Skip to main content

Advertisement

Springer Nature Link
Log in

Loss of imprinting of IGF2 and H19, loss of heterozygosity of IGF2R and CTCF, and Helicobacter pylori infection in laryngeal squamous cell carcinoma

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Imprinting analyses of IGF2 and H19, loss of heterozygosity (LOH) analyses of IGF2R and CTCF and Helicobacter pylori detection, were performed on 35 human laryngeal squamous cell carcinomas (LSCC). Forty-six percent of the tumors were heterozygous for IGF2, and 54% were informative for the H19. Biallelic expression of IGF2 was observed in 33% (5 out of 15) of the tumors and in 27% (4 out of 15) of adjacent non-tumorous laryngeal tissues. H19 loss of imprinting (LOI) was observed in 24% (4 out of 17) of the tumors. For IGF2R and CTCF, 71% (25 out of 35) and 50% (17/34), respectively, of the samples were heterozygous, and LOH was detected in 12% (3 out of 25) and 6% (1 out of 17), respectively, of the tumors. H. pylori was found in 26% (9/35) of these tumors. Among them, four were informative for the imprinting analysis. The presence of H. pylori had no effect on IGF2/H19 imprinting. Only the H. pylori detection was further broadened with an additional 47 laryngeal tumors, resulting in a total final positivity of close to 16% (13 out of 82). This study represents the largest comprehensive IGF2/H19 imprinting study done to date on well-defined samples of human laryngeal carcinomas and corresponding non-tumorous tissue. For the first time, the analyses of IGF2/H19 imprinting have been broadened with LOH analyses of IGF2R and CTCF, with both of these genes acting as modulators of IGF2 and H19 activity. Although there were indications that H. pylori may be present in LSCC, we are the first to show its presence in LSCC by two direct techniques: Giemsa staining and nested-PCR.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Cattaruzza MS, Maisonneuve P, Boyle P (1996) Epidemiology of laryngeal cancer. Eur J Cancer B Oral Oncol 32B:293–305

    Article  PubMed  CAS  Google Scholar 

  2. Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6:597–610 doi:10.1038/nrg1655

    Article  PubMed  CAS  Google Scholar 

  3. O’Dell SD, Day IN (1998) Insulin-like growth factor II (IGF-II). Int J Biochem Cell Biol 30:767–771 doi:10.1016/S1357-2725(98)00048-X

    Article  PubMed  CAS  Google Scholar 

  4. Vu TH, Hoffman AR (1994) Promoter specific imprinting of the human insulin-like growth factor II gene. Nature 371:714–717 doi:10.1038/371714a0

    Article  PubMed  CAS  Google Scholar 

  5. Hankins GR, De Souza AT, Bentley RC, Patel MR, Marks JR, Iglehart JD, Jirtle RL (1996) M6P/IGF2 receptor: a candidate breast tumor suppressor gene. Oncogene 12:2003–2009

    PubMed  CAS  Google Scholar 

  6. Chappell SA, Walsh T, Walker RA, Shaw JA (1997) Loss of heterozygosity at chromosome 6q in pre-invasive and early invasive breast carcinoma. Brit J Cancer 75:1324–1329

    PubMed  CAS  Google Scholar 

  7. Noviello C, Courjal F, Theillet C (1996) Loss of heterozygosity on the long arm of chromosome 6 in breast cancer: possibly four regions of deletion. Clin Cancer Res 2:1601–1606

    PubMed  CAS  Google Scholar 

  8. Sheng ZM, Marchetti A, Buttitta F, Champeme MH, Campani D, Bistocchi M, Lidereau R, Callahan R (1996) Multiple regions of chromosome 6q affected by loss of heterozygosity in primary human breast carcinomas. Brit J Cancer 73:144–147

    PubMed  CAS  Google Scholar 

  9. Saito S, Sirahama S, Matsushima M, Suzuki M, Sagae S, Kudo R, Saito J, Noda K, Nakamura Y (1996) Definition of a commonly deleted region in ovarian cancers to a 300-kb segment of chromosome 6q27. Cancer Res 56:5586–5589

