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Frequent deletion of ING2 locus at 4q35.1 associates with advanced tumor stage in head and neck squamous cell carcinoma

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Abstract

Background

Loss of heterozygosity (LOH) in the ING family members has been shown in head and neck squamous cell carcinoma (HNSCC) except for ING2. Like all the other members of ING family, ING2, which is located at chromosome 4q35.1, is a promising tumor suppressor gene (TSG). In this study, we performed LOH analysis of ING2 in HNSCC and compared it with clinicopathological variables.

Materials and methods

We performed LOH analysis in DNAs from 80 paired of normal and HNSCC tissues, using a specifically designed microsatellite marker on chromosome 4q35.1, which detects allelic loss of ING2. TP53 mutation analysis and its relationship with ING2 chromosomal deletion were also performed in available 68 of the samples. The correlation between LOH status and clinicopathological characteristics was evaluated by using statistical methods. The overall survival (OS) and disease free survival (DFS) were also determined.

Results

LOH was detected in 54.6% (30/55) of the informative samples. Statistical significance was obtained between LOH and tumor (T) stage (P = 0.02), application of radiotherapy and chemotherapy. Positive node status (N) appeared to be the only independent prognostic factor for both OS (P = 0.031) and DFS (P = 0.044).

Conclusions

Our study showed allelic loss of 4q35.1 in HNSCC. The high percentage of LOH suggests ING2 as a candidate TSG in HNSCC. High LOH frequency was statistically associated with advanced T stage, suggesting that ING2 LOH might occur in late stages during HNSCC progression.

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References

  • Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, van Tuinen P, Ledbetter DH, Barker DF, Nakamura Y, White R, Vogelstein B (1989) Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244(4901):217–221. doi:10.1126/science.2649981

    Article  PubMed  CAS  Google Scholar 

  • Beder LB, Gunduz M, Ouchida M, Gunduz E, Sakai A, Fukushima K, Nagatsuka H, Ito S, Honjo N, Nishizaki K, Shimizu K (2006) Identification of a candidate tumor suppressor gene RHOBTB1 located at a novel allelic loss region 10q21 in head and neck cancer. J Cancer Res Clin Oncol 132(1):19–27. doi:10.1007/s00432-005-0033-0

    Article  PubMed  CAS  Google Scholar 

  • Bradford CR, Zhu S, Poore J, Fisher SG, Beals TF, Thoraval D, Hanash SM, Carey TE, Wolf GT (1997) p53 mutation as a prognostic marker in advanced laryngeal carcinoma. Department of Veterans Affairs Laryngeal Cancer Cooperative Study Group. Arch Otolaryngol Head Neck Surg 123(6):605–609

    PubMed  CAS  Google Scholar 

  • Cabelguenne A, Blons H, de Waziers I, Carnot F, Houllier AM, Soussi T, Brasnu D, Beaune P, Laccourreye O, Laurent-Puig P (2000) p53 alterations predict tumor response to neoadjuvant chemotherapy in head and neck squamous cell carcinoma: a prospective series. J Clin Oncol 18(7):1465–1473

    PubMed  CAS  Google Scholar 

  • Cengiz B, Gunduz M, Nagatsuka H, Beder L, Gunduz E, Tamamura R, Mahmut N, Fukushima K, Ali MA, Naomoto Y, Shimizu K, Nagai N (2007) Fine deletion mapping of chromosome 2q21-37 shows three preferentially deleted regions in oral cancer. Oral Oncol 43(3):241–247. doi:10.1016/j.oraloncology.2006.03.004

    Article  PubMed  CAS  Google Scholar 

  • Cheung KJ Jr, Bush JA, Jia W, Li G (2000) Expression of the novel tumour suppressor p33ING1 is independent of p53. Br J Cancer 83(11):1468–1472. doi:10.1054/bjoc.2000.1464

    Article  PubMed  CAS  Google Scholar 

  • Coles AH, Liang H, Zhu Z, Marfella CG, Kang J, Imbalzano AN, Jones SN (2007) Deletion of p37Ing1 in mice reveals a p53-independent role for Ing1 in the suppression of cell proliferation, apoptosis, and tumorigenesis. Cancer Res 67(5):2054–2061. doi:10.1158/0008-5472.CAN-06-3558

