF/5, DNA rearrangement of IRF-1 was detected, and the expression of IRF-1 was decreased (28) . Previous studies of HCC showed that loss of heterozygosity was found frequently in chromosome 5q, where the IRF-1 locus exists (29) . On the other hand, IRF-1 was inactivated by exon skipping in human hematopoietic neoplasia (22) . In gastric cancer, there was loss of heterozygosity at the IRF-1 locus (24) . It is unclear how IRF-1 is inactivated in HCC. We consider IRF-1 to be an important tumor-suppressor gene in human malignancies, including HCC. The molecular mechanisms of early hepatic carcinogenesis are poorly understood. p53, one of the most important tumor-suppressor genes, is not mutated in well-differentiated HCC (30) . Ornithine decarboxylase, one of the tumor growth genes, is not activated in well-differentiated HCC (31 , 32) . We found that IRF-1 was not decreased in well-differentiated HCC and was less expressed in poorly differentiated hepatoma. IRF-1 was lower in HCC with portal thrombus than in HCC without portal thrombus. These results suggest that IRF-1 is inactivated at a late stage of human hepatocarcinogenesis.

Previous studies have reported that p21 expression is reduced predominantly by p53 aberrations, which were considered initially a downstream mediator of p53 function (12, 13, 14) . In our study, p21 expression was reduced in 6 of the 7 (86%) HCCs with p53 mutations, consistent with the results of prior investigations. However, p21 expression was also reduced in 13 of the 25 (53%) HCCs without p53 mutations. Recent studies suggest that p21 is also regulated by p73 and c-jun, independent of p53 (19 , 33 , 34) . It has been shown that the p21 promoter has several binding sites for IRF-1, one of the transcriptional factors that regulates p21 expression. We examined the relationship between p21 expression and IRF-1 expression in human hepatoma with wild-type p53. Among 25 HCCs with wild-type p53, p21 expression was reduced in 7 of the 11 (64%) HCCs with reduced IRF-1 expression. In four tumors with reduced IRF-1 expression but normal p21 expression, p53 mutations were not detected. We believe that p21 expression was rescued by wild-type p53 in such cases. These results suggest that p53 predominantly and IRF-1 cooperatively regulate p21 expression in HCC.

Our previous study showed that IFN decreased the incidence of HCC in patients with chronic hepatitis and liver cirrhosis (35) . However, it is unclear how IFN prevents HCC without viral clearance. After IFN treatment, HCC developed in some patients with HCV. In the HCC cell line, IFN-{alpha} induced apoptosis and suppressed cell proliferation (36) . IRF-1 mRNA was induced by IFN-{alpha} in human hepatoma cell lines and by IFN-{gamma} in some cancer cell lines (28 , 37 , 38) . Perhaps chemoprevention with IFN is related to the expression of IRF-1. In patients with chronic hepatitis, IRF-1 is inactivated after the breakdown of IFN regulation. IRF-1 function should therefore be examined in patients scheduled to receive IFN chemoprevention.

In conclusion, our results suggest that IRF-1 is an important tumor-suppressor gene in HCC that may regulate p21 expression either independently or cooperatively with p53.


   ACKNOWLEDGMENTS
 
We thank A. Tatsumi for technical assistance and Prof. H. Kinoshita for critical reading of the manuscript.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by the Ministry of Education and of Health and Welfare, Japan. Back

2 To whom requests for reprints should be addressed, at Third Department of Internal Medicine, Osaka City University Medical School, 1-4-3, Asahi-machi, Abenoku, Osaka 545-8585, Japan. Phone: 81-6-6645-3811; Fax: 81-6-6645-3813; E-mail: atamori{at}med.osaka-cu.ac.jp Back

3 The abbreviations used are: HCC, hepatocellular carcinoma; AFP, {alpha}-fetoprotein; IRF, interferon regulatory factor; RT-PCR, reverse transcription-PCR; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HCVAb, HCV antibody; SSCP, single-strand conformation polymorphism. Back

