Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2011

Open Access 01-12-2011 | Research article

Decreased expression of 17β-hydroxysteroid dehydrogenase type 1 is associated with DNA hypermethylation in colorectal cancer located in the proximal colon

Authors: Agnieszka Anna Rawłuszko, Karolina Horbacka, Piotr Krokowicz, Paweł Piotr Jagodziński

Published in: BMC Cancer | Issue 1/2011

Login to get access

Abstract

Background

The importance of 17β-estradiol (E2) in the prevention of large bowel tumorigenesis has been shown in many epidemiological studies. Extragonadal E2 may form by the aromatase pathway from androstenedione or the sulfatase pathway from estrone (E1) sulfate followed by E1 reduction to E2 by 17-β-hydroxysteroid dehydrogenase (HSD17B1), so HSD17B1 gene expression may play an important role in the production of E2 in peripheral tissue, including the colon.

Methods

HSD17B1 expression was analyzed in colorectal cancer cell lines (HT29, SW707) and primary colonic adenocarcinoma tissues collected from fifty two patients who underwent radical colon surgical resection. Histopathologically unchanged colonic mucosa located at least 10-20 cm away from the cancerous lesions was obtained from the same patients. Expression level of HSD17B1 using quantitative PCR and western blot were evaluated. DNA methylation level in the 5' flanking region of HSD17B1 CpG rich region was assessed using bisulfite DNA sequencing and HRM analysis. The influence of DNA methylation on HSD17B1 expression was further evaluated by ChIP analysis in HT29 and SW707 cell lines. The conversion of estrone (E1) in to E2 was determined by electrochemiluminescence method.

Results

We found a significant decrease in HSD17B1 transcript (p = 0.0016) and protein (p = 0.0028) levels in colorectal cancer (CRC) from the proximal but not distal colon and rectum. This reduced HSD17B1 expression was associated with significantly increased DNA methylation (p = 0.003) in the CpG rich region located in the 5' flanking sequence of the HSD17B1 gene in CRC in the proximal but not distal colon and rectum. We also showed that 5-dAzaC induced demethylation of the 5' flanking region of HSD17B1, leading to increased occupation of the promoter by Polymerase II, and increased transcript and protein levels in HT29 and SW707 CRC cells, which contributed to the increase in E2 formation.