    PubMed  CAS  Google Scholar 

  10. Tibiletti MG, Bernasconi B, Furlan D, Riva C, Trubia M, Buraggi G, Franchi M, Bolis P, Mariani A, Frigerio L, Capella C, Taramelli R (1996) Early involvement of 6q in surface epithelial ovarian tumors. Cancer Res 56:4493–4498

    PubMed  CAS  Google Scholar 

  11. Hao Y, Crenshaw T, Moulton E, Newcomb E, Tycko B (1993) Tumor-suppressor activity of H19 RNA. Nature 365:764–767

    Article  PubMed  CAS  Google Scholar 

  12. Reid LH, West A, Gioeli DG, Phillips KK, Kelleher KF, Araujo D, Stanbridhe D, Dowdy SF, Gerhard DS, Weissman BE (1996) Localization of a tumor suppressor gene in 11p15.5 using the G401 Wilms’ tumor assay. Hum Mol Genet 5:239–247

    Article  PubMed  CAS  Google Scholar 

  13. Matouk IJ, DeGroot N, Mezan S, Ayesh S, Abu-lail R, Hochberg A, Galun E (2007) The H19 non-coding RNA is essential for human tumor growth. PLoS ONE 2:e845 doi:10.1371/journal.pone.0000845

    Article  PubMed  Google Scholar 

  14. Hark AT, Schoenherr CJ, Katz DJ, Ingram RS, Levrose JM, Tilghman SM (2000) CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature 405:486–489 doi:10.1038/35013106

    Article  PubMed  CAS  Google Scholar 

  15. Takai D, Gonzales FA, Tsai YC, Thayer MJ, Jones PA (2001) Large scale mapping of methylcytosines in CTCF-binding sites in the human H19 promoter and aberrant hypomethylation in human bladder cancer. Hum Mol Genet 10:2619–2626

    Article  PubMed  CAS  Google Scholar 

  16. Filippova GN, Lindblom A, Meincke LJ, Klenova EM, Neiman PE, Collins SJ, Doggett NA, Lobanenkov VV (1998) A widely expressed transcription factor with multiple DNA sequence specificity, CTCF, is localized at chromosome segment 16q22.1 within one of the smallest regions of overlap for common deletions in breast and prostate cancers. Genes Chromosomes Cancer 22:26–36

    Article  PubMed  CAS  Google Scholar 

  17. Aygenc E, Selcuk A, Celikkanat S, Ozbek C, Ozdem C (2001) The role of Helicobacter pylori infection in the cause of squamous cell carcinoma of the larynx. Otolaryngol Head Neck Surg 125:120–121 doi:10.1067/mhn.2001.119438

    Article  Google Scholar 

  18. Akbayir N, Basak T, Seven H, Sungun A, Erdem L (2005) Investigation of Helicobacter pylori colonization in laryngeal neoplasia. Eur Arch Otorhinolaryngol 262:170–172 doi:10.1007/s00405-004-0794-0

    Article  PubMed  Google Scholar 

  19. Kizilay A, Saydam L, Aydin A, Kalcioglu MT, Ozturan O, Aydin NE (2006) Histopathologic examination for Helicobacter pylori as a possible etiopathogenic factor in laryngeal carcinoma. Chemotherapy 52:80–82 doi:10.1159/000091727

    Article  PubMed  CAS  Google Scholar 

  20. Li T, Vu TH, Lee KO, Yang Y, Nguyen CV, Bui HQ, Zeng ZL, Nguyen BT, Hu JF, Murphy SK, Jirtle RL, Hoffman AR (2002) An imprinted PEG1/MEST antisense expressed predominantly in human testis and in mature spermatozoa. J Biol Chem 277:13518–13527 doi:10.1074/jbc.M200458200

    Article  PubMed  CAS  Google Scholar 

  21. Mühlisch J, Bajanowski T, Rickert CH, Roggendorf W, Würthwein G, Jürgens H, Frühwald MC (2007) Frequent but borderline methylation of p16 (INK4a) and TIMP3 in medulloblastoma and sPNET revealed by quantitative analyses. J Neurooncol 83:17–29 doi:10.1007/s11060-006–9309-8

    Article  PubMed  Google Scholar 

  22. Hol FA, Geurds MP, Hamel BC, Mariman EC (1992) Improving the polymorphism content of the 3’ UTR of the human IGF2R gene. Hum Mol Genet 1:347

    Article  PubMed  CAS  Google Scholar 

  23. Gall-Troselj K, Mravak-Stipetic M, Jurak I, Ragland WL, Pavelic J (2001) Helicobacter pylori colonization of tongue mucosa—increased incidence in atrophic glossitis and burning mouth syndrome (BMS). J Oral Pathol Med 30:560–563 doi:10.1034/j.1600–0714.2001.300909.x

    Article  PubMed  CAS  Google Scholar 

  24. Grbesa I, Ivkic M, Pegan B, Gall-Troselj K (2006) Loss of imprinting and promoter usage of the IGF2 in laryngeal squamous cell carcinoma. Cancer Lett 238:224–229 doi:10.1016/J.CANLET.2005.07.003

    Article  PubMed  CAS  Google Scholar 

  25. El-Naggar AK, Lai S, Tucker SA, Clayman GL, Goepfert H, Hong WK, Huff V (1999) Frequent loss of imprinting at the IGF2 and H19 genes in head and neck squamous carcinoma. Oncogene 18:7063–7069

    Article  PubMed  CAS  Google Scholar 

  26. Rainho CA, Kowalski LP, Rogatto SR (2001) Loss of imprinting and loss of heterozygosity on 11p15.5 in head and neck squamous cell carcinomas. Head Neck 23:851–859 doi:10.1002/hed.1124

    Article  PubMed  CAS  Google Scholar 

  27. Ulaner GA, Yang Y, Hu JF, Li T, Vu TH, Hoffman AR (2003) CTCF binding at the insulin-like growth factor-II (IGF2)/H19 imprinting control region is insufficient to regulate IGF2/H19 expression in human tissues. Endocrinology 144:4420–4426

    Article  PubMed  CAS  Google Scholar 

  28. Cui H, Horon IL, Ohlsson R, Hamilton SR, Feinberg AP (1998) Loss of imprinting in normal tissue of colorectal cancer patients with microsatellite instability. Nat Med 4:1276–1280 doi:10.1038/3260

    Article  PubMed  CAS  Google Scholar 

  29. Wang WH, Duan JX, Vu TH, Hoffman AR (1996) Increased expression of insulin-like growth factor-II gene in Wilms’ tumor is not dependent on loss of genomic imprinting or loss of heterozygosity. J Biol Chem 271:27863–27870

    Article  PubMed  CAS  Google Scholar 

  30. Kim HT, Choi BH, Niikawa N, Lee TS, Chang SI (1998) Frequent loss of imprinting of the H19 and IGF2 genes in ovarian tumors. Am J Med Genet 80:391–395

    Article  PubMed  CAS  Google Scholar 

  31. Douc-Rasy S, Barrois M, Fogel S, Ahomadegbe JC, Stehelin D, Coll J, Riou G (1996) High incidence of loss of heterozygosity and abnormal imprinting of H19 and IGF2 genes in invasive cervical carcinomas. Uncoupling of H19 and IGF2 expression and biallelic hypomethylation of H19. Oncogene 12:423–430

    PubMed  CAS  Google Scholar 

  32. Fu VX, Schwarze SR, Kenowski ML, Leblanc S, Svaren J, Jarrard DF (2004) A loss of insulin-like growth factor-2 imprinting is modulated by CCCTC-binding factor down-regulation at senescence in human epithelial cells. J Biol Chem 279:52218–52226 doi10.1074/jbc.M405015200

