2006 Fiscal Year Final Research Report Summary
Functional Analysis of Tumor Suppressor ING Family in Oral Cancer
| Project/Area Number |
17591911
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Morphological basic dentistry
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| Research Institution | Okayama University |
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Principal Investigator |
MEHMET Gunduz Okayama University, Oral Pathology and Medicine, Assistant Professor, 大学院医歯薬学総合研究科, 助手 (70333507)
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| Co-Investigator(Kenkyū-buntansha) |
NAGAI Noriyuki Okayama University, Oral Pathology and Medicine, Professor, 大学院医歯薬学総合研究科, 教授 (90085770)
NAGATSUKA Hitoshi Okayama University, Oral Pathology and Medicine, Associate Professor, 大学院医歯薬学総合研究科, 助教授 (70237535)
TAMAMURA Ryo Okayama University, Oral Pathology and Medicine, Assistant Professor, 大学院医歯薬学総合研究科, 助手 (00403494)
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| Project Period (FY) |
2005 – 2006
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| Keywords | Oral cancer / ING family / Splicing variant / p53 / Apoptosis / Tumor suppressor / Methylation |
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| Research Abstract |
1. Oral cancer occurs through inactivation of multiple tumor suppressor genes and activation of oncogenes. In this research, we examined the functions of the ING family members genes ING1b, ING1c and ING3, which we previously identified. mRNA expression analysis of splicing variants ING1b and ING1c showed 30% and 58% decrease in tumor samples as compared with the matched normal counterparts. On the other hand, ING3 mRNA was down-regulated in 50% of cancer samples. Restriction endonuclease-based methylation analysis demonstrated 51% methylation of ING1b variant, while it was not detected in ING1c. These results suggested that different splicing variants and members have various role and mechanisms in oral cancer.
2. Flag-tagged expression vectors of ING1b, ING1c and ING3 were constructed for in vitro functional analysis. Each of these vectors alone and combination with p53 expression vectors were transfected into the cell lines of HEK293, SCCKN, HSC3, HSC3 and cell proliferation and apop
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tosis assay were performed. These assays showed that INGlc-p53 combination gave a better cell inhibitory effect. Each gene and combination with p53 also resulted in apoptotic changes.
3. To examine the response of the ING family and proapoptotic as well as antiapoptotic genes to the cytotoxic drugs, we treated the cells with 5-FU, Cisplatin and Etoposide and mRNA expressions of ING1lb, ING1c, ING3, Bax and Bc1-2 were checked by quantitative RT-PCR. These experiments showed different reactions with various drugs in each cell line, suggesting that signaling of each variant and member has different mechanism.
4. We also examined ING3 mRNA expression in over 70 cancer samples and compared with clinicopathological variables. This study demonstrated ING3 mRNA value as a possible prognostic marker. The samples with ING3 down-regulation had bad prognosis with a 40% survival rate as compared to 60% survival in normal ING3 mRNA expression. Future studies will include suppression work of each ING family member by siRNA and examination of the results in animal experiments. Identification of all networks of ING family will lead to development of novel molecular therapies In various cancer types including oral cancer. Less
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[Journal Article] Heparanase Promotes Angiogenesis through Cox-2 and HIF1α.2007
Author(s)
Naomoto Y, Gunduz M, Takaoka M, Okawa T, Gunduz E, Nobuhisa T, Kobayashi M, Shirakawa Y, Yamatsuji T, Sonoda R, Matsuoka J, Tanaka N.
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Journal Title
Med Hypotheses 68(1)
Pages: 162-5
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Fine deletion mapping of chromosome 2q21-37 shows three preferentially deleted regions in oral cancer.2007
Author(s)
Cengiz B, Gunduz M, Nagatsuka H, Beder L, Gunduz E, Tamamura R, Mahmut N, Fukushima K, Mahmoud ASA, Naomoto Y, Shimizu K, Nagai N.
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Journal Title
Oral Oncol 43(3)
Pages: 241-7
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The close relationship between heparanase and COX-2 expressions in signet ring cell carcinoma of the stomach.2006
Author(s)
Ohtawa Y, Naomoto Y, Shirakawa Y, Takaoka M, Murata T, Sonoda R, Sakurama K, Yamatsuji T, Gunduz M, Tsujigiwa H, Nagatsuka H, Terada N, Itano S, Horiki S, Yanagihara K, Nakajima M, Tanaka N.
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Journal Title
Hum Pathol 37(9)
Pages: 1145-52
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Frequent Deletion of BRG1 Locus at 19p13 Predicts Previous Cancer History in Oral Squamous Cell Carcinomas.2006
Author(s)
Gunduz E, Gunduz M, Nagatsuka H, Beder L, Tamamura R, Katase N, Mahmut N, Cengiz B, Fukushima K, Nishizaki K, Shimizu K, Nagai N.
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Journal Title
J Hard Tissue Biol 15(1)
Pages: 20-26
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] COX-2 induction by heparanase in the progression of breast cancer.2006
Author(s)
Imada T, Matsuoka J, Nobuhisa T, Okawa T, Murata T, Tabuchi Y, Shirakawa Y, Ohara N, Gunduz M, Nagatsuka H, Umeoka T, Yamamoto Y, Nakajima M, Tanaka N, Naomoto Y.