Received 7/28/00; revised 1/29/01; accepted 1/29/01.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Di Bisceglie A. M., Rustgi V. K., Hoofnagle J. H., Dusheiko G. M., Lotze M. T. NIH conference. Hepatocellular carcinoma. Ann. Intern. Med., 108: 390-401, 1988.
  2. Parkin D. M., Stjernsward J., Muir C. S. Estimates of the worldwide frequency of 12 major cancers. Bull. World Health Organ., 62: 163-182, 1984.[Medline]
  3. Beasley R. P., Hwang L. Y., Lin C. C., Chien C. S. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22,707 men in Taiwan. Lancet, 2: 1129-1133, 1981.[CrossRef][Medline]
  4. Sakuma K., Saitoh N., Kasai M., Jitsukawa H., Yoshino I., Yamaguchi M., Nobutomo K., Yamumi M., Tsuda F., Komazawa T. Relative risks of death due to liver disease among Japanese male adults having various statuses for hepatitis B s and e antigen/antibody in serum: a prospective study. Hepatology, 8: 1642-1646, 1988.[Medline]
  5. Saito I., Miyamura T., Ohbayashi A., Harada H., Katayama T., Kikuchi S., Watanabe Y., Koi S., Onji M., Ohta Y. Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc. Natl. Acad. Sci. USA, 87: 6547-6549, 1990.[Abstract/Free Full Text]
  6. Nishioka K., Watanabe J., Furuta S., Tanaka E., Iino S., Suzuki H., Tsuji T., Yano M., Kuo G., Choo Q. L. A high prevalence of antibody to the hepatitis C virus in patients with hepatocellular carcinoma in Japan. Cancer (Phila.), 67: 429-433, 1991.[CrossRef][Medline]
  7. Tamori A., Nishiguchi S., Kubo S., Koh N., Moriyama Y., Fujimoto S., Takeda T., Shiomi S., Hirohashi K., Kinoshita H., Otani S., Kuroki T. Possible contribution to hepatocarcinogenesis of X transcript of hepatitis B virus in Japanese patients with hepatitis C virus. Hepatology, 29: 1429-1434, 1999.[CrossRef][Medline]
  8. Arii M., Takada S., Koike K. Identification of three essential regions of hepatitis B virus X protein for transactivation function. Oncogene, 7: 397-403, 1992.[Medline]
  9. Moriya K., Fujie H., Shintani Y., Yotsuyanagi H., Tsutsumi T., Ishibashi K., Matsuura Y., Kimura S., Miyamura T., Koike K. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat. Med., 4: 1065-1067, 1998.[CrossRef][Medline]
  10. Kern S. E., Kinzler K. W., Bruskin A., Jarosz D., Friedman P., Prives C., Vogelstein B. Nucleotide, genome identification of p53 as a sequence-specific DNA-binding protein. Science (Wash. DC), 252: 1708-1711, 1991.[Abstract/Free Full Text]
  11. Xiong Y., Hannon G. J., Zhang H., Casso D., Kobayashi R., Beach D. p21 is a universal inhibitor of cyclin kinases. Nature (Lond.), 366: 701-704, 1993.[CrossRef][Medline]
  12. Ozcelik H., Mousses S., Andrulis I. L. Low levels of expression of an inhibitor of cyclin-dependent kinases (CIP1/WAF1) in primary breast carcinomas with p53 mutations. Clin. Cancer Res., 1: 907-912, 1995.[Abstract]
  13. 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, 75: 817-825, 1993.[CrossRef][Medline]
  14. Hui A. M., Kanai Y., Sakamoto M., Tsuda H., Hirohashi S. Reduced p21(WAF1/CIP1) expression and p53 mutation in hepatocellular carcinomas. Hepatology, 25: 575-579, 1997.[CrossRef][Medline]
  15. 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., 54: 3391-3395, 1994.[Abstract/Free Full Text]
  16. Miyamoto M., Fujita T., Kimura Y., Maruyama M., Harada H., Sudo Y., Miyata T., Taniguchi T. Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-ß gene regulatory elements. Cell, 54: 903-913, 1988.[CrossRef][Medline]
  17. Harada H., Takahashi E., Itoh S., Harada K., Hori T. A., Taniguchi T. Structure and regulation of the human interferon regulatory factor 1 (IRF-1) and IRF-2 genes: implications for a gene network in the interferon system. Mol. Cell. Biol., 14: 1500-1509, 1994.[Abstract/Free Full Text]
  18. Taniguchi T., Lamphier M. S., Tanaka N. IRF-1: the transcription factor linking the interferon response and oncogenesis. Biochim. Biophys. Acta, 1333: M9-M17, 1997.[Medline]
  19. Tanaka N., Ishihara M., Lamphier M. S., Nozawa H., Matsuyama T., Mak T. W., Aizawa S., Tokino T., Oren M., Taniguchi T. Cooperation of the tumour-suppressors IRF-1 and p53 in response to DNA damage. Nature (Lond.), 382: 816-818, 1996.[CrossRef][Medline]
