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Loss of Imprinting and Elevated Expression of Wild-Type p73 in Human Gastric Adenocarcinoma¹

Department of Pathology [M-J. K., B-J. P., D-S. B., J-I. P., J-H. P., S-G. C.] and Division of Gastroenterology [H-J. K.], Department of Internal Medicine, School of Medicine, Kyung Hee University, 130-701 Seoul, Republic of Korea

	ABSTRACT

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The p73 gene located at 1p36.3 encodes for a protein with significant similarity to p53. To investigate the penetrance of p73 in gastric carcinogenesis, we analyzed the expression, allelotype, and mutation of p73 in five cell lines and 75 tissues. Although extremely low levels of p73 expression were observed in all noncancerous gastric tissues and four of five cell lines, a significant elevation of p73 was detected in 37 of 39 (94.9%) carcinoma tissues. Furthermore, a tumor-specific increase of p73 was identified in 14 of 16 (87.5%) matched sets. Allelotyping analysis using a StyI or BanI polymorphism revealed that 5 of 21 (23.8%) informative carcinomas, but none of 19 noncancerous cases, express p73 biallelically, suggesting the transcriptional activation of a silent allele in a subset of cancers. Whereas the transcription of an active allele was markedly induced by serum starvation or clump formation of the cells, treatment with 5-aza-2'deoxycytidine activated a silent allele with a subsequent up-regulation of an active allele, supporting the genomic imprinting and autoregulation of the gene. Allelic deletion or mutation of the gene was not found, and no association of p73 expression with the mutational status of p53 or expression of p21^Waf1 was recognized. Taken together, this study argues that p73 is not a target of genetic alteration in gastric carcinogenesis and suggests that overexpression of p73 might be triggered by physiological stresses accompanied with outgrowth of tumors, such as hypoxia or nutrient deprivation.

	INTRODUCTION

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Although gastric cancer is one of the most common malignancies worldwide, the pathogenesis of this disease and the molecular genetic events that contribute to its development are poorly understood (1) . Recently, the first homologue of p53, termed p73, has been cloned at 1p36 (2) . p73 shares remarkable sequence identity to the DNA-binding, transactivation, and oligomerization domains of p53. Transient overexpression of p73 induces G₁ cell cycle arrest and apoptosis in a p53-like manner and activates the transcription of p53-responsive genes, such as p21^Waf1 (3 , 4) . In addition, p73 is expressed monoallelically in neuroblastoma cell lines and tumor specimens, as well as in normal peripheral blood, supporting the notion that p73 is paternally imprinted with regard to the discrete deletions in neuroblastomas (2) .

Despite a striking similarity to p53, p73 is expressed at low levels in all normal tissues and is not induced by UV irradiation or actinomycin D, which is known to induce p53, and differently regulates cellular p53 target genes (3 , 4) . In addition, p73 inactivation is not required for virus-induced tumor development, and none of the p53-inactivating viral oncoproteins, such as adenovirus E1B 55K, SV40 T antigen, and human papillomavirus E6, destabilize p73 (5 , 6) . Recent studies demonstrated that the tyrosine kinase c-Abl phosphorylates p73 and stimulates p73-mediated transactivation and mismatch repair-dependent apoptosis (7, 8, 9) . The ability of c-Abl to phosphorylate p73 is markedly increased by -irradiation or cisplatin, suggesting that p73 participates in the apoptotic response to DNA damage through a c-Abl-dependent mechanism. Together, these studies indicate that p53 and p73 are not functionally equivalent and involved in distinct cellular pathways.

The observation that p73 is monoallelically expressed by imprinting raised the interesting possibility that functional inactivation of p73 would require only a single event leading to preferential loss or mutation of the expressed allele (2) . However, mutations of p73 have been found to be extremely rare in primary human cancers, including tumors showing loss of heterozygosity (4) at 1p36 (10, 11, 12) . Furthermore, biallelic overexpression of p73 has been frequently observed in diverse human tumors, including lung, prostate, and kidney cancer, with the transcriptional activation of the silent allele (13, 14, 15, 16) . These observations suggest that p73 is not a tumor suppressor gene to fit a two-hit model of tumorigenesis or is not the relevant target of 1p36 deletions.