Conclusions

Our results showed that reduced HSD17B1 expression can be associated with DNA methylation in the 5' flanking region of HSD17B1 in CRC from the proximal colon.
Appendix
Available only for authorised users
Literature
1.
Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin. 2010, 60 (5): 277-300. 10.3322/caac.20073.CrossRefPubMed
2.
Ferlay J, Parkin DM, Steliarova-Foucher E: Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2008, 46 (4): 765-781.CrossRef
3.
Brenner H, Hoffmeister M, Arndt V, Haug U: Gender differences in colorectal cancer: implications for age at initiation of screening. Br J Cancer. 2007, 96 (5): 828-831. 10.1038/sj.bjc.6603628.CrossRefPubMedPubMedCentral
4.
Ries LA, Wingo PA, Miller DS, Howe HL, Weir HK, Rosenberg HM, Vernon SW, Cronin K, Edwards BK: The annual report to the nation on the status of cancer, 1973-1997, with a special section on colorectal cancer. Cancer. 2000, 88 (10): 2398-2424. 10.1002/(SICI)1097-0142(20000515)88:10<2398::AID-CNCR26>3.0.CO;2-I.CrossRefPubMed
5.
Qiu Y, Langman MJ, Eggo MC: Targets of 17beta-oestradiol-induced apoptosis in colon cancer cells: a mechanism for the protective effects of hormone replacement therapy?. J Endocrinol. 2004, 181 (2): 327-337. 10.1677/joe.0.1810327.CrossRefPubMed
6.
Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD: Postmenopausal hormone replacement therapy: scientific review. Jama. 2002, 288 (7): 872-881. 10.1001/jama.288.7.872.CrossRefPubMed
7.
Rennert G, Rennert HS, Pinchev M, Lavie O, Gruber SB: Use of hormone replacement therapy and the risk of colorectal cancer. J Clin Oncol. 2009, 27 (27): 4542-4547. 10.1200/JCO.2009.22.0764.CrossRefPubMedPubMedCentral
8.
Simpson ER: Sources of estrogen and their importance. J Steroid Biochem Mol Biol. 2003, 86 (3-5): 225-230. 10.1016/S0960-0760(03)00360-1.CrossRefPubMed
9.
Mindnich R, Moller G, Adamski J: The role of 17 beta-hydroxysteroid dehydrogenases. Mol Cell Endocrinol. 2004, 218 (1-2): 7-20. 10.1016/j.mce.2003.12.006.CrossRefPubMed
10.
Luu The V, Labrie C, Zhao HF, Couet J, Lachance Y, Simard J, Leblanc G, Cote J, Berube D, Gagne R, et al: Characterization of cDNAs for human estradiol 17 beta-dehydrogenase and assignment of the gene to chromosome 17: evidence of two mRNA species with distinct 5'-termini in human placenta. Mol Endocrinol. 1989, 3 (8): 1301-1309. 10.1210/mend-3-8-1301.CrossRefPubMed
11.
Luu-The V, Labrie C, Simard J, Lachance Y, Zhao HF, Couet J, Leblanc G, Labrie F: Structure of two in tandem human 17 beta-hydroxysteroid dehydrogenase genes. Mol Endocrinol. 1990, 4 (2): 268-275. 10.1210/mend-4-2-268.CrossRefPubMed
12.
Miettinen MM, Mustonen MV, Poutanen MH, Isomaa VV, Vihko RK: Human 17 beta-hydroxysteroid dehydrogenase type 1 and type 2 isoenzymes have opposite activities in cultured cells and characteristic cell- and tissue-specific expression. Biochem J. 1996, 314 (Pt 3): 839-845.CrossRefPubMedPubMedCentral
13.
Poutanen M, Moncharmont B, Vihko R: 17 beta-hydroxysteroid dehydrogenase gene expression in human breast cancer cells: regulation of expression by a progestin. Cancer Res. 1992, 52 (2): 290-294.PubMed
14.
Kondo Y: Epigenetic cross-talk between DNA methylation and histone modifications in human cancers. Yonsei Med J. 2009, 50 (4): 455-463. 10.3349/ymj.2009.50.4.455.CrossRefPubMedPubMedCentral
15.
Luczak MW, Jagodzinski PP: The role of DNA methylation in cancer development. Folia Histochem Cytobiol. 2006, 44 (3): 143-154.PubMed
16.