    Article  PubMed  CAS  Google Scholar 

  • Devarajan E, Sahin AA, Chen JS, Krishnamurthy RR, Aggarwal N, Brun AM, Sapino A, Zhang F, Sharma D, Yang XH, Tora AD, Mehta K (2002) Down-regulation of caspase 3 in breast cancer: a possible mechanism for chemoresistance. Oncogene 21(57):8843–8851. doi:10.1038/sj.onc.1206044

    Article  PubMed  CAS  Google Scholar 

  • Erber R, Conradt C, Homann N, Enders C, Finckh M, Dietz A, Weidauer H, Bosch FX (1998) TP53 DNA contact mutations are selectively associated with allelic loss and have a strong clinical impact in head and neck cancer. Oncogene 16(13):1671–1679. doi:10.1038/sj.onc.1201690

    Article  PubMed  CAS  Google Scholar 

  • Garkavtsev I, Grigorian IA, Ossovskaya VS, Chernov MV, Chumakov PM, Gudkov AV (1998) The candidate tumour suppressor p33ING1 cooperates with p53 in cell growth control. Nature 391(6664):295–298. doi:10.1038/34675

    Article  PubMed  CAS  Google Scholar 

  • Gunduz M, Ouchida M, Fukushima K, Hanafusa H, Etani T, Nishioka S, Nishizaki K, Shimizu K (2000) Genomic structure of the human ING1 gene and tumor-specific mutations detected in head and neck squamous cell carcinomas. Cancer Res 60(12):3143–3146

    PubMed  CAS  Google Scholar 

  • Gunduz M, Ouchida M, Fukushima K, Ito S, Jitsumori Y, Nakashima T, Nagai N, Nishizaki K, Shimizu K (2002) Allelic loss and reduced expression of the ING3, a candidate tumor suppressor gene at 7q31, in human head and neck cancers. Oncogene 21(28):4462–4470. doi:10.1038/sj.onc.1205540

    Article  PubMed  CAS  Google Scholar 

  • Gunduz M, Nagatsuka H, Demircan K, Gunduz E, Cengiz B, Ouchida M, Tsujigiwa H, Yamachika E, Fukushima K, Beder L, Hirohata S, Ninomiya Y, Nishizaki K, Shimizu K, Nagai N (2005) Frequent deletion and down-regulation of ING4, a candidate tumor suppressor gene at 12p13, in head and neck squamous cell carcinomas. Gene 356:109–117. doi:10.1016/j.gene.2005.02.014

    Article  PubMed  CAS  Google Scholar 

  • Gunduz M, Gunduz E, Rivera RS, Nagatsuka H (2008a) The inhibitor of growth (ING) gene family: potential role in cancer therapy. Curr Cancer Drug Targets 8(4):275–284. doi:10.2174/156800908784533454

    Article  PubMed  CAS  Google Scholar 

  • Gunduz M, Beder LB, Gunduz E, Nagatsuka H, Fukushima K, Pehlivan D, Cetin E, Yamanaka N, Nishizaki K, Shimizu K, Nagai N (2008b) Downregulation of ING3 mRNA expression predicts poor prognosis in head and neck cancer. Cancer Sci 99(3):531–538. doi:10.1111/j.1349-7006.2007.00708.x

    Article  PubMed  CAS  Google Scholar 

  • Hasan MK, Yaguchi T, Sugihara T, Kumar PK, Taira K, Reddel RR, Kaul SC, Wadhwa R (2002) CARF is a novel protein that cooperates with mouse p19ARF (human p14 ARF) in activating p53. J Biol Chem 277(40):37765–37770. doi:10.1074/jbc.M204177200

    Article  PubMed  CAS  Google Scholar 

  • Hinds PW, Weinberg RA (1994) Tumor suppressor genes. Curr Opin Genet Dev 4(1):135–141. doi:10.1016/0959-437X(94)90102-3

    Article  PubMed  CAS  Google Scholar 

  • Högmo A, Börresen-Dale AL, Blegen H, Lindholm J, Kuylenstierna R, Auer G, Munck-Wikland E (1999) TP53 mutations do not correlate with locoregional recurrence in stage I tongue carcinomas. Anticancer Res 19(4C):3433–3438

    PubMed  Google Scholar 

  • Huang W, Horvath E, Eklund EA (2007) PU.1, interferon regulatory factor (IRF) 2, and the interferon consensus sequence-binding protein (ICSBP/IRF8) cooperate to activate NF1 transcription in differentiating myeloid cells. J Biol Chem 282(9):6629–6643. doi:10.1074/jbc.M607760200

    Article  PubMed  CAS  Google Scholar 

  • Iuchi T, Namba H, Iwadate Y, Shishikura T, Kageyama H, Nakamura Y, Ohira M, Yamaura A, Osato K, Sakiyama S, Nakagawara A (2002) Identification of the small interstitial deletion at chromosome band 1p34-p35 and its association with poor outcome in oligodendroglial tumors. Genes Chromosomes Cancer 35(2):170–175. doi:10.1002/gcc.10080

    Article  PubMed  CAS  Google Scholar 

  • 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 3:4–12. doi:10.1186/1471-2407-3-4

    Article  PubMed  Google Scholar 

  • Jin CY, Park C, Cheong J, Choi BT, Lee TH, Lee JD, Lee WH, Kim GY, Ryu CH, Choi YH (2007) Genistein sensitizes TRAIL-resistant human gastric adenocarcinoma AGS cells through activation of caspase-3. Cancer Lett 257(1):56–64. doi:10.1016/j.canlet.2007.06.019

    Article  PubMed  CAS  Google Scholar 

  • Lane DP (1992) Cancer. p53, guardian of the genome. Nature 358(6381):15–16. doi:10.1038/358015a0

    Article  PubMed  CAS  Google Scholar 

  • Le QT, Giaccia AJ (2003) Therapeutic exploitation of the physiological and molecular genetic alterations in head and neck cancer. Clin Cancer Res 9(12):4287–4295

    PubMed  CAS  Google Scholar 

  • Lee WH, Bookstein R, Hong F, Young LJ, Shew JY, Lee EY (1987) Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science 235(4794):1394–1399. doi:10.1126/science.3823889

    Article  PubMed  CAS  Google Scholar 

  • Lydiatt WM, Davidson BJ, Schantz SP, Caruana S, Chaganti RS (1998) 9p21 deletion correlates with recurrence in head and neck cancer. Head Neck 20(2):113–118. doi:10.1002/(SICI)1097-0347(199803)20:2<113::AID-HED3>3.0.CO;2-5

    Article  PubMed  CAS  Google Scholar 

  • Mao L, Lee JS, Fan YH, Ro JY, Batsakis JG, Lippman S, Hittelman W, Hong WK (1996) Frequent microsatellite alterations at chromosomes 9p21 and 3p14 in oral premalignant lesions and their value in cancer risk assessment. Nat Med 2(6):682–685. doi:10.1038/nm0696-682

    Article  PubMed  CAS  Google Scholar 

  • Morin PJ (2005) Claudin proteins in human cancer: promising new targets for diagnosis and therapy. Cancer Res 65(21):9603–9606. doi:10.1158/0008-5472.CAN-05-2782

    Article  PubMed  CAS  Google Scholar 

  • Nagashima M, Shiseki M, Miura K, Hagiwara K, Linke SP, Pedeux R, Wang XW, Yokota J, Riabowol K, Harris CC (2001) DNA damage-inducible gene p33ING2 negatively regulates cell proliferation through acetylation of p53. Proc Natl Acad Sci USA 98(17):9671–9676. doi:10.1073/pnas.161151798

    Article  PubMed  CAS  Google Scholar 

  • Nakamura E, Kozaki KI, Tsuda H, Suzuki E, Pimkhaokham A, Yamamoto G, Irie T, Tachikawa T, Amagasa T, Inazawa J, Imoto I (2008) Frequent silencing of a putative tumor suppressor gene melatonin receptor 1 A (MTNR1A) in oral squamous-cell carcinoma. Cancer Sci 99(7):1390–1400. doi:10.1111/j.1349-7006.2008.00838.x

    Article  PubMed  CAS  Google Scholar 

  • Nakaya K, Yamagata HD, Arita N, Nakashiro KI, Nose M, Miki T, Hamakawa H (2007) Identification of homozygous deletions of tumor suppressor gene FAT in oral cancer using CGH-array. Oncogene 26(36):5300–5308. doi:10.1038/sj.onc.1210330