  20. Giandomenico V., Vaccari G., Fiorucci G., Percario Z., Vannuchi S., Matarrese P., Malorni W., Romeo G., Affabris G. R. Apoptosis and growth inhibition of squamous carcinoma cells treated with interferon-{alpha}, IFN-ß, and retinoic acid are associated with induction of the cyclin-dependent kinase inhibitor p21. Eur. Cytokine Netw., 9: 619-631, 1998.[Medline]
  21. Kirchhoff S., Hauser H. Cooperative activity between HER oncogenes and the tumor-suppressor IRF-1 results in apoptosis. Oncogene, 18: 3725-3736, 1999.[CrossRef][Medline]
  22. Harada H., Kondo T., Ogawa S., Tamura T., Kitagawa M., Tanaka N., Lamphier M. S., Hirai H., Taniguchi T. Accelerated exon skipping of IRF-1 mRNA in human myelodysplasia/leukemia: a possible mechanism of tumor suppressor inactivation. Oncogene, 9: 3313-3320, 1994.[Medline]
  23. Nozawa H., Oda E., Ueda S., Tamura G., Maesawa C., Muto T., Taniguchi T., Tanaka N. Functionally inactivating point mutation in the tumor-suppressor IRF-1 gene identified in human gastric cancer. Int. J. Cancer, 77: 522-527, 1998.[CrossRef][Medline]
  24. Tamura G., Ogasawara S., Nishizuka S., Sakata K., Maesawa C., Suzuki Y., Terashima M., Saito K., Satodate R. Two distinct regions of deletion on the long arm of chromosome 5 in differentiated adenocarcinomas of the stomach. Cancer Res., 56: 612-615, 1996.[Abstract/Free Full Text]
  25. Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science (Wash. DC), 253: 49-53, 1991.[Abstract/Free Full Text]
  26. Orita M., Suzuki Y., Sekiya T., Hayashi K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics, 5: 874-879, 1989.[CrossRef][Medline]
  27. Sugio K., Ishida T., Yokoyama H., Inoue T., Sugimachi K., Sasazuki T. Ras gene mutations as a prognostic marker in adenocarcinoma of the human lung without lymph node metastasis. Cancer Res., 52: 2903-2906, 1992.[Abstract/Free Full Text]
  28. Tada S., Saito H., Tsunematsu S., Ebinuma H., Wakabayashi K., Masuda T., Ishii H. Interferon regulatory factor-1 gene abnormality and loss of growth inhibitory effect of interferon-{alpha} in human hepatoma cell lines. Int. J. Oncol., 13: 1207-1216, 1998.[Medline]
  29. 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, 64: 1083-1087, 1991.[Medline]
  30. Hayashi H., Sugio K., Matsumata T., Adachi E., Takenaka K., Sugimachi K. The clinical significance of p53 gene mutation in hepatocellular carcinomas from Japan. Hepatology, 22: 1702-1707, 1995.[CrossRef][Medline]
  31. Tamori A., Nishiguchi S., Kuroki T., Seki S., Kobayashi K., Kinoshita H., Otani S. Relationship of ornithine decarboxylase activity and histological findings in human hepatocellular carcinoma. Hepatology, 20: 1179-1186, 1994.[CrossRef][Medline]
  32. Tamori A., Nishiguchi S., Kuroki T., Koh N., Kobayashi K., Yano Y., Otani S. Point mutation of ornithine decarboxylase gene in human hepatocellular carcinoma. Cancer Res., 55: 3500-3503, 1995.[Abstract/Free Full Text]
  33. Zhu J., Jiang J., Zhou W., Chen X. The potential tumor-suppressor p73 differentially regulates cellular p53 target genes. Cancer Res., 58: 5061-5065, 1998.[Abstract/Free Full Text]
  34. Wang C. H., Tsao Y. P., Chen H. J., Chen H. L., Wang H. W., Chen S. L. Transcriptional repression of p21((Waf1/Cip1/Sdi1)) gene by c-jun through Sp1 site. Biochem. Biophys. Res. Commun., 270: 303-310, 2000.[CrossRef][Medline]
  35. Nishiguchi S., Kuroki T., Nakatani S., Morimoto H., Takeda T., Nakajima S., Shiomi S., Seki S., Kobayashi K., Otani S. Randomised trial of effects of interferon-{alpha} on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet, 346: 1051-1055, 1995.[CrossRef][Medline]
  36. Yano H., Iemura A., Haramaki M., Ogasawara S., Takayama A., Akiba J., Kojiro M. Interferon {alpha} receptor expression and growth inhibition by interferon {alpha} in human liver cancer cell lines. Hepatology, 29: 1708-1717, 1999.[CrossRef][Medline]
  37. Burke F., Smith P. D., Crompton M. R., Upton C., Balkwill F. R. Cytotoxic response of ovarian cancer cell lines to IFN-{gamma} is associated with sustained induction of IRF-1 and p21 mRNA. Br. J. Cancer, 80: 1236-1244, 1999.[CrossRef][Medline]
  38. Um S. J., Kim E. J., Hwang E. S., Kim S. J., Namkoong S. E., Park J. S. Antiproliferative effects of retinoic acid/interferon in cervical carcinoma cell lines: cooperative growth suppression of IRF-1 and p53. Int. J. Cancer, 85: 416-423, 2000.[CrossRef][Medline]



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