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Journal of Cancer Research and Clinical Oncology

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01.05.2009 | Original Paper

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

verfasst von: Silvia S. Borkosky, Mehmet Gunduz, Hitoshi Nagatsuka, Levent Bekir Beder, Esra Gunduz, Mahmoud AL Sheikh Ali, Andrea P. Rodriguez, Mehmet Zeynel Cilek, Susumu Tominaga, Noboru Yamanaka, Kenji Shimizu, Noriyuki Nagai

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 5/2009

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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.

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 PubMedCrossRef

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 PubMedCrossRef

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):605–609PubMed

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):1465–1473PubMed

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 PubMedCrossRef

Cheung KJ Jr, Bush JA, Jia W, Li G (2000) Expression of the novel tumour suppressor p33^ING1 is independent of p53. Br J Cancer 83(11):1468–1472. doi:10.1054/bjoc.2000.1464 PubMedCrossRef

Coles AH, Liang H, Zhu Z, Marfella CG, Kang J, Imbalzano AN, Jones SN (2007) Deletion of p37^Ing1 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 PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

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):3143–3146PubMed

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 PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

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 p19^ARF (human p14 ^ARF) in activating p53. J Biol Chem 277(40):37765–37770. doi:10.1074/jbc.M204177200 PubMedCrossRef

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

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):3433–3438PubMed

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 PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

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

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

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 PubMedCrossRef

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;2-5PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

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):738–742PubMed

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):545–549PubMed

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 PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

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):1228–1231PubMed

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 PubMedCrossRef

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 PubMedCrossRef

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):93–98PubMed

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 PubMedCrossRef

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 PubMedCrossRef

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):1156–1158PubMed

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 PubMedCrossRef

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 PubMedCrossRef

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):1227–1232PubMed

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 PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

Titel: Frequent deletion of ING2 locus at 4q35.1 associates with advanced tumor stage in head and neck squamous cell carcinoma
verfasst von: Silvia S. Borkosky
Mehmet Gunduz
Hitoshi Nagatsuka
Levent Bekir Beder
Esra Gunduz
Mahmoud AL Sheikh Ali
Andrea P. Rodriguez
Mehmet Zeynel Cilek
Susumu Tominaga
Noboru Yamanaka
Kenji Shimizu
Noriyuki Nagai
Publikationsdatum: 01.05.2009
Verlag: Springer-Verlag
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 5/2009
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-008-0507-y

Springer Medizin

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