Chomczynski P, Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987, 162 (1): 156-159.CrossRefPubMed
17.
Radonic A, Thulke S, Mackay IM, Landt O, Siegert W, Nitsche A: Guideline to reference gene selection for quantitative real-time PCR. Biochem Biophys Res Commun. 2004, 313 (4): 856-862. 10.1016/j.bbrc.2003.11.177.CrossRefPubMed
18.
Szabo A, Perou CM, Karaca M, Perreard L, Palais R, Quackenbush JF, Bernard PS: Statistical modeling for selecting housekeeper genes. Genome Biol. 2004, 5 (8): R59-10.1186/gb-2004-5-8-r59.CrossRefPubMedPubMedCentral
19.
20.
21.
22.
Bock C, Reither S, Mikeska T, Paulsen M, Walter J, Lengauer T: BiQ Analyzer: visualization and quality control for DNA methylation data from bisulfite sequencing. Bioinforma (Oxford, England). 2005, 21 (21): 4067-4068. 10.1093/bioinformatics/bti652.CrossRef
23.
Rohde C, Zhang Y, Jurkowski TP, Stamerjohanns H, Reinhardt R, Jeltsch A: Bisulfite sequencing Data Presentation and Compilation (BDPC) web server--a useful tool for DNA methylation analysis. Nucleic Acids Res. 2008, 36 (5): e34-10.1093/nar/gkn083.CrossRefPubMedPubMedCentral
24.
Wojdacz TK, Dobrovic A: Methylation-sensitive high resolution melting (MS-HRM): a new approach for sensitive and high-throughput assessment of methylation. Nucleic Acids Res. 2007, 35 (6): e41-10.1093/nar/gkm013.CrossRefPubMedPubMedCentral
25.
26.
Kim YI: Nutritional epigenetics: impact of folate deficiency on DNA methylation and colon cancer susceptibility. J Nutr. 2005, 135 (11): 2703-2709.PubMed
27.
Hermann S, Rohrmann S, Linseisen J: Lifestyle factors, obesity and the risk of colorectal adenomas in EPIC-Heidelberg. Cancer Causes Control. 2009, 20 (8): 1397-1408. 10.1007/s10552-009-9366-3.CrossRefPubMed
28.
van Duijnhoven FJ, Bueno-De-Mesquita HB, Ferrari P, Jenab M, Boshuizen HC, Ros MM, Casagrande C, Tjonneland A, Olsen A, Overvad K, et al: Fruit, vegetables, and colorectal cancer risk: the European Prospective Investigation into Cancer and Nutrition. American J Clin Nutr. 2009, 89 (5): 1441-1452. 10.3945/ajcn.2008.27120.CrossRef
29.
Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell. 1990, 61 (5): 759-767. 10.1016/0092-8674(90)90186-I.CrossRefPubMed
30.
Kim MS, Lee J, Sidransky D: DNA methylation markers in colorectal cancer. Cancer Metastasis Rev. 2010, 29 (1): 181-206. 10.1007/s10555-010-9207-6.CrossRefPubMed
31.
Miyakura Y, Sugano K, Konishi F, Ichikawa A, Maekawa M, Shitoh K, Igarashi S, Kotake K, Koyama Y, Nagai H: Extensive methylation of hMLH1 promoter region predominates in proximal colon cancer with microsatellite instability. Gastroenterol. 2001, 121 (6): 1300-1309. 10.1053/gast.2001.29616.CrossRef
32.
Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, Hubbell FA, Ascensao J, Rodabough RJ, Rosenberg CA, Taylor VM, Harris R, Chen C, et al: Estrogen plus progestin and colorectal cancer in postmenopausal women. New England J Med. 2004, 350 (10): 991-1004. 10.1056/NEJMoa032071.CrossRef
33.
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002, 288 (3): 321-333. 10.1001/jama.288.3.321.CrossRefPubMed
34.
Hartman J, Edvardsson K, Lindberg K, Zhao C, Williams C, Strom A, Gustafsson JA: Tumor repressive functions of estrogen receptor beta in SW480 colon cancer cells. Cancer Res. 2009, 69 (15): 6100-6106. 10.1158/0008-5472.CAN-09-0506.CrossRefPubMed
35.
Castiglione F, Taddei A, Degl'Innocenti DR, Buccoliero AM, Bechi P, Garbini F, Chiara FG, Moncini D, Cavallina G, Marascio L, et al: Expression of estrogen receptor beta in colon cancer progression. Diagn Mol Pathol. 2008, 17 (4): 231-236. 10.1097/PDM.0b013e3181656d67.CrossRefPubMed
36.
Weige CC, Allred KF, Allred CD: Estradiol alters cell growth in nonmalignant colonocytes and reduces the formation of preneoplastic lesions in the colon. Cancer Res. 2009, 69 (23): 9118-9124. 10.1158/0008-5472.CAN-09-2348.CrossRefPubMed
37.
Zhao C, Dahlman-Wright K, Gustafsson JA: Estrogen receptor beta: an overview and update. Nucl Recept signal. 2008, 6: e003-PubMedPubMedCentral
38.
Papaxoinis K, Triantafyllou K, Sasco AJ, Nicolopoulou-Stamati P, Ladas SD: Subsite-specific differences of estrogen receptor beta expression in the normal colonic epithelium: implications for carcinogenesis and colorectal cancer epidemiology. Eur J Gastroenterol Hepatol. 2010, 22 (5): 614-619. 10.1097/MEG.0b013e328335ef50.CrossRefPubMed
39.
Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB: Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet. 1994, 7 (4): 536-540. 10.1038/ng0894-536.CrossRefPubMed
40.
McCashland TM, Brand R, Lyden E, de Garmo P: Gender differences in colorectal polyps and tumors. Am J Gastroenterol. 2001, 96 (3): 882-886. 10.1111/j.1572-0241.2001.03638.x.CrossRefPubMed
41.
Sarli L, Michiara M, Sgargi P, Iusco D, De Lisi V, Leonardi F, Bella MA, Sgobba G, Roncoroni L: The changing distribution and survival of colorectal carcinoma: an epidemiological study in an area of northern Italy. Eur J Gastroenterol Hepatol. 2005, 17 (5): 567-572. 10.1097/00042737-200505000-00014.CrossRefPubMed
42.
Cho NL, Javid SH, Carothers AM, Redston M, Bertagnolli MM: Estrogen receptors alpha and beta are inhibitory modifiers of Apc-dependent tumorigenesis in the proximal colon of Min/+ mice. Cancer Res. 2007, 67 (5): 2366-2372. 10.1158/0008-5472.CAN-06-3026.CrossRefPubMed
43.
Fiorelli G, Picariello L, Martineti V, Tognarini I, Tonelli F, Brandi ML: Estrogen metabolism in human colorectal cancer cells. J Steroid Biochem Mol Biol. 2002, 81 (3): 281-289. 10.1016/S0960-0760(02)00075-4.CrossRefPubMed
44.
Hanahan D, Weinberg RA: The hallmarks of cancer. Cell. 2000, 100 (1): 57-70. 10.1016/S0092-8674(00)81683-9.CrossRefPubMed
45.
Chan AO, Broaddus RR, Houlihan PS, Issa JP, Hamilton SR, Rashid A: CpG island methylation in aberrant crypt foci of the colorectum. Am J Pathol. 2002, 160 (5): 1823-1830. 10.1016/S0002-9440(10)61128-5.CrossRefPubMedPubMedCentral
46.
Suehiro Y, Hinoda Y: Genetic and epigenetic changes in aberrant crypt foci and serrated polyps. Cancer Sci. 2008, 99 (6): 1071-1076. 10.1111/j.1349-7006.2008.00784.x.CrossRefPubMed
47.
Qu Z, Yan P, Fu J, Jiang J, Grusby MJ, Smithgall TE, Xiao G: DNA methylation-dependent repression of PDZ-LIM domain-containing protein 2 in colon cancer and its role as a potential therapeutic target. Cancer Res. 2010, 70 (5): 1766-1772. 10.1158/0008-5472.CAN-09-3263.CrossRefPubMedPubMedCentral
48.
Belanger AS, Tojcic J, Harvey M, Guillemette C: Regulation of UGT1A1 and HNF1 transcription factor gene expression by DNA methylation in colon cancer cells. BMC mol biol. 2010, 11: 9-10.1186/1471-2199-11-9.CrossRefPubMedPubMedCentral
49.
Ghoshal K, Motiwala T, Claus R, Yan P, Kutay H, Datta J, Majumder S, Bai S, Majumder A, Huang T, et al: HOXB13, a target of DNMT3B, is methylated at an upstream CpG island, and functions as a tumor suppressor in primary colorectal tumors. PloS one. 2010, 5 (4): e10338-10.1371/journal.pone.0010338.CrossRefPubMedPubMedCentral
50.
Wendt MK, Johanesen PA, Kang-Decker N, Binion DG, Shah V, Dwinell MB: Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasis. Oncogene. 2006, 25 (36): 4986-4997. 10.1038/sj.onc.1209505.CrossRefPubMedPubMedCentral
51.
Jass JR: Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathol. 2007, 50 (1): 113-130. 10.1111/j.1365-2559.2006.02549.x.CrossRef
52.
Glebov OK, Rodriguez LM, Nakahara K, Jenkins J, Cliatt J, Humbyrd CJ, DeNobile J, Soballe P, Simon R, Wright G, et al: Distinguishing right from left colon by the pattern of gene expression. Cancer Epidemiol Biomarkers Prev. 2003, 12 (8): 755-762.PubMed
53.
Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP: CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA. 1999, 96 (15): 8681-8686. 10.1073/pnas.96.15.8681.CrossRefPubMedPubMedCentral
54.
Leibovitz A, Stinson JC, McCombs WB, McCoy CE, Mazur KC, Mabry ND: Classification of human colorectal adenocarcinoma cell lines. Cancer Res. 1976, 36 (12): 4562-4569.PubMed
55.
von Kleist S, Chany E, Burtin P, King M, Fogh J: Immunohistology of the antigenic pattern of a continuous cell line from a human colon tumor. J Natl Cancer Inst. 1975, 55 (3): 555-560.PubMed
56.
57.
Lorincz MC, Dickerson DR, Schmitt M, Groudine M: Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells. Nat Struct Mol Biol. 2004, 11 (11): 1068-1075. 10.1038/nsmb840.CrossRefPubMed
58.
Tian XQ, Zhang Y, Sun D, Zhao S, Xiong H, Fang J: Epigenetic silencing of LRRC3B in colorectal cancer. Scand J gastroenterol. 2009, 44 (1): 79-84. 10.1080/00365520802400834.CrossRefPubMed
59.
Liu M, Peng Y, Wang X, Guo Q, Shen S, Li G: NGX6 gene mediated by promoter methylation as a potential molecular marker in colorectal cancer. BMC Cancer. 2010, 10: 160-10.1186/1471-2407-10-160.CrossRefPubMedPubMedCentral
60.
Lin J, Lai M, Huang Q, Ruan W, Ma Y, Cui J: Reactivation of IGFBP7 by DNA demethylation inhibits human colon cancer cell growth in vitro. Cancer biol ther. 2008, 7 (12): 1896-1900. 10.4161/cbt.7.12.6937.CrossRefPubMed
Metadata
Title
Decreased expression of 17β-hydroxysteroid dehydrogenase type 1 is associated with DNA hypermethylation in colorectal cancer located in the proximal colon
Authors
Agnieszka Anna Rawłuszko
Karolina Horbacka
Piotr Krokowicz
Paweł Piotr Jagodziński
Publication date
01-12-2011
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2011
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-11-522

Other articles of this Issue 1/2011

BMC Cancer 1/2011 Go to the issue

Research article

Detection of antibodies directed at M. hyorhinis p37 in the serum of men with newly diagnosed prostate cancer

Study protocol

Neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy for patients with resectable gastric cancer (CRITICS)

Study protocol

Sequential FDG-PET and induction chemotherapy in locally advanced adenocarcinoma of the Oesophago-gastric junction (AEG): The Heidelberg Imaging program in Cancer of the oesophago-gastric junction during Neoadjuvant treatment: HICON trial

Research article

The combination of gefitinib and RAD001 inhibits growth of HER2 overexpressing breast cancer cells and tumors irrespective of trastuzumab sensitivity

Case report

Malignant melanoma arising from a perianal fistula and harbouring a BRAFgene mutation: a case report

Research article

Overexpression of eIF-5A2 in mice causes accelerated organismal aging by increasing chromosome instability
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits