A Comprehensive Study of Pathological Significance of Atypical Cytosine Methylation during Tumorigenesis and Progression

• Project/Area Number: 18390114
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human pathology
• Research Institution: Kobe University
• Principal Investigator: MAEDA Sakan Kobe University, 大学院・医学研究科, 戦略的客員教授 (50030911)
• Co-Investigator(Kenkyū-buntansha): KITAZAWA Sohei 神戸大学, 大学院・医学研究科, 特命教授 (90186239) ; KITAZAWA Riko 神戸大学, 大学院・医学研究科, 特命講師 (00273780) ; KONDO Takeshi 神戸大学, 大学院・医学研究科, 特命講師 (20335441)
• Project Period (FY): 2006 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥15,580,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥1,680,000); Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2008: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2007: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2006: ¥8,300,000 (Direct Cost: ¥8,300,000)
• Keywords: エピジェネティクス / in situ hybridization / 非CpGアイランド / メチル化シトシン / 遺伝子プロモータ / 膀胱癌 / BANBI / 転写制御 / BAMBI / 非CpG-island / 膵癌 / TrkA