    Article  PubMed  CAS  Google Scholar 

  • O’Donovan N, Crown J, Stunell H, Hill AD, McDermott E, O’Higgins N, Duffy MJ (2003) Caspase 3 in breast cancer. Clin Cancer Res 9(2):738–742

    PubMed  CAS  Google Scholar 

  • Okano T, Gemma A, Hosoya Y, Hosomi Y, Nara M, Kokubo Y, Yoshimura A, Shibuya M, Nagashima M, Harris CC, Kudoh S (2006) Alterations in novel candidate tumor suppressor genes, ING1 and ING2 in human lung cancer. Oncol Rep 15(3):545–549

    PubMed  CAS  Google Scholar 

  • Oliveira SS, Morgado-Díaz JA (2007) Claudins: multifunctional players in epithelial tight junctions and their role in cancer. Cell Mol Life Sci 64(1):17–28. doi:10.1007/s00018-006-6314-1

    Article  PubMed  CAS  Google Scholar 

  • Pedeux R, Sengupta S, Shen JC, Demidov ON, Saito S, Onogi H, Kumamoto K, Wincovitch S, Garfield SH, McMenamin M, Nagashima M, Grossman SR, Appella E, Harris CC (2005) ING2 regulates the onset of replicative senescence by induction of p300-dependent p53 acetylation. Mol Cell Biol 25(15):6639–6648. doi:10.1128/MCB.25.15.6639-6648.2005

    Article  PubMed  CAS  Google Scholar 

  • Perez-Ordoñez B, Beauchemin M, Jordan RC (2006) Molecular biology of squamous cell carcinoma of the head and neck. J Clin Pathol 59(5):445–453. doi:10.1136/jcp.2003.007641

    Article  PubMed  Google Scholar 

  • Roz L, Wu CL, Porter S, Scully C, Speight P, Read A, Sloan P, Thakker N (1996) Allelic imbalance on chromosome 3p in oral dysplastic lesions: an early event in oral carcinogenesis. Cancer Res 56(6):1228–1231

    PubMed  CAS  Google Scholar 

  • Sarker KP, Kataoka H, Chan A, Netherton SJ, Pot I, Huynh MA, Feng X, Bonni A, Riabowol K, Bonni S (2008) ING2 as a novel mediator of Transforming Growth Factor-β-dependent responses in epithelial cells. J Biol Chem 283(19):13269–13279. doi:10.1074/jbc.M708834200

    Article  PubMed  CAS  Google Scholar 

  • Shimada Y, Saito A, Suzuki M, Takahashi E, Horie M (1998) Cloning of a novel gene (ING1L) homologous to ING1, a candidate tumor suppressor. Cytogenet Cell Genet 83(3–4):232–235. doi:10.1159/000015188

    Article  PubMed  CAS  Google Scholar 

  • Shinno Y, Gunduz E, Gunduz M, Nagatsuka H, Tsujigiwa H, Cengiz B, Lee YJ, Tamamura R, Ouchida M, Fukushima K, Shimizu K, Nagai N (2005) Fine deletional mapping of chromosome 4q22-35 region in oral cancer. Int J Mol Med 16(1):93–98

    PubMed  CAS  Google Scholar 

  • Sironi E, Cerri A, Tomasini D, Sirchia SM, Porta G, Rossella F, Grati FR, Simoni G (2004) Loss of heterozygosity on chromosome 4q32-35 in sporadic basal cell carcinomas: evidence for the involvement of p33ING2/ING1L and SAP30 genes. J Cutan Pathol 31(4):318–322. doi:10.1111/j.0303-6987.2004.0187.x

    Article  PubMed  Google Scholar 

  • Tannapfel A, Weber A (2001) Tumor markers in squamous cell carcinoma of the head and neck: clinical effectiveness and prognostic value. Eur Arch Otorhinolaryngol 258(2):83–88. doi:10.1007/s004050000303

    Article  PubMed  CAS  Google Scholar 

  • van der Riet P, Nawroz H, Hruban RH, Corio R, Tokino K, Koch W, Sidransky D (1994) Frequent loss of chromosome 9p21-22 early in head and neck cancer progression. Cancer Res 54(5):1156–1158

    PubMed  Google Scholar 

  • Wang Y, Li G (2006) ING3 promotes UV-induced apoptosis via Fas/Caspase-8 pathway in melanoma cells. J Biol Chem 281(17):11887–11893. doi:10.1074/jbc.M511309200

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Wang J, Li G (2006) Leucine zipper-like domain is required for tumor suppressor ING2-mediated nucleotide excision repair and apoptosis. FEBS Lett 580(16):3787–3793. doi:10.1016/j.febslet.2006.05.065

    Article  PubMed  CAS  Google Scholar 

  • Winter RN, Kramer A, Borkowski A, Kyprianou N (2001) Loss of caspase-1 and caspase-3 protein expression in human prostate cancer. Cancer Res 61(3):1227–1232

    PubMed  CAS  Google Scholar 

  • Zamora M, Meroño C, Viñas O, Mampel T (2004) Recruitment of NF-kappaB into mitochondria is involved in adenine nucleotide translocase 1 (ANT1)-induced apoptosis. J Biol Chem 279(37):38415–38423. doi:10.1074/jbc.M404928200

    Article  PubMed  CAS  Google Scholar 

  • Zamora M, Ortega JA, Alaña L, Viñas O, Mampel T (2006) Apoptotic and anti-proliferative effects of all-trans retinoic acid. Adenine nucleotide translocase sensitizes HeLa cells to all-trans retinoic acid. Exp Cell Res 312(10):1813–1819. doi:10.1016/j.yexcr.2006.02.014

    Article  PubMed  CAS  Google Scholar 

  • Zhang HK, Pan K, Wang H, Weng DS, Song HF, Zhou J, Huang W, Li JJ, Chen MS, Xia JC (2008) Decreased expression of ING2 gene and its clinicopathological significance in hepatocellular carcinoma. Cancer Lett 261(2):183–192. doi:10.1016/j.canlet.2007.11.019

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was partially supported by grants-in-aid for scientific researches from the Ministry of Education, Culture, Sports, Science and Technology [19592109 (to HN), 18-06262 (to EG), 17406027 (to NN)], Seed Innovation Research from Japan Science and Technology Agency (to MG), from Sumitomo Trust Haraguchi Memorial Cancer Research Promotion (to MG) and Astrazeneca Research Grant (to MG).

Conflict of interest statement

None of the authors has any potential conflict of interest.

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Authors and Affiliations

  1. Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1, Shikatacho, Okayama, 700-8525, Japan

    Silvia S. Borkosky, Mehmet Gunduz, Hitoshi Nagatsuka, Mahmoud AL Sheikh Ali, Andrea P. Rodriguez & Noriyuki Nagai

  2. Department of Otolaryngology Head and Neck Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Shikatacho 2-5-1, Okayama, Japan

    Susumu Tominaga

  3. Department of Molecular Genetics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Shikatacho 2-5-1, Okayama, Japan

    Esra Gunduz & Kenji Shimizu

  4. Department of Otolaryngology Head and Neck Surgery, Wakayama Medical University, 811-1, Kimiidera, Wakayama, 641-8509, Japan

    Mehmet Gunduz, Levent Bekir Beder & Noboru Yamanaka

  5. Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1, Shikatacho, Okayama, 700-8525, Japan

    Mehmet Zeynel Cilek

  6. Cátedra de Anatomía y Fisiología Patológicas, Facultad de Odontología, Universidad Nacional de Tucumán, Av. Benjamin Araóz 800, 4000, San Miguel de Tucumán, Argentina

    Silvia S. Borkosky

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  1. Silvia S. Borkosky
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  2. Mehmet Gunduz
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  3. Hitoshi Nagatsuka
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  4. Levent Bekir Beder
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  5. Esra Gunduz
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  6. Mahmoud AL Sheikh Ali
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  7. Andrea P. Rodriguez
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  8. Mehmet Zeynel Cilek
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  9. Susumu Tominaga
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  10. Noboru Yamanaka
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  11. Kenji Shimizu
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  12. Noriyuki Nagai
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Correspondence to Mehmet Gunduz.

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Borkosky, S.S., Gunduz, M., Nagatsuka, H. et al. Frequent deletion of ING2 locus at 4q35.1 associates with advanced tumor stage in head and neck squamous cell carcinoma. J Cancer Res Clin Oncol 135, 703–713 (2009). https://doi.org/10.1007/s00432-008-0507-y

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