To investigate the penetrance of p73 in gastric carcinogenesis, we analyzed expression level, allele-specific expression, and mutational alteration of p73 in 75 tissues and five cell lines. Here, we demonstrate that p73 is not a target of genetic alteration in gastric carcinogenesis and also show that wild-type p73 is frequently overexpressed in carcinoma tissues by the transcriptional induction of an active allele and/or the activation of a silent allele.

	MATERIALS AND METHODS

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Gastric Tissues, Cell Lines, and 5 Aza-dC⁴ Treatment.
A total of 75 gastric tissues (including 39 adenocarcinomas, 3 adenomas, 6 hamartomas, 7 hyperplastic polyps, and 20 noncancerous tissues) were obtained from 39 gastric cancer patients and 16 noncancer patients by surgical resection in the Kyung Hee University Medical Center (Seoul, Korea). Tissue specimens were snap-frozen in liquid N₂ and stored at -70°C until used. Five gastric carcinoma cell lines (SNU-1, SNU-5, SNU-16, AGS, and KATO-III) were obtained from Korea Cell Line Bank (Seoul National University, Seoul, Korea) or American Type Culture Collection (Manassas, VA). Five human cell lines, derived from neuroblastoma (IMR32 and SK-N-SH), breast carcinoma (MCF7), and leukemia (HL60 and U937) were included to validate the quantitative RT-PCR approach for p73 expression. To achieve demethylation, cell lines were treated with 5 Aza-dC (Sigma Chemical Co., St. Louis, MO) at a concentration of 2 µM for 2–5 days.

Quantitative PCR Analysis.
Our PCR-based strategies and sequences of oligonucleotide primers used for quantitation of expression and genomic status of p73 were described previously (15) . Briefly, expression of p73 was analyzed using primers p73–1 and p73–14, and GAPDH was used as an endogenous expression standard. For detection of alternatively spliced and ß variants, primers p73–11 and p73–9 were used. For quantitative DNA/PCR analysis, intron-specific primers p73-E2S and p73–12 were used for amplification of the exon 2 region of the gene, and primers G3 (sense, 5'-AACCATGAGAAGTATGACAACAGC-3') and G5 (antisense, 5'-GAGTCCTTCCACGATACCAAAG-3') were used for amplification of the intron 5 region of GAPDH. Quantitation was achieved by densitometric scanning of the ethidium bromide-stained gels, and absolute area integrations of the curves representing each specimen were compared after adjustment for GAPDH. Integration and analysis were performed using Molecular Analyst software program (Bio-Rad, Hercules, CA).

Allelic Expression of p73.
Allelotyping assay using a StyI polymorphism in exon 2 was performed as described previously (15) . For allelotyping using a banI polymorphism, the exon 5 region was amplified by primers p73–15 (sense, 5'-ACTCCCCGCTCTTGAAGAAAC-3') and p73–2 (antisense, 5'-TGGCTGGAGCAGACTGTCCTTCGT-3') for transcripts, and p73–15 (see above) and p73-E5AS (antisense, 5'-TGCTGTCCGGGATGCTGGGCAA-3') for genomic DNA. Twenty microliters of the PCR products were digested with banI (Boehringer Mannheim, Mannheim, Germany) overnight and resolved on a 3% agarose gel.

Nonisotopic RT-PCR-SSCP Analysis.
Nonisotopic RT-PCR-SSCP analysis of the entire coding region of the p73 transcript was carried out as reported previously (15) .