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Journal Title
Int J Mol Med 17(2)
Pages: 221-228
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Identification of a novel hotspot and a candidate tumor suppressor gene at 10q21, RHOBTBI, in head and neck cancer.2006
Author(s)
Beder LB, Gunduz M, Ouchida M, Gunduz E, Sakai A, Fukushima K, Nagatsuka H, Ito S, Honjo N, Nishizaki K, Shimizu K.
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Journal Title
J Can Res Clin Oncol 132(1)
Pages: 19-27
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Three Cases of Adenocarcinoma Arising in the Extremely Long-segment Barrett's Esophagus.2006
Author(s)
Fujiwara T, Naomoto Y, Yamatsuji T, Shirakawa Y, Noguchi H, Fujiwara Y, Oohara N, Gunduz M, Nagatsuka H, Nishie M, Uetsuka H, Tanaka N.
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Journal Title
Dig Dis Sci 51(3)
Pages: 533-8
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Lymphoepithelial cyst of the cervical esophagus.2006
Author(s)
Asami S, Naomoto Y, Yamatsuji T, Shirakawa Y, Murata T, Kobayashi M, Sakurama K, Ohara N, Gunduz M, Nakatani S, Takubo K, Tanaka N.
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Journal Title
J Gastroenterol 41(1)
Pages: 88-9
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Epigenetic Alterations of BRG1 Leads to Cancer Development through its Nuclear-cytoplasmic Shuttling Abnormalities.2006
Author(s)
Gunduz E, Gunduz M, Nagatsuka H, Beder L, Demircan K, Tamamura R, Hatipoglu OM, Mahmut N, Katase N, Naomoto Y, Nagai N.
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Journal Title
Med Hypotheses 67(6)
Pages: 1313-6
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Heparanase is involved in angiogenesis in esophageal cancer through induction of cyclooxygenase-2.2005
Author(s)
Okawa T, Naomoto Y, Nobuhisa T, Takaoka M, Motoki T, Shirakawa Y, Yamatsuji T, Inoue H, Ouchida M, Gunduz M, Nakajima M, Tanaka N.
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Journal Title
Clin Cancer Res 11(22)
Pages: 7995-8005
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Effects of imatinib vary with the types of KIT-mutation in gastrointestinal stromal tumor (GIST) cell lines.2005
Author(s)
Noma K, Naomoto Y, Gunduz M, Matsuoka J, Yamatsuji T, Shirakawa Y, Nobuhisa T, Okawa T, Takaoka M, Tomono Y, Hiroyuki O, Gunduz E, Tanaka N.
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Journal Title
Oncol Rep 14(3)
Pages: 645-50
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Fine deletional mapping of chromosome 4q22-35 region in oral cancer.2005
Author(s)
Shinno Y, Gunduz E, Gunduz M, Nagatsuka H, Tsujigiwa H, Cengiz B, Lee YJ, Tamamura R, Ouchida M, Fukushima K, Shimizu, Nagai N.
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Journal Title
Int J Mol Med 16(1)
Pages: 93-98
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Frequent deletion and down-regulation of ING4, a candidate tumor suppressor gene at 12p13, in head and neck squamous cell carcinomas.2005
Author(s)
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.
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Emergence of nuclear heparanase induces differentiation of human mammary cancer cells.2005
Author(s)
Nobuhisa T, Takaoka M, Tabuchi Y, Ookawa K, Kitamoto D, Gunduz E, Gunduz M, Nagatsuka H, Haisa M, Matsuoka J, Nakajima M, Tanaka N.
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Journal Title
Biochem Biophys Res Commun 331
Pages: 175-180
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Heparanase expression correlates with malignant potential in human colon cancer.2005
Author(s)
Nobuhisa T, Naomoto Y, Ohkawa T, Takaoka M, Ono R, Murata T, Gunduz M, Shirakawa Y, Yamatsuji T, Haisa M, Matsuoka J, Tsujigiwa H, Nagatsuka H, Nakajima M, Tanaka N.
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Journal Title
J Cancer Res Clin Oncol 131(4)
Pages: 229-237
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Translocation of heparanase into nucleus results in cell differentiation.
Author(s)
Nobuhisa T, Naomoto Y, Okawa T, Takaoka M, Gunduz M, Nagatsuka H, Tsujigiwa H, Shirakawa Y, Yamatsuji T, Haisa M, Matsuoka J, Nakajima M, Taniguchi S, Sagara J, Dong J, Tanaka N.
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Journal Title
Cancer Sci 2007 Jan 31 [Epub ahead of print]
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Palatinose Based Enteral Formula (MHN-01) Carbohydrate-adjusted Fluid Diet in Improving the Metabolism of Carbohydrates and Lipids in Patients with Esophageal Cancer Complicated by Diabetes Mellitus.
Author(s)
Fujiwara T, Naomoto Y, Motoki T, Shigemitsu K, Shirakawa Y, Yamatsuji T, Kataoka M, Haisa M, Fujiwara T, Egi M, Morimatsu H, Hanazaki M, Katayama H, Morita K, Mizumoto K, Asou T, Arima H, Sasaki H, Matsuura M, Gunduz M, Tanaka N. Effects of a Novel
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Journal Title
J Surg Res 2007 Jan 23 [Epub ahead of print]
Description
「研究成果報告書概要(欧文)」より
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