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(American Journal of Pathology. 2003;162:1823-1829.)
© 2003 American Society for Investigative Pathology

Mutation of p53 in Recurrent Hepatocellular Carcinoma and Its Association with the Expression of ZBP-89

George G. Chen*{dagger}, Juanita L. Merchant{ddagger}§, Paul B. S. Lai*, Rocky L. K. Ho*, Xu Hu*, Morihiro Okada{ddagger}, Sheng F. Huang*||, Albert K. K. Chui*, David J. Law, Yong G. Li||, Wan Y. Lau* and Arthur K. C. Li*

From the Department of Surgery* and the Sir Y. K. Pao Center for Cancer,{dagger} Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong; the Departments of Internal Medicine{ddagger} and Physiology§ and the Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan; and the Department of Surgery,|| The Second Affiliated Hospital, Xiang Ya Medical School, Changsha, Hunan, China


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
p53 has recently been identified as a downstream target of ZBP-89, a zinc finger transcription factor. ZBP-89 promotes growth arrest through stabilization of the p53 protein. The aim of this study is to determine the status of the p53 gene in recurrent human hepatocellular carcinoma (HCC) and test the link between the expression of ZBP-89 and the p53 gene. The results showed that mutations in the p53 gene were frequently detected in recurrent HCC. The interval between surgical resection and the recurrence of HCC was significantly longer in patients with the wild-type p53 gene than those with mutations, strongly suggesting a pathological role for the mutant p53 gene in HCC recurrence. Among those positive for the p53 protein, nearly 85% (18 of 21) showed nuclear localization of the p53 protein while only about 14% (3 of 21) were positive for the p53 protein in the cytoplasm. ZBP-89 co-localized with p53 in the nucleus in about 67% (12 of 18) of all cases positive for the nuclear p53 protein, suggesting that ZBP-89 may play a role in the nuclear accumulation of the p53 protein in a subset of recurrent HCC. With accumulation of p53 protein in the nucleus, tumor cells undergo apoptosis and thus are more susceptible to radiotherapy and chemotherapy. Therefore, co-localization of p53 protein with ZBP-89 may define a subgroup of recurrent HCC that is more sensitive to treatment.

The p53 gene functions as a tumor suppressor and plays a central role in regulating transcriptional activation of crucial growth regulatory genes that control cell cycle progression and cell division. The p53 protein is normally present at low levels in the cell, but it can be up-regulated by stimuli such as DNA damage, hypoxia, viral proteins, or the deregulated cell cycle progression caused by ectopic oncogene expression.1 The biological consequence of p53 up-regulation is the induction of pathways that lead to either cell cycle arrest or apoptosis.

Mutations in the p53 gene abrogate its normal functions, leading to genomic instability and loss of growth control. Many studies have shown that p53 is frequently mutated in human hepatocellular carcinoma (HCC).2-5 Although altered p53 expression has been reported to correlate with advanced tumor grade, progression, therapy, and survival,4-7 information on how the mutations in the p53 gene is linked to recurrence of HCC is limited and the expression of ZBP-89, a four-zinc finger transcription factor that regulates the expression of several genes related to cell growth through binding to GC-rich DNA elements,11 has not been reported in HCC. HCC is an extremely aggressive disease and the mortality of this disease is very high. Surgical resection of the tumor is currently the most effective treatment for HCC. With the advance of early diagnosis, the short-term prognosis has been improved. However, recurrent tumor after surgical resection remains a serious obstacle to improve the prognosis of patients with HCC. Furthermore, recurrent tumors usually grow faster and have lower chemo- or radiosensitivity, which is believed to be affected by the status of the p53 gene.9,10

Our recent studies have further revealed that the inhibitory mechanism of ZBP-89 involves activation of p21wafl stabilization of p53.12,13 ZBP-89 stabilizes p53 through direct protein contact, which leads to retention of p53 in the nucleus. Moreover, tumor cells with a mutation in the p53 gene are resistant to ZBP-89-mediated stabilization.13 In the present study we examine the pattern of p53 mutations and ZBP-89 expression to test the possible correlation between ZBP-89 and p53 in recurrent HCC.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Tissue Samples

Thirty-three Hong Kong Chinese patients with HCC were selected for the study. These patients were found to have recurrent intrahepatic or extrahepatic tumors after surgical resection of primary tumor at Prince of Wales Hospital, Hong Kong. All patients studied were found to be positive for hepatitis B virus. The tumors were confirmed by compatible histopathology. The interval between resection surgery and the appearance of recurrence ranged from 2 to 31 months (mean 6.8 months).

