H19 DMR methylation correlates to the progression of esophageal squamous cell carcinoma through IGF2 imprinting pathway
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
H19 gene has been proved to be essential for human tumor growth which contains CpG rich regions. Imprinted gene expression in many cancers is usually associated with the function of methylation. We performed this study to better understand wether H19 DMR methylation correlates to the progression of esophageal squamous cell carcinoma through IGF2 imprinting pathway.
LOI of IGF2 was detected in 276 samples, which were determined as heterozygote with ApaI polymorphism in exon 9 of IGF2 by PCR–RFLP and RT-PCR–RFLP. Methylation status of H19 DMR in informative samples was analyzed by bisulfite sequencing PCR. IGF2 expression was examined by real-time PCR and IHC.
208 ESCC patients were informative for ApaI polymorphism. 92 tumor and 30 normal tissues showed IGF2 LOI. Methylation status of H19 CBS6 was higher in patients with IGF2 LOI compared to patients with IGF2 MOI (p < 0.05). IGF2 expression in patients with IGF2 LOI was higher than patients with IGF2 MOI (p < 0.05) which was correlated with lymph node involvement, neoplastic grade and metastasis (p < 0.05).
Our results suggested that H19 CBS6 hypermethylation is related to the LOI of IGF2 which usually leads to an overexpression of IGF2, playing important roles in the occurrence, development as well as metastasis of ESCC. Therefore, H19 CBS6 methylation potentially represents a novel clinically relevant epigenetic marker to identify individuals at increased risk for the occurrence, progression and prognosis of ESCC.
- Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. CrossRef
- Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. Eur J Cancer. 2011;37(Suppl 8):S4–66.
- Luo M, Li Z, Wang W, Zeng Y, Liu Z, Qiu J. Upregulated H19 contributes to bladder cancer cell proliferation by regulating ID2 expression. FEBS J. 2013;280(7):1709–16. CrossRef
- Sorin V, Ohana P, Gallula J, Birman T, Matouk I, Hubert A, et al. H19-promoter-targeted therapy combined with gemcitabine in the treatment of pancreatic cancer. ISRN Oncol. 2012;2012:351750.
- Cui H, Onyango P, Brandenburg S, Wu Y, Hsieh CL, Feinberg AP. Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cancer Res. 2002;62:6442–6.
- Murphy SK, Huang Z, Wen Y, Spillman MA, Whitaker RS, Simel LR, et al. Frequent IGF2/H19 domain epigenetic alterations and elevated IGF2 expression in epithelial ovarian cancer. Mol Cancer Res. 2006;4:283–92. CrossRef
- Gicquel C, Rossignol S, Cabrol S, Houang M, Steunou V, Barbu V, et al. Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver–Russell syndrome. Nat Genet. 2005;37:1003–7. CrossRef
- Eggermann T, Eggermann K, Schonherr N. Growth retardation versus overgrowth: Silver–Russell syndrome is genetically opposite to Beckwith–Wiedemann syndrome. Trends Genet. 2008;24:195–204. CrossRef
- Ohlsson R, Hedborg F, Holmgren L, Walsh C, Ekstrom TJ. Overlapping patterns of IGF2 and H19 expression during human development: biallelic IGF2 expression correlates with a lack of H19 expression. Development. 1994;120(2):361–8.
- Ogawa O, Eccles MR, Szeto J, McNoe LA, Yun K, Maw MA, et al. Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms’ tumour. Nature (Lond.). 1993;362:749–51.
- Mori M, Inoue H, Shiraishi T. Relaxation of insulin-like growth factor 2 gene imprinting in esophageal cancer. Int J Cancer. 1996;68:441–6. CrossRef
- Xu W, Fan H, He X, Zhang J, Xie W. LOI of IGF2 is associated with esophageal cancer and linked to methylation status of IGF2 DMR. J Exp Clin Cancer Res. 2006;25:543–7.