	RESULTS

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p73 Expression in Gastric Carcinoma Cell Lines.
To explore the candidacy of p73 as a suppressor in gastric carcinogenesis, we initially evaluated expression levels of p73 mRNA in five gastric carcinoma cell lines (SNU-1, SNU-5, SNU-16, AGS, and KATO-III). As we reported previously, p73 expression levels in five p73-characterized human cell lines were examined for validation of our quantitative RT-PCR approach (15) . IMR32, SK-N-SH, and MCF7, which carry one, two, and three alleles of p73, respectively, were included as expression controls, and U937 and HL60 were chosen to exemplify nonexpressor (2) . As shown in Fig. 1A , predicted levels of p73 expression were observed in three expressor cell lines, whereas no expression was detected in U937 and HL60, indicating that the expression level determined by our RT-PCR assay is well consistent with previously characterized genomic and expression status of the gene. Interestingly, p73 expression was not detectable in gastric cell lines, except SNU-16. To address that the absence of mRNA expression results from gene deletion, genomic level of p73 was determined by quantitative DNA/PCR. However, no significant difference was recognized in p73 gene levels among the five cell lines. Allelotyping analysis of the gene also demonstrated that AGS is heterozygous for StyI and banI polymorphisms and SNU-1 and KATO-III are heterozygous for a banI polymorphism (Figs. 1 and 2) . Thus, our result shows that p73 mRNA is undetectable in four of the five gastric cell lines despite no evidence for an allelic deletion of the gene.

View larger version (46K): [in this window] [in a new window]   Fig. 1. Expression and allelotyping analyses of p73 in gastric cell lines and tissues. A, mRNA expression level and genomic status of p73 were examined by quantitative PCR. IMR32 (one allele), SK-N-SH (two alleles), and MCF7 (three alleles) were used as expressor controls, and U937 (two alleles) and HL60 (one allele) were included as nonexpressor controls. B, allelotyping analysis of p73 transcripts using a StyI polymorphism in cell lines and informative tissue specimens. IMR32 (A/T allele) and MCF7 (G/C allele) were used as allele-type controls. N, normal tissue; Ha, hamartoma; Hp, hyperplastic polyps; Ad, adenoma; Ca, carcinoma.

View larger version (43K): [in this window] [in a new window]   Fig. 2. Transcriptional up-regulation of an active p73 allele in gastric cell lines by serum starvation. Expression of p73 mRNA in cell lines cultured with (+) or without (-) serum was analyzed by RT-PCR. Exons 2 and 5 regions of the p73 transcripts expressed in these cells were amplified using nest-PCR approach and subjected to digestion with StyI and BanI, respectively, to define the allelic origin of the induced transcripts.

Overexpression of Wild-Type p73 in Gastric Carcinomas.
Compared with noncancerous tissues, significantly increased expression of p73 was found in 37 of 39 (94.9%) carcinomas and 2 of 3 (66.7%) adenomas (Fig. 1A) . Furthermore, tumor-specific overexpression was identified in 14 of 16 (87.5%) matched sets. Whereas p73 variant mRNA was clearly observed, p73ß mRNA was nearly undetectable (data not shown). Among the 39 overexpressors, 21 (53.8%) were heterozygous for StyI or banI and 5 (23.8%) of these were found to express p73 biallelically (Fig. 1B) . p73 expression showed no correlation with the histopathological characteristics of the tumors. Quantitative DNA/PCR and RT-PCR-SSCP analyses showed no allelic deletion and mutations, except the previously described polymorphisms (17) . Collectively, these data suggest that wild-type p73 is frequently overexpressed in gastric carcinoma tissues, possibly due to the induction of an active allele and/or the transcriptional activation of a silent allele.

Induction of p73 by Serum Deprivation.
To gain further understanding of the molecular basis of p73 induction, we examined the transcriptional response of the p73 gene to various stimuli in the four gastric cell lines showing no p73 mRNA expression. Although p73 mRNA was not induced by DNA-damaging agents such as etoposide, a significant and rapid increase of p73 expression was found in all cell lines following serum starvation (Fig. 2) . In addition, p73 induction in SNU-16 was associated with clump formation of the cells (data not shown). Allelotyping analysis for the three informative cell lines demonstrated that the p73 transcripts induced by serum starvation were originated from an active allele [StyI(+) allele in AGS, BanI(-) allele in SNU-1, and banI(+) allele in KATO-III]. Thus, this result further supports the transcriptional silencing of one allele in these cells and suggests that p73 would be up-regulated in cancer tissues in response to the physiological stresses such as nutrient deprivation or hypoxia.

Activation of a Silent Allele by 5 Aza-dC Treatment.
To explore the implication of hypermethylation in the transcriptional silencing of the p73 gene, we treated the four nonexpressor cell lines with the demethylating agent 5 Aza-dC. As shown in Fig. 3 , a significant increase of p73 expression was detected in all treated cells. Allelotyping analysis revealed that the induced p73 transcripts were originated from a silent allele [StyI(-) allele in AGS, banI(+) allele in SNU-1, and banI(-) allele in KATO-III], indicating the functional importance of methylation in the transcriptional silencing of one p73 allele. Interestingly, however, the transcripts from an active allele were subsequently increased after a 72-h treatment, suggesting that the transcription of p73 might be stimulated directly or indirectly by the elevated p73 protein products.

View larger version (23K): [in this window] [in a new window]   Fig. 3. Transcriptional activation of a silent allele in gastric cell lines by the demethylating agent 5 Aza-dC (2 µM) treatment. Expression of p73 mRNA was analyzed by RT-PCR analysis. Exons 2 and 5 regions of the p73 transcripts were amplified using nest-PCR approach and digested with StyI and BanI, respectively, to define the allelic origin of the transcripts induced by 5 Aza-dC treatment.

	DISCUSSION

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In the present study, we demonstrate that wild-type p73 is frequently overexpressed in gastric carcinoma tissues through the monoallelic induction of an active allele and/or the activation of a silent allele, suggesting that, unlike p53, p73 may not be a target of genetic alteration in gastric carcinogenesis and that overexpression of p73 rather than as tumor suppressor may contribute to the tumorigenesis. This result is consistent with recent reports of more intense expression of p73 in lung, prostate, and bladder tumors than in normal tissues and loss of genomic imprinting in renal cell carcinomas (13, 14, 15, 16) .

Genomic imprinting of p73 raises the interesting possibility that loss of the transcriptionally active allele by a single event might be sufficient to contribute to human carcinogenesis (2) . In this study, allelotyping analysis revealed the monoallelic expression of p73 in normal gastric tissues and 5 Aza-dC treatment led to the transcriptional activation of a silent allele, suggesting the genomic imprinting of p73 in the stomach. However, no allelic deletion or mutation of p73 was observed and p73 expression is markedly increased in carcinomas, and biallelic expression was found in a subset of tumors. Interestingly, the transcriptional induction of an active allele was followed by the activation of a silent allele by 5 Aza-dC treatment, resulting in a significant elevation of p73. This finding suggests that the release of p73 imprinting could lead to a biallelic overexpression of p73 in tumor cells, possibly by the autoregulation of gene transcription. Collectively, these results indicate that p73 is unlikely to be a tumor suppressor gene that conforms to a two-hit model of tumorigenesis.

There are currently no genetic evidences that inactivation of p73 is required for transformation or malignant progression of human tumors, except recent reports of the epigenetic silencing of p73 in specific types of hematological malignancies, such as acute lymphoblastic leukemias or lymphomas and Burkitt’s lymphomas (18 , 19) . Recently, Yoshikawa et al. (17) examined the mutational alterations of p73 in 54 human cancer cell lines and found 3 lung cell lines carrying p73 mutations. However, no evidences for p73 mutations in primary lung cancers raise the possibility that the mutations occur in cell culture. Our RT-PCR-SSCP analysis also suggests that mutations in p73 might be rare in gastric cancer. In addition, no correlation of p73 expression with the mutational status of p53 or expression levels of p21^Waf1 was recognized. Thus, our result is inconsistent with the hypothesis that disruption of normal p53 function results in compensatory or deleterious up-regulation of p73 or that overexpressed wild-type p73 may mimic mutant p53, thus acting as a dominant-negative factor in wild-type p53-carrying tumor cells (2 , 14) . Two of the three lung cell lines with p73 mutations have been also reported to carry p53 mutations (17) .