Tissue samples were collected at the time of surgical resection of primary tumors. After collection, samples were immediately stored in liquid nitrogen (-160°C) until experiments were performed.

Immunohistochemistry

Tissues underwent immunohistochemical processing, were embedded in paraffin, and were formalin-fixed for 30 hours to preserve the antigen for immunohistochemistry. Tissues were sectioned at 4 mm thick. Immunostaining was performed on paraffin sections according to our previous publications.14,15 The ZBP-89 antibody was raised against amino acids 1–521 of rat ZBP-89 (dilution 1:1000).14 The p53 antibody was purchased from Santa Cruz Biotechnology (Santa Cruz, CA) and used at a concentration of 1:200. Negative controls were prepared by using PBS instead of the primary antibody.

DNA Extraction

Genomic DNA was isolated from frozen tissues by proteinase K digestion and spin columns using QIAamp DNA mini kit (QIAGEN, Hilden, Germany). The quality of DNA was checked by running DNA on 1% agarose gel and the concentration of DNA was determined spectrophotometrically at 260 nm.

Analysis of p53 Mutation

p53 mutations in exons 2 to 8 were analyzed by direct sequencing. The primers listed in Table 1 were designed for sequencing relevant exons. The sequencing was done by ABI PRISM 310 Genetic Analyzer using BigDye Terminator Cycle Sequencing Kit (PE Applied Biosystems, Foster City, CA). Experiment was performed according to the manufacturer’s instructions.


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  		Table 1. Sequences of Primers Used in p53 Mutation Analysis

 
Immunoprecipitation

Hep 3B cells, transfected with wild-type or mutant p53, were infected with ZBP-89-containing recombinant adenovirus.12,13 Co-precipitation of p53 and ZBP-89 was carried out using whole-cell lysate and specific antibodies as described above. The first antibody (p53)-associated proteins were precipitated with protein A-Sepharose. After washing, immunoprecipitates were separated and immunoblotted with the second antibody (ZBP-89). Hep 3B cells is a hepatocarcinoma cell line, whose p53 gene has been deleted.8

Statistical Analysis

Student’s t-test or Mann-Whitney U-test was used for continuous variables. {chi}2 or Fisher exact test was carried out for categorical variables. Regression and correlation analyses of parametric and nonparametric data were performed by Pearson and Spearman methods respectively. A P value of less than 0.05 was considered statistically significant.


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Mutations in the p53 Gene

Mutations in the p53 gene were frequently detected in recurrent HCC. Of 33 recurrent cases studied, 16 (48.5%) had mutations in the p53 gene. All except one mutation detected was a single nucleotide mismatch that occurred in the core domain between codons 68 and 281 (from exon 4 to exon 8) (Table 2) . One mutation in exon 3 resulted from a deletion of 7 nucleotides with a 2-nucleotide insertion. Among all mutations detected, 7 cases (43.8%) were located in exon 7, especially in codon 249, which accounted for 5 cases (31.3%) of all mutations found.


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  		Table 2. Mutation of the p53 Gene in Recurrent HCC

 
Patient demographics are shown in Table 3 . The patients with recurrent HCC and mutations in the p53 gene were younger than those with the wild-type p53 gene. However, the difference did not reach statistical significance, probably due to the wide variations in age, which ranged from 14 to 75 years. The level of {alpha}-fetoprotein (AFP) in patients with mutations in the p53 gene was significantly lower than those without mutations. There was no difference in other clinical values between patients with and without mutations in the p53 genes.


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  		Table 3. Demographic Data on Patients with Recurrent HCC

 
Association of p53 Mutations with Tumor Recurrence

The interval between surgical resection and the appearance of recurrence was significantly longer in patients with the wild-type p53 gene than those with mutations in the p53 gene (Figure 1) , strongly suggesting a pathological role for the p53 gene in HCC recurrence. Since codon 249 in exon 7 was the most frequent site for mutation, we specifically calculated the interval for recurrent HCC with this particular mutation. The mean interval for recurrent HCC with a mutation in codon 249 of exon 7 was 5.4 months, which was much shorter than that in all other codons (9.6 months, P < 0.05). The detailed distribution of intervals between the two groups of recurrent HCC is shown in Figure 2 .



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  		Figure 1. Mean interval of recurrence in HCC patients with mutations in p53 gene was significantly shorter than those without mutations in p53.

 


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  		Figure 2. Distribution of interval in recurrent HCC with or without mutations in p53.

 
Expression of ZBP-89 in HCC

The frequency of ZBP-89 protein detection was significantly higher in cancerous tissues (28 cases) than in noncancerous ones (18 cases, P = 0.0148). ZBP-89 protein was detected in both the cytoplasm and the nucleus. The intensity was stronger in the nucleus than in the cytoplasm in HCC patients regardless of the presence of p53 mutations (Figure 3A) . However, the expression of ZBP-89 was more readily detected in the cytoplasm of recurrent HCC when p53 mutations were present (Figure 3A) whereas it was more likely to be present in the nucleus of recurrent HCC when there were no mutations in the p53 gene (Figure 3B) .



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  		Figure 3. Immunohistochemical analysis of p53 and ZBP-89 in liver tissues obtained from recurrent HCC with or without mutations in p53. A: Expression of ZBP-89 in recurrent HCC with mutant p53 gene. ZBP-89 was stained in brown. B: Expression of ZBP-89 in recurrent HCC with wild-type p53 gene. ZBP-89 was stained in brown. C: Expression of p53 in recurrent HCC with mutant p53 gene. p53 was stained in brown. D: Expression of p53 in recurrent HCC with wild-type p53 gene. p53 was stained in brown. E: Co-expression of ZBP-89 and p53 in recurrent HCC with wild-type p53 gene. ZBP-89 was stained in brown and p53 in blue. F: Co-expression of ZBP-89 and p53 in recurrent HCC with mutant p53 gene. ZBP-89 was stained in brown and p53 in blue. Magnification, x400.

 
Co-Localization of p53 and ZBP-89 in Hepatoma Cells

The expression of p53 protein was detected in 21 of 33 cases (63.6%). The positive rate of p53 protein detection was significantly higher in recurrent HCC patients with mutations in the p53 gene than those without (P < 0.01). All 16 cases of recurrent HCC with p53 mutations showed p53 signals and only 5 cases with p53 expression did not have underlying mutations in the p53 gene. p53 protein was more likely to accumulate in the cytoplasm of recurrent HCC if mutations were present in the p53 gene (Figure 3C) . Nuclear localization of p53 was also observed, especially in those with the wild-type p53 gene (Figure 3D) . Since ZBP-89 was able to bind to p53 and co-localize to the nucleus,13 we performed double-staining of both proteins in tissues positive for p53 protein. Indeed, ZBP-89 was present in the nuclear compartment where p53 protein was found (Figure 3E) . In most cases where ZBP-89 and p53 proteins co-localized in the nucleus, there were no mutations in the p53 genes. Co-localization of ZBP-89 and p53 proteins was also observed in the cytoplasm. Cytoplasmic co-localization was detected in recurrent HCC tumors primarily with mutant p53 gene. However, ZBP-89 localization could also be observed with some tumors with cytoplasmic wild-type p53 (Figure 3F) .

Direct Interaction Between ZBP-89 and p53

Since ZBP-89 and p53 were co-localized in most recurrent HCC, we examined whether this occurred by direct contact. Co-immunoprecipitation was performed to assess whether both proteins could bind each other. Hep 3B, a p53-negative liver cancer cell line,8 was infected with ZBP-89-containing recombinant adenovirus. Cell extracts were subjected to immunoprecipitation with the p53 antibody followed by immunoblotting with ZBP-89 antibody. Figure 4 shows that ZBP-89 co-precipitated with wild-type 53 and some p53 mutants whose mutations occurred in the N-terminal domains. Mutations in the p53 transactivation domain (35 frameshift) and PXXP domain (G68A) did not affect the binding between ZBP89 and p53. All mutations in the DNA binding domain, except those located in the most N-terminal region of DNA binding domain (V157P and A159P), abolished the direct interaction between ZBP-89 and p53.



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  		Figure 4. Co-immunoprecipitation of ZBP-89 and p53. Hep 3B cells, transfected with various forms of p53 (lanes 1–11) or vector (lane 12), were infected with Ad5-ZBP-89. After cell lysis, the extract was react with p53 antibody (the first antibody) followed by ZBP-89 antibody (the second antibody).

 

   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
It is well known that mutations in the p53 gene are closely associated with HCC.2-5 However, the pattern of mutations varies, depending on the geographic areas and types of patients selected. The present study focuses on recurrent HCC in a Chinese population in Hong Kong. Within the population examined, mutations in the p53 gene were detected in 48.5% of recurrent HCC, which is much higher than the 23.1% reported in a previous study of HCC in Hong Kong Chinese.16 The pattern of p53 mutations detected between these two studies was also different. In the present study, mutations in exon 7 of the p53 gene, which is a hot spot in many studies performed in Asia,17,18 accounted for 43.8% of all alterations found, and therefore the present study suggests that the exon 7 should be considered a prevalent site of p53 mutation. In the previous study, mutations in exon 7 of the p53 gene were detected in 33.3% of cases; however, these two studies may not be comparable, as one was performed on newly diagnosed and recurrent HCC patients in general while the other was conducted only on recurrent HCC.

The mean interval between surgical resection and the appearance of recurrence in patients with mutations in the p53 gene was 7.8 months, whereas those with the wild-type p53 gene was about two-fold as long (16.4 months). This finding establishes a potential link between mutations in the p53 gene and recurrent tumor. Such a link may be of clinical significance if it can be further confirmed in a large number of patients. The behaviors of the recurrent tumor usually differ from that of the primary tumor. Of particular importance, recurrent tumors grow faster and are less sensitive to chemotherapy and radiotherapy.10,11,19,20 These features may be strongly linked to the function of p53 protein. Mutant p53 provides tumor cells with a selective survival advantage during non-surgical therapy and thus decrease the sensitivity to chemo- and radiodrugs.21,22 Functioning as a transcription factor, p53 binds to DNA in a sequence-specific manner and regulates the transcription of the gene responsible for the promotion of apoptosis and the inhibition of angiogenesis,23 both of which are believed to be critical for the prevention or the inhibition of the development of tumors. This concept is supported by both animal and human data. Although p53-null mice are able to develop normally, they are susceptible to an array of spontaneous tumors in early adult life.24 When the wild-type p53 allele is lost, a variety of mesenchymal and epithelial tumors develop in patients with Li-Fraumeni syndrome, which carries heterozygous p53 mutations in the germline.25 In recurrent HCC, p53 dysfunction caused by the mutation may create a similar scenario to the one observed in p53-null mice or p53 allele deletion, in which the growth of a tumor is promoted. If this is true, it would be easier to understand why HCC patients with a mutant p53 gene are more likely to have tumor recurrence within a short interval after surgical resection for the primary tumor.

The central domain of p53, which consists of amino acids 100 to 293, is required for sequence-specific DNA binding.23 All p53 gene mutations except two found in recurrent HCC of this study are located in the DNA-binding domain. Mutations in the central domain alter either the structural integrity of the domain or the amino acids that directly contact the DNA, as demonstrated by the study of the crystal structure of the p53 protein.26 The N terminus of the p53 protein encoded by exons 2 to 4 has an abundance of acidic amino acids that are involved in the transcriptional function of p53.23 It is reported that multiple point mutations in this region are usually required to block the transcriptional transactivation of the p53 gene.27 In the present study, two patterns of mutant p53 gene in this region were found in two patients with recurrent HCC, one was a single point mutation in exon 4 and the other was a frameshift in exon 3. The interval between surgical resection and the appearance of tumor in these two patients were 12 months and 5 months respectively, which were much shorter than the mean 16.4 months in those patients without mutations in the p53 gene. Therefore, we believe that these two p53 mutants within the N-terminus are pathologically significant. This is consistent with the report which indicated that a point mutation in codon 68 of exon 4 decreased approximately 35% transcriptional activity of the p53 gene.28

The p53 nuclear import or retention is essential for its normal function in growth inhibition or induction of apoptosis.23,29 A defect in the regulation of p53 nuclear import or export may result in tumorigenesis. Dysfunctional transportation of p53 between the nucleus and the cytoplasm is known to occur in a subset of human tumors and in such a situation, p53 is sequestered either in the cytoplasm or in the nucleus.30,31 In normal cells, the wild-type p53 protein is kept at a low concentration by rapid degradation. Therefore, the wild-type p53 protein is usually undetected or detected at a very low level. However, when there are mutations within the p53 gene, they result in a dysfunctional protein product with a prolonged half-life that enables them to accumulate in the cell. Accumulation of p53 protein either in the cytoplasm or in the nucleus is considered a pathological index.23 In the present study, nearly 58% (19 of 33) of recurrent HCC showed a nuclear localization of p53 protein and about 9% (3 of 33) was positive for the p53 protein in the cytoplasm. Detailed analysis revealed that accumulation of p53 protein in the nucleus occurred in recurrent HCC regardless of whether the p53 gene was mutated, whereas the cytoplasmic p53 protein was found in all recurrent HCC with mutant p53 gene. Mechanisms responsible for the sequestration of a particular mutant p53 protein in the nucleus or the cytoplasm are very complicated and not yet completely known.

The nuclear localization signals are located within the carboxyl terminus of p53 protein (amino acids 293 to 393).23 Mutations in this nuclear signal region can affect the nuclear import or export of p53. However, none of the mutations detected in the current study were within this nuclear signal region. Recently, we have demonstrated that ZBP-89 protein can stabilize p53 through a direct protein contact, leading to its retention in the nucleus.13 In the present study it was found that ZBP-89 co-localized with p53 in the nucleus in about 63% (12 of 19) of all cases positive for the nuclear p53 protein, suggesting that ZBP-89 may play a role in the nuclear accumulation of p53 protein in a subset of recurrent HCC. Indeed, ZBP-89 is able to bind wild-type p53 and some forms of p53 mutants, as demonstrated by co-immunoprecipitation experiment. Mutation within p53 non-binding N-terminal domains retains its ability to bind ZBP-89, whereas mutation in DNA binding domain (after codon 175) abolishes the direct interaction between ZBP-89 and p53. These p53 mutations may thus eliminate ZBP-89-mediated stabilization of p53.13 In agreement with the co-immunoprecipitation experiment reported here, ZBP-89 was found to co-localize not only with wild-type p53 but also with the mutant protein. This further confirms that the ZBP-89-interaction domain in some mutant p53 proteins remains intact. Co-localization of ZBP-89 and p53 in the nucleus may be clinically significant in certain types of patients who possess functional p53. The function of p53 protein depends on the nuclear localization.23 With accumulation of p53 protein in the nucleus, tumor cells are more likely to undergo apoptosis and are thus more susceptible to radiotherapy and chemotherapy.9,10 Therefore, by co-localizing p53 protein, the expression of ZBP-89 may define a subgroup of recurrent HCC that is more suitable to receive radiotherapy and chemotherapy.

The present study also revealed that the level of serum {alpha}-fetoprotein (AFP) was much lower in recurrent HCC with mutant p53 than those without. This finding is not consistent with an in vitro study that demonstrated that wild-type p53 inhibits the expression of AFP and that mutant one loses its ability to repress AFP production.31 We are unable to explain the difference at the present, but it may be due to the different model of experiments, one is in vivo and the other in vitro. Although AFP is a well-established conventional tumor marker for HCC, there is a report indicating that recurrent HCC may not have an increase in serum {alpha}-fetoprotein level.32 Also, serum AFP is in general not disease-stage-dependent.33


   Footnotes
 
Address reprint requests to George G. Chen, The Chinese University of Hong Kong, Sir Pao Center for Cancer, Department of Surgery, Wales Hospital, Shatin, Hong Kong. E-mail: gchen{at}cuhk.edu.hk

Supported by CUHK Summer Research Grant 2001 (to G.G.C.) and U.S. Public Health Service NIH grant DK 55732 and the Robert and Sally Funderburg Award from the American Digestive Health Foundation (to J.L.M.). S. F. H. was supported by CUHK United College Resident Fellowship. J. L. Merchant is an assistant investigator of the Howard Hughes Medical Institute.

Accepted for publication February 20, 2003.


   References
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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