    Article  PubMed  CAS  Google Scholar 

  33. van Gurp RJ, Oosterhuis JW, Kalscheuer V, Mariman EC, Looijenga LH (1994) Biallelic expression of the H19 and IGF2 genes in human testicular germ cell tumors. J Natl Cancer Inst 86:1070–1075

    Article  PubMed  Google Scholar 

  34. Kondo M, Suzuki H, Ueda R, Osada H, Takagi K, Takahashi T, Takahashi T (1995) Frequent loss of imprinting of the H19 gene is often associated with its overexpression in human lung cancers. Oncogene 10:1193–1198

    PubMed  CAS  Google Scholar 

  35. Elkin M, Shevelev A, Schulze E, Tykocinsky M, Cooper M, Ariel I, Pode D, Kopf E, de Groot N, Hochberg A (1995) The expression of the imprinted H19 and IGF-2 genes in human bladder carcinoma. FEBS Lett 374:57–61 doi:10.1016/0014-5793(95)01074-O

    Article  PubMed  CAS  Google Scholar 

  36. Byun H-M, Wong H-L, Birnstein EA, Wolff EM, Liang G, Yang AS (2007) Examination of IGF2 and H19 loss of imprinting in bladder cancer. Cancer Res 67:10753–10758 doi:10.1158/0008-5472.CAN-07-0329

    Article  PubMed  CAS  Google Scholar 

  37. Hibi K, Nakamura H, Hirai A, Fujikake Y, Kasai Y, Akiyama S, Ito K, Takagi H (1996) Loss of H19 imprinting in esophageal cancer. Cancer Res 56:480–482

    PubMed  CAS  Google Scholar 

  38. Ulaner GA, Vu TH, Li T, Hu JF, Yao XM, Yang Y, Gorlick R, Meyers P, Healey J, Ladanyi M, Hoffman AR (2003) Loss of imprinting of IGF2 and H19 in osteosarcoma is accompanied by reciprocal methylation changes of a CTCF-binding site. Hum Mol Gen 12:535–549 doi:10.1093/hmg/ddg034

    Article  PubMed  CAS  Google Scholar 

  39. Cui H, Onyango P, Brandenburg S, Wu Y, Hsieh CL, Feinberg AP (2002) Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cancer Res 62:6442–6446

    PubMed  CAS  Google Scholar 

  40. Pham NV, Nguyen MT, Hu JF, Vu TH, Hoffman AR (1998) Dissociation of IGF2 and H19 imprinting in human brain. Brain Res 810:1–8 doi:10.1016/S0006-8993(98)00783-5

    Article  PubMed  CAS  Google Scholar 

  41. Yang Y, Hu JF, Ulaner GA, Li T, Yao X, Vu TH, Hoffman AR (2003) Epigenetic regulation of Igf2/H19 imprinting at CTCF insulator binding sites. J Cell Biochem 90:1038–1055 doi:10.1002/jcb.10684

    Article  PubMed  CAS  Google Scholar 

  42. Chen HL, Li T, Qiu XW, Wu J, Ling JQ, Sun ZH, Wang W, Chen W, Hou A, Vu TH, Hoffman AR, Hu JF (2006) Correction of aberrant imprinting of IGF2 in human tumors by nuclear transfer-induced epigenetic reprogramming. EMBO J 25:5329–5338 doi:10.1038/sj.emboj.7601399

    Article  PubMed  CAS  Google Scholar 

  43. Jamieson TA, Brizel DM, Killian JK, Oka Y, Jang HS, Fu X, Clough RW, Vollmer RT, Anscher MS, Jirtle RL (2003) M6P/IGF2R loss of heterozygosity in head and neck cancer associated with poor patient prognosis. BMC Cancer 3:4 doi:10.1186/1471-2407-3-4

    Article  PubMed  Google Scholar 

  44. Kong FM, Anscher MS, Washington MK, Killian JK, Jirtle RL (2000) M6P/IGF2R is mutated in squamous cell carcinoma of the lung. Oncogene 19:1572–1578