- Cruz-Correa M, Cui H, Giardiello FM. Loss of imprinting of insulin growth factor II gene: a potential heritable bio-marker for colon neoplasia predisposition. Gastroenterology. 2004;126:964–70. CrossRef
- Liou JM, Wu MS, Lin JT. Loss of imprinting of insulin-like growth factor II is associated with increased risk of proximal colon cancer. Eur J Cancer. 2007;43:1276–82. CrossRef
- Leighton PA, Ingram RS, Eggenschwiler J, Efstratiadis A, Tilghman SM. Disruption of imprinting caused by deletion of the H19 gene region in mice. Nature. 1995;375(6526):34–9.
- Hark AT, Schoenherr CJ, Katz DJ, Ingram RS, Levorse JM, Tilghman SM. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature. 2000;405(6785):486–89.
- Cui H, Horon IL, Ohlsson R, Hamilton SR, Feinberg AP. Loss of imprinting in normal tissue of colorectal cancer patients with microsatellite instability. Nat Med. 1998;4:1276–80. CrossRef
- Boissonnas CC, Abdalaoui HE, Haelewyn V, Fauque P, Dupont JM, Gut I, et al. Specific epigenetic alterations of IGF2-H19 locus in spermatozoa from infertile men. Eur J Hum Genet. 2010;18(1):73–80. CrossRef
- Cui H. Loss of imprinting of IGF2 as an epigenetic marker for the risk of human cancer. Dis Markers. 2007;23:105–12. CrossRef
- Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst. 2000;92:1472–89. CrossRef
- Furstenberger G, Senn HJ. Insulin-like growth factors and cancer. Lancet Oncol. 2002;2:298–302. CrossRef
- Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev. 2007;28:20–47. CrossRef
- Sakatani T, Kaneda A, Iacobuzio-Donahue CA. Loss of imprinting of Igf2 alters intestinal maturation and tumori-genesis in mice. Science. 2005;307:1976–8. CrossRef
- Ravenel JD, Broman KW, Perlman EJ. Loss of imprinting of insulin-like growth factor-II (IGF2) gene in distinguishing specific biologic subtypes of Wilms tumor. J Natl Cancer Inst. 2001;93:1698–703. CrossRef
- Woodson K, Flood A, Green L. Loss of insulin-like growth factor-II imprinting and the presence of screen-detected colorectal adenomas in women. J Natl Cancer Inst. 2004;96:407–10. CrossRef
- Feinberg AP, Gehrke CW, Kuo KC, Ehrlich M. Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res. 1988;48:1159–61.
- Baylin SB, Hoppener JW, de Bustros A, Steenbergh PH, Lips CJ, Nelkin BD. DNA methylation patterns of the calcitonin gene in human lung cancers and lymphomas. Cancer Res. 1986;46:2917–22.
- Rainier S, Johnson LA, Dobry CJ, Ping AJ, Grundy PE, Feinberg AP. Relaxation of imprinted genes in human cancer. Nature (Lond.). 1993;362:747–9. CrossRef
- Byun HM, Wong HL, Birnstein EA, Wolff EM, Liang G, Yang AS. Examination ofIGF2 and H19 loss of imprinting in bladder cancer. Cancer Res. 2007;67(22):10753–8. CrossRef
- Bhusari S, Yang B, Kueck J, Huang W, Jarrard DF. Insulin-like growth factor-2 (IGF2) loss of imprinting marks a field defect within human prostates containing cancer. Prostate. 2011;71(15):1621–30. CrossRef
- H19 DMR methylation correlates to the progression of esophageal squamous cell carcinoma through IGF2 imprinting pathway
Clinical and Translational Oncology
Volume 16, Issue 4 , pp 410-417
- Cover Date
- Print ISSN
- Online ISSN
- Springer Milan
- Additional Links
- H19 CBS
- Industry Sectors
- Author Affiliations
- 1. Central Laboratory, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210029, Jiangsu, China
- 2. Department of Life Sciences, Nanjing Normal University, Nanjing, 210046, Jiangsu, China