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[Cancer Research 62, 6820-6822, December 1, 2002]
© 2002 American Association for Cancer Research

Advances in Brief

Aberrant Methylation of the HPP1 Gene in Ulcerative Colitis-associated Colorectal Carcinoma1

Fumiaki Sato2, David Shibata2, Noam Harpaz, Yan Xu, Jing Yin, Yuriko Mori, Suna Wang, Andreea Olaru, Elena Deacu, Florin M. Selaru, Martha C. Kimos, Prodromos Hytiroglou, Joanne Young, Barbara Leggett, Adi F. Gazdar, Shinichi Toyooka, John M. Abraham and Stephen J. Meltzer3

Gastroenterology Division, Department of Medicine, University of Maryland School of Medicine and Gastroenterology Service, Department of Medicine, Baltimore VA Hospital, Baltimore, Maryland 21201 [F. S., Y. X., J. Yi., Y. M., S. W., A. O., E. D., F. M. S., M. C. K., J. M. A., S. J. M.]; Division of Surgical Oncology, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201 [D. S.]; Department of Pathology, The Mount Sinai School of Medicine, New York, New York 10029 [N. H., P. H.]; Gastroenterology Unit, Queensland Institute of Medical Research, Brisbane 4029, Australia [J. Yo., B. L.]; and University of Texas Southwestern Medical Center, Hamon Cancer Center, Dallas, Texas 75390 [A. F. G., S. T.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
The HPP1 gene was cloned as a frequently methylated gene in hyperplastic polyps of the colon. It has been shown that HPP1 expression is silenced by HPP1 gene hypermethylation in sporadic colorectal cancers. To determine the role of HPP1 in ulcerative colitis (UC)-associated carcinogenesis, the prevalence of HPP1 methylation was investigated in three different histological stages of UC-associated carcinogenesis (non-neoplastic UC colon, dysplasia, and carcinoma). Quantitative methylation-specific PCR and quantitative reverse transcription-PCR were used to determine HPP1 gene methylation and expression levels, respectively. HPP1 methylation was observed in 24 of 48 (50%) adenocarcinomas and in 4 of 10 (40%) dysplasias. In contrast, no non-neoplastic UC mucosa showed HPP1 methylation. HPP1 expression in the HCT116 colon cancer cell line was restored after treatment with the demethylating agent 5-aza-2'-deoxycytidine. In conclusion, our data suggest that methylation of HPP1 is a relatively common early event in UC-associated carcinogenesis. HPP1 offers potential as a biomarker for the early detection of cancer or dysplasia in UC.


   Introduction
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 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
UC4 is a chronic disease characterized by inflammation of the mucosa and submucosa of the large intestine. The duration and extent to which a patient suffers from UC correlate directly with an increased propensity to develop colorectal carcinoma (1 , 2) . For patients who have had UC for more than 20 years, the incidence of colorectal cancer is 10–20-fold greater than that of the general population, and the average age of onset is 20 years earlier (3) . UC-associated colorectal carcinoma is different from sporadic carcinoma: unlike sporadic colorectal carcinoma, which arises from adenomatous polyps, UC-associated colorectal carcinoma progresses from areas of dysplastic mucosa. Although the molecular events that facilitate the progression of adenoma to carcinoma in sporadic colorectal cancer have been well investigated (4) , much remains to be learned regarding molecular events underlying the progression of UC mucosa to dysplasia and carcinoma.

Adenomas are the precursors of most sporadic colorectal cancers. Using a strategy that isolates differentially methylated sequences from hyperplastic polyps and normal mucosa, Young et al. (5) identified a 370-bp sequence containing the 5'-untranslated region and the first exon of a gene encoding a transmembrane protein. This gene was named HPP1 and noted to contain two follistatin modules and an EGF-like domain. By RT-PCR, HPP1 was found to be expressed in 28 of 30 (93%) normal colonic samples but in only 7 of 30 (23%) colorectal cancers. The 5' region of HPP1 included a CpG island containing 49 CpG sites, 96% of which were methylated in colonic tumor.

To determine whether HPP1 hypermethylation occurs during the progression of UC mucosa to carcinoma, the frequency and timing of HPP1 hypermethylation were investigated in clinical samples ranging from non-neoplastic UC mucosa to colorectal carcinoma.


   Materials and Methods
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 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Tissue Samples.
Fifty-eight tumor tissues and five non-neoplastic UC mucosae were obtained at the time of surgical resection from 47 patients with one or more UC-associated colorectal neoplasms. The UC-associated neoplasms consisted of 48 adenocarcinomas and 10 dysplasias. All tissues were grossly dissected free of normal surrounding tissue, and parallel sections were used for histological characterization. Although microdissection was not performed, the tissues were selected to include only those tumors containing >70% tumor cells by H&E staining.

DNA and RNA Extraction.
Genomic normal and tumor DNAs were extracted using previously published protocols (6 , 7) . RNAs were extracted by Trizol reagent (Invitrogen).

Quantitative MSP.
DNA methylation of HPP1 was determined by quantitative MSP (8) using the Taqman system. MSP distinguishes methylated alleles of a given gene based on DNA sequence alterations after bisulfite treatment of DNA, which converts unmethylated but not methylated cytosines to uracils. Subsequent PCR using primers and probe specific to the corresponding methylated DNA sequences is then performed. Primers and probe for quantitative MSP were designed using the GenBank AF264150 sequence for HPP1. Primer and probe sequences for HPP1 are listed in Table 1Citation . ß-Actin was selected as an internal control, and analysis was performed using previously published primer and probe sequences (8) . Briefly, 0.5 µg of genomic DNA was denatured by treatment with NaOH and modified by sodium bisulfite. DNA samples were purified using Wizard DNA purification resin (Promega), treated with NaOH, precipitated with ethanol, and resuspended in 50 µl of water. The PCR mixture consisted of 12.5 µl of Taqman Universal Master Mix without UNG (Applied Biosystems, CA), 0.25 µl of each forward and reverse primer of both HPP1 and ß-Actin (10 µM), 2.0 µl of probe for both HPP1 and ß-Actin (2.5 µM), 50 mg of bisulfite-treated DNA, and H2O (up to 25 µl in total volume). PCR reaction and real-time data collection were performed using an ABI7700 Sequence Detection System (Applied Biosystems, CA) for activation of Taq polymerase at 95°C for 10 min and 50 cycles consisting of denaturation at 95°C for 15 s and annealing and extension at 60°C for 1 min. CpGenome Universal Methylated DNA (Intergen) was used to generate a standard curve for each reaction. Reaction mix without any bisulfite-treated DNA was used as a negative control. MSP values were calculated using the formula below.

HPP1-S and HPP1-T represent levels of HPP1 methylation in the sample and totally methylated control DNAs, respectively. ß-Actin-S and ß-Actin-T correspond to amplified ß-Actin in the sample and totally methylated DNAs, respectively. Because the ß-Actin primer and probe sequences do not contain any CpGs, ß-Actin amplification is unaffected by methylation status. Consequently, the quantitative MSP value is representative of the percentage of sample DNA that is densely methylated.


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  		Table 1 Sequences of primers and probes for HPP1 gene

 
Quantitative RT-PCR.
The expression level of the HPP1 gene was measured using the Taqman quantitative RT-PCR system. The primer and probe sequences for HPP1 are listed in Table 1Citation . The reverse primer was designed to overlap the exon 1–2 boundary of the HPP1 mRNA sequence to avoid amplification of potentially contaminated genomic DNA. cDNA from samples was synthesized by the conversion of 2 µg of total RNA using the SuperScript II kit (Invitrogen) and random primers (N6), according to the manufacturer’s recommendations. cDNA generated from 500 ng of tRNA was used for each reaction. The PCR mixture consisted of 12.5 µl of Taqman Universal MasterMix with UNG (Applied Biosystems, CA): 0.25 µl of each forward and reverse primer (10 µM), and probe (2.5 µM) of both HPP1 and ß-Actin, cDNA, and H2O (up to 25 µl in total volume). The Taqman RNase control reagent (VIC dye-labeled; Applied Biosystems) was used for normalization of data. A standard curve was generated in each experiment by cDNA from an unpublished gastric fibroblast cell strain that highly expressed HPP1 mRNA. Ratio to this standard sample represented the relative expression level of HPP1 mRNA.

5-Aza-dC Treatment of Colon Cancer Cell Line HCT116.
HCT116 (American Type Culture Collection) is a colorectal cancer cell line that expresses very low levels of HPP1 by quantitative RT-PCR and in which the HPP1 gene is highly methylated as determined by quantitative MSP. The 5-Aza-dC (Sigma) treatment procedure has been published previously (9) . Briefly, cells (1 x 105) were seeded in a 100-mm dish. Twenty-four h later, cells were treated with 10-6 M 5-Aza-dC for 24 h. The media were changed at the end of the treatment and once for 3 days. DNA and RNA were obtained at 2, 4, and 6 days after the treatment.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Quantitative MSP and RT-PCR of HPP1 in Colon Cancer Cell Line HCT116.
HPP1 demethylation by 5-Aza-dC and the associated restoration of HPP1 expression are illustrated in Fig. 1Citation . The HPP1 gene in HCT116 was highly methylated before 5-Aza-dC treatment. However, the level of methylation was gradually diminished after 5-Aza-dC treatment. This was associated with a concomitant increase in the level of HPP1 mRNA expression.



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  		Fig. 1. Effect of 5-Aza-dC treatment on demethylation of the HPP1 gene and restoration of HPP1 expression. The solid line represents HPP1 MSP values (left Y axis), and the dashed line represents HPP1 expression levels (right Y axis), whereas the gray area indicates the timing of 5-Aza-dC treatment. The HPP1 RT-PCR value was expressed as a relative expression ratio to a reference sample, which was used to generate a standard curve. HPP1 methylation levels increased between days 4 and 6 after removal of 5-Aza-dC, possibly due to a growth advantage for methylated cells.

 
Quantitative MSP and RT-PCR of HPP1 in Clinical Tissues.
An inverse relationship between HPP1 methylation and expression levels is suggested by the analysis of eight tumors and one dysplastic tissue specimen (Fig. 2)Citation . All three samples in which the HPP1 MSP value was <0.1 exhibited high HPP1 mRNA expression. Therefore, we designated a MSP value of 0.1 as a cutoff point to assign negative or positive methylation status. Using this limit, five of six methylation-positive samples expressed low levels of HPP1 mRNA.



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  		Fig. 2. Relationship of HPP1 methylation and expression levels in UC-associated clinical tissues. HPP1 methylation and expression levels of UC-associated colorectal tumor and one dysplasia are displayed in a scatter plot format (X axis, HPP1 mRNA expression level; Y axis, HPP1 methylation level).

 
Quantitative MSP of HPP1 in UC-associated Colorectal Cancers.
The HPP1 methylation status of UC-associated colorectal tumors is displayed in Fig. 3Citation . Using a MSP value of 0.1 as the determinant, aberrant methylation of HPP1 was observed in 4 of 10 (40%) dysplasias and 24 of 48 (50%) carcinomas, whereas no methylation was detected in 5 non-neoplastic UC mucosae.



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  		Fig. 3. Prevalence of HPP1 methylation in UC-associated colorectal neoplasms. HPP1 methylation rate in each group was estimated using a MSP value cutoff point of 0.1.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
The purpose of this study was to determine the frequency and timing of HPP1 hypermethylation in UC-associated colorectal carcinogenesis. In this study, hypermethylation of HPP1 was present in 4 of 10 (40%) dysplasias and in 24 of 48 (50%) carcinomas. Using conventional MSP, Young et al. (5) reported that the frequency of HPP1 hypermethylation is 63% in hyperplastic colonic polyps, 66% in colonic adenomas, and 84% in sporadic colorectal cancers. In comparison with these data, our HPP1 hypermethylation frequencies are relatively lower. In our study, we used quantitative PCR techniques for both MSP and RT-PCR. Using a MSP value of 0.1 as a dichotomization point may exclude low levels of methylation (1:100 to 1:1000 diluted totally methylated DNA) that could produce visible bands by conventional MSP (10 , 11) . This may potentially explain the differences in HPP1 hypermethylation prevalence between sporadic colorectal and UC-associated neoplasms.

HPP1 aberrant methylation was observed in the early stages of UC-associated carcinogenesis and is similar to what is observed during the development of sporadic colorectal cancers. Aberrant methylation of age- and cancer-related genes (e.g., estrogen receptor, p16INK4a, E-cadherin, hMLH1, p14ARF, and so forth) has been reported in the setting of UC-associated dysplasia and colorectal cancers (11, 12, 13, 14, 15) . Furthermore, hypermethylation of tumor suppressor genes has been reported in other precancerous lesions associated with chronic inflammation [e.g., E-cadherin in chronic gastritis and APC, p16INK4a, and E-cadherin in Barrett’s esophagus (16 , 17) ]. Therefore, a chronic inflammatory status may predispose to the early onset of aberrant methylation of multiple genes.

In this study, we demonstrated that HPP1 expression was restored in the colon cancer cell line HCT116 by 5-Aza-dC treatment. Young et al. (5) have also demonstrated that HPP1 expression was restored in two colon cancer cell lines (HT29 and Lovo) by 5-Aza-dC treatment. Recently, Liang et al. (18) demonstrated differential gene expression between 5-Aza-dC-treated cells and nontreated cells. In this microarray-based study, some genes were up-regulated, whereas others were down-regulated by 5-Aza-dC treatment. This would suggest that changes in gene expression caused by 5-Aza-dC may reflect a balance between inducible negative and positive transcriptional factors. In our temporal analysis of methylation and expression, HPP1 expression was up-regulated on day 6 in the face of a slightly elevated methylation level. Some unknown positive regulators of HPP1 may have affected the expression of HPP1 at this particular time point. Hypermethylation may represent a major regulatory process in the expression of HPP1.

In our study, we encountered one clinical sample that exhibited relatively high HPP1 mRNA expression in the setting of positive methylation. This finding may be explained by the fact that HPP1 is expressed not only in epithelial cells but also in myofibroblasts (5) . Variable levels of contamination by myofibroblasts could have resulted in this paradoxical observation. Alternatively, due to the competing influences of methylation versus inducible transcription factors, methylation of the HPP1 locus may not consistently correlate with complete silencing of HPP1 mRNA expression.

The HPP1 molecule has both a transmembranous form and a soluble form, with one EGF module and two follistatin modules in the extracellular domain and a potential G protein-activating motif in the cytoplasmic domain (19) . This suggests that HPP1 may be a multifunctional protein and that it could play roles as both a growth factor and a receptor. HPP1 stimulates tyrosine phosphorylation of erbB4 (EGFR4) in the gastric cancer cell line MKN28 (19) and can prolong the survival of neural cells (20) . However, the significance of HPP1 function in the gastrointestinal tract remains unclear.

In conclusion, our data suggest that aberrant methylation of HPP1 is a relatively common and early event in UC-associated carcinogenesis. HPP1 is worthy of further study to elucidate its biological function and also to explore its potential as a biomarker for the early detection of cancer or dysplasia in UC.


   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 USPHS Grants DK47717, CA95323, CA85069, and CA 77057 and Early Detection Research Network Grant 5U01CA8497102 (National Cancer Institute, Bethesda, MD). Back

2 These authors contributed equally to this work. Back

3 To whom requests for reprints should be addressed, at University of Maryland School of Medicine, Room N3W62, 22 South Greene Street, Baltimore, MD 21201. Phone: (410) 706-3375; Fax: (410) 706-1325; E-mail: smeltzer{at}medicine.umaryland.edu Back

4 The abbreviations used are: UC, ulcerative colitis; MSP, methylation-specific PCR; RT-PCR, reverse transcription-PCR; 5-Aza-dC, 5-aza-2'-deoxycytidine; EGF, epidermal growth factor. Back

Received 5/ 2/02. Accepted 10/18/02.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

  1. Lashner B. A., Silverstein M. D., Hanauer S. B. Hazard rates for dysplasia and cancer in ulcerative colitis. Results from a surveillance program. Dig. Dis. Sci., 34: 1536-1541, 1989.[Medline]
  2. Ekbom A., Helmick C., Zack M., Adami H. O. Ulcerative colitis and colorectal cancer. A population-based study. N. Engl. J. Med., 323: 1228-1233, 1990.[Abstract]
  3. Harpaz N., Talbot I. C. Colorectal cancer in idiopathic inflammatory bowel disease. Semin. Diagn. Pathol., 13: 339-357, 1996.[Medline]
  4. Fearon E. R., Vogelstein B. A genetic model for colorectal tumorigenesis. Cell, 61: 759-767, 1990.[Medline]
  5. Young J., Biden K. G., Simms L. A., Huggard P., Karamatic R., Eyre H. J., Sutherland G. R., Herath N., Barker M., Anderson G. J., Fitzpatrick D. R., Ramm G. A., Jass J. R., Leggett B. A. HPP1: a transmembrane protein-encoding gene commonly methylated in colorectal polyps and cancers. Proc. Natl. Acad. Sci. USA, 98: 265-270, 2001.[Abstract/Free Full Text]
  6. Meltzer S. J., Yin J., Manin B., Rhyu M. G., Cottrell J., Hudson E., Redd J. L., Krasna M. J., Abraham J. M., Reid B. J. Microsatellite instability occurs frequently and in both diploid and aneuploid cell populations of Barrett’s-associated esophageal adenocarcinomas. Cancer Res., 54: 3379-3382, 1994.[Abstract/Free Full Text]
  7. Boynton R. F., Blount P. L., Yin J., Brown V. L., Huang Y., Tong Y., McDaniel T., Newkirk C., Resau J. H., Raskind W. H., et al Loss of heterozygosity involving the APC and MCC genetic loci occurs in the majority of human esophageal cancers. Proc. Natl. Acad. Sci. USA, 89: 3385-3388, 1992.[Abstract/Free Full Text]
  8. Eads C. A., Lord R. V., Wickramasinghe K., Long T. I., Kurumboor S. K., Bernstein L., Peters J. H., DeMeester S. R., DeMeester T. R., Skinner K. A., Laird P. W. Epigenetic patterns in the progression of esophageal adenocarcinoma. Cancer Res., 61: 3410-3418, 2001.[Abstract/Free Full Text]
  9. Bender C. M., Gonzalgo M. L., Gonzales F. A., Nguyen C. T., Robertson K. D., Jones P. A. Roles of cell division and gene transcription in the methylation of CpG islands. Mol. Cell. Biol., 19: 6690-6698, 1999.[Abstract/Free Full Text]
  10. Herman J. G., Graff J. R., Myohanen S., Nelkin B. D., Baylin S. B. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc. Natl. Acad. Sci. USA, 93: 9821-9826, 1996.[Abstract/Free Full Text]
  11. Sato F., Harpaz N., Shibata D., Xu Y., Yin J., Mori Y., Zou T. T., Wang S., Desai K., Leytin A., Selaru F. M., Abraham J. M., Meltzer S. J. Hypermethylation of the p14ARF gene in ulcerative colitis-associated colorectal carcinogenesis. Cancer Res., 62: 1148-1151, 2002.[Abstract/Free Full Text]
  12. Issa J. P., Ahuja N., Toyota M., Bronner M. P., Brentnall T. A. Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res., 61: 3573-3577, 2001.[Abstract/Free Full Text]
  13. Hsieh C. J., Klump B., Holzmann K., Borchard F., Gregor M., Porschen R. Hypermethylation of the p16INK4a promoter in colectomy specimens of patients with long-standing and extensive ulcerative colitis. Cancer Res., 58: 3942-3945, 1998.[Abstract/Free Full Text]
  14. Wheeler J. M., Kim H. C., Efstathiou J. A., Ilyas M., Mortensen N. J., Bodmer W. F. Hypermethylation of the promoter region of the E-cadherin gene (CDH1) in sporadic and ulcerative colitis associated colorectal cancer. Gut, 48: 367-371, 2001.[Abstract/Free Full Text]
  15. Fleisher A. S., Esteller M., Harpaz N., Leytin A., Rashid A., Xu Y., Liang J., Stine O. C., Yin J., Zou T. T., Abraham J. M., Kong D., Wilson K. T., James S. P., Herman J. G., Meltzer S. J. Microsatellite instability in inflammatory bowel disease-associated neoplastic lesions is associated with hypermethylation and diminished expression of the DNA mismatch repair gene, hMLH1. Cancer Res., 60: 4864-4868, 2000.[Abstract/Free Full Text]
  16. Tamura G., Yin J., Wang S., Fleisher A. S., Zou T., Abraham J. M., Kong D., Smolinski K. N., Wilson K. T., James S. P., Silverberg S. G., Nishizuka S., Terashima M., Motoyama T., Meltzer S. J. E-Cadherin gene promoter hypermethylation in primary human gastric carcinomas. J. Natl. Cancer Inst. (Bethesda), 92: 569-573, 2000.[Abstract/Free Full Text]
  17. Eads C. A., Lord R. V., Kurumboor S. K., Wickramasinghe K., Skinner M. L., Long T. I., Peters J. H., DeMeester T. R., Danenberg K. D., Danenberg P. V., Laird P. W., Skinner K. A. Fields of aberrant CpG island hypermethylation in Barrett’s esophagus and associated adenocarcinoma. Cancer Res., 60: 5021-5026, 2000.[Abstract/Free Full Text]
  18. Liang G., Gonzales F. A., Jones P. A., Orntoft T. F., Thykjaer T. Analysis of gene induction in human fibroblasts and bladder cancer cells exposed to the methylation inhibitor 5-aza-2'-deoxycytidine. Cancer Res., 62: 961-966, 2002.[Abstract/Free Full Text]
  19. Uchida T., Wada K., Akamatsu T., Yonezawa M., Noguchi H., Mizoguchi A., Kasuga M., Sakamoto C. A novel epidermal growth factor-like molecule containing two follistatin modules stimulates tyrosine phosphorylation of erbB-4 in MKN28 gastric cancer cells. Biochem. Biophys. Res. Commun., 266: 593-602, 1999.[Medline]
  20. Horie M., Mitsumoto Y., Kyushiki H., Kanemoto N., Watanabe A., Taniguchi Y., Nishino N., Okamoto T., Kondo M., Mori T., Noguchi K., Nakamura Y., Takahashi E., Tanigami A. Identification and characterization of TMEFF2, a novel survival factor for hippocampal and mesencephalic neurons. Genomics, 67: 146-152, 2000.[Medline]



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