The question then arises as to why wild-type p73 is elevated in a variety of solid tumors. Our observation of the dramatic induction of p73 by serum starvation or clump formation of cells raises the possibility that p73 overexpression is associated with unfavorable growth conditions within outgrowing tumors. Recent study also showed that p73 expression is physiological condition dependent and that monoallelic expression of p73 is not strictly maintained in tumors (20) . In this context, we speculate that the physiological stresses accompanied with cancerous outgrowth of solid tumors, such as hypoxia, nutrient deprivation, or imbalances between growth-regulating signals, can trigger the transcription of p73, leading to apoptosis or growth inhibition of tumor cells. However, the absence of mutational inactivation of p73 in human tumors suggests that p73 induction may not be sufficient to suppress the malignant progression of tumors.

Taken together, we show here that wild-type p73 is frequently overexpressed in gastric carcinoma tissues, which argues that inactivation of p73 is not a target of genetic alteration in gastric carcinogenesis. Further work will be required to ascertain the biological significance of elevated p73 in the growth and apoptosis of gastric tumor cells.

	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 in part by a grant from the Ministry of Public Health and Welfare (1999), Republic of Korea, and by Intramural Grant-in-Aid from the Kyung Hee University (1999), Seoul, Korea.

² These authors contributed equally to this article.

³ To whom requests for reprints should be addressed, at Department of Pathology, College of Medicine, Kyung Hee University, 130-701 Seoul, Republic of Korea. Phone: 02-961-0533; Fax: 02-960-2871; E-mail: sgchi{at}nms.kyunghee.ac.Kr

⁴ The abbreviations used are: 5 Aza-dC, 5-aza-2'deoxycytidine; RT-PCR, reverse transcription-PCR; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; SSCP, single-strand conformational polymorphism.

Received 11/23/99; revised 1/26/00; accepted 1/27/00.

	REFERENCES

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1. Tahara E. Genetic alterations in human gastrointestinal cancers. The application of molecular diagnosis. Cancer (Phila.), 75(Suppl.): 1410-1417, 1995.[CrossRef][Medline]
2. Kaghad M., Bonnet H., Yang A., Creancier L., Biscan J-C., Valent A., Minty A., Chalon P., Lelias J-M., Dumont X., Ferrara P., McKeon F., Caput D. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell, 90: 809-819, 1997.[CrossRef][Medline]
3. Jost C. A., Marin M. C., Kaelin W. G., Jr. p73 is a human p53-related protein that can induce apoptosis. Nature (Lond.), 389: 191-194, 1997.[CrossRef][Medline]
4. 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]
5. Marin M. C., Jost C. A., Irwin M. S., DeCaprio J. A., Caput D., Kaelin W. G., Jr. Viral oncoproteins discriminate between p53 and the p53 homolog p73. Mol. Cell. Biol., 18: 6316-6324, 1998.[Abstract/Free Full Text]
6. Roth J., Konig C., Wienzek S., Weigel S., Ristea S., Dobbelstein M. Inactivation of p53 but not p73 by adenovirus type 5 E1B 55-kilodalton and E4 34-kilodalton oncoproteins. J. Virol., 72: 8510-8516, 1998.[Abstract/Free Full Text]
7. Gong J. G., Costanzo A., Yang H-Q., Melino G., Kaelin W. G., Jr., Levrero M., Wang J. Y. J. The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature (Lond.), 399: 806-809, 1999.[CrossRef][Medline]
8. Agami R., Blandino G., Oren M., Shaul Y. Interation of c-Abl and p73 and their collaboration to induce apoptosis. Nature (Lond.), 399: 809-813, 1999.[CrossRef][Medline]
9. Yuan Z-M., Shioya H., Ishiko T., Sun X., Gu J., Huang Y. Y., Lu H., Kharbanda S., Weichselbaum R., Kufe D. p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage. Nature (Lond.), 399: 814-817, 1999.[CrossRef][Medline]
10. Ichimiya S., Nimura Y., Kageyama H., Takada N., Sunahara M., Shishikura T., Nakamura Y., Sakiyama S., Seki N., Ohira M., Kaneko Y., McKeon F., Caput D., Nakagawara A. p73 at 1p36.3 is lost in advanced stage neuroblastoma but its mutation is infrequent. Oncogene, 18: 1061-1066, 1999.[CrossRef][Medline]
11. Han S., Semba S., Abe T., Makino N., Furukawa T., Fukushige G., Takahashi H., Sakurada A., Sata M., Shiiba K., Matsuno S., Nimura Y., Nakagawara A., Horii A. Infrequent somatic mutations of the p73 gene in various human cancers. Eur. J. Surg. Oncol., 25: 194-198, 1999.[CrossRef][Medline]
12. Nomoto S., Haruki N., Kondo M., Konishi H., Takahashi T., Takahashi T., Takahashi T. Search for mutations and examination of allelic expression imbalance of the p73 gene at 1p36.33 in human lung cancers. Cancer Res., 58: 1380-1383, 1998.[Abstract/Free Full Text]
13. Takahashi H., Ichimiya S., Nimura Y., Watanabe M., Furusato M., Wakui S., Yatani R., Aizawa S., Nakagawara A. Mutation, allelotyping and transcription analysis of the p73 gene in prostatic carcinoma. Cancer Res., 58: 2076-2077, 1998.[Abstract/Free Full Text]
14. Mai M., Yokomizo A., Qian C., Yang P., Tindall D. J., Smith D. I., Liu W. Activation of p73 silent allele in lung cancer. Cancer Res., 58: 2347-2349, 1998.[Abstract/Free Full Text]
15. Chi S. G., Chang S. G., Lee S. J., Lee C. H., Kim J. I., Park J. H. Elevated and biallelic expression of p73 is associated with progression of human bladder cancer. Cancer Res., 59: 2791-2793, 1999.[Abstract/Free Full Text]
16. Mai M., Qian C., Yokomizo A., Tindall D. J., Bostwick D., Polychronakos C., Smith D. I., Liu W. Loss of imprinting and allele switching of p73 in renal cell carcinoma. Oncogene, 17: 1739-1741, 1998.[CrossRef][Medline]
17. Yoshikawa H., Nagashima M., Khan M. A., McMenamin M. G., Hagiwara K., Harris C. C. Mutational analysis of p73 and p53 in human cancer cell lines. Oncogene, 18: 3415-3421, 1999.[CrossRef][Medline]
18. Corn P. G., Kuerbitz S. J., van Noesel M. M., Esteller M., Compitello N., Baylin S. B., Herman J. G. Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt’s lymphoma is associated with 5'CpG island methylation. Cancer Res., 59: 3352-3356, 1999.[Abstract/Free Full Text]
19. Kawano S., Miller C. W., Gombart A. F., Bartram C. R., Matsuo Y., Asou H., Sakashita A., Said J., Tatsumi E., Koeffler H. P. Loss of p73 gene expression in leukemia/lymphomas due to hypermethylation. Blood, 94: 1113-1120, 1999.[Abstract/Free Full Text]
20. Yokomizo A., Mai M., Tindall D. J., Cheng L., Bostwick D. G., Naito S., Smith D. I., Liu W. Overexpression of the wild type p73 gene in human bladder cancer. Oncogene, 18: 1629-1633, 1999.[CrossRef][Medline]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kang, M.-J. Articles by Chi, S.-G. Search for Related Content PubMed PubMed Citation Articles by Kang, M.-J. Articles by Chi, S.-G.