    Article  PubMed  CAS  Google Scholar 

  45. Mummert SK, Lobanenkov VA, Feinberg AP (2005) Association of chromosome arm 16q loss with loss of imprinting of insulin-like growth factor-II in Wilms’ tumor. Genes Chromosomes Cancer 43:155–161 doi:10.1002/gcc.20176

    Article  PubMed  CAS  Google Scholar 

  46. Aulmann S, Bläker H, Penzel R, Rieker RJ, Otto HF, Sinn HP (2003) CTCF gene mutations in invasive ductal breast cancer. Breast Cancer Res Treat 80:347–352 doi:10.1023/A:1024930404629

    Article  PubMed  CAS  Google Scholar 

  47. Yeh A, Wei M, Golub SB, Yamashiro DJ, Murty VV, Tycko B (2002) Chromosome arm 16q in Wilms’ tumors: unbalanced chromosomal translocations, loss of heterozygosity, and assessment of the CTCF gene. Genes Chromosomes Cancer 35:156–163 doi:10.1002/gcc.10110

    Article  PubMed  CAS  Google Scholar 

  48. Spaventi R, Pecur L, Pavelic K, Pavelic ZP, Spaventi S, Stambrook PJ (1994) Human tumour bank in Croatia: a possible model for a small bank as part of the future European tumour bank network. Eur J Cancer 30:419 doi:10.1016/0959-8049(94)90277-1

    Article  Google Scholar 

  49. Miyazaki T, Murayama Y, Shinomura Y, Yamamoto T, Watabe K, Tsutsui S, Kiyohara T, Tamura S, Hayashi N (2007) E-cadherin gene promoter hypermethylation in H. pylori-induced enlarged fold gastritis. Helicobacter 12:523–533 doi:10.1111/j.1523-5378.2007.00519.x

    Article  PubMed  CAS  Google Scholar 

  50. Nakajima T, Maekita T, Oda I, Gotoda T, Yamamoto S, Umemura S, Ichinose M, Sugimura T, Ushijima T, Saito D (2006) Higher methylation levels in gastric mucosae significantly correlate with higher risk of gastric cancers. Cancer Epidemiol Biomarkers Prev 15:2317–2322

    Article  PubMed  CAS  Google Scholar 

  51. Kang GH, Lee S, Cho NY, Gandamihardja T, Long TI, Weisenberger DJ, Campan M, Laird PW (2008) DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis. Lab Invest 88:161–170 doi:10.1038/labinvest.3700707

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Ms. Iva Karlovic for technical assistance and Mr. Aaron Etra, J.D. and Prof. William Ragland, Ph.D., for carefully revising the manuscript. This work was supported by grant 098-0982464-2511, Ministry of Science, Education and Sport, Republic of Croatia.

Author information

Authors and Affiliations

  1. Laboratory of Molecular Pathology, Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia

    Ivana Grbesa, Marino Marinkovic, Renata Novak-Kujundzic, Ozren Bogdanovic & Koraljka Gall-Troselj

  2. Department of Otorhinolaryngology and Head and Neck Surgery, Sestre milosrdnice University Hospital, Zagreb, Croatia

    Mirko Ivkic, Boris Pegan & Vladimir Bedekovic

  3. Ljudevit Jurak Department of Pathology, Sestre milosrdnice University Hospital, Zagreb, Croatia

    Bozo Kruslin

Authors
  1. Ivana Grbesa
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Marino Marinkovic
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Mirko Ivkic
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Bozo Kruslin
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Renata Novak-Kujundzic
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Boris Pegan
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Ozren Bogdanovic
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Vladimir Bedekovic
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Koraljka Gall-Troselj
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Ivana Grbesa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grbesa, I., Marinkovic, M., Ivkic, M. et al. Loss of imprinting of IGF2 and H19, loss of heterozygosity of IGF2R and CTCF, and Helicobacter pylori infection in laryngeal squamous cell carcinoma. J Mol Med 86, 1057–1066 (2008). https://doi.org/10.1007/s00109-008-0369-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-008-0369-4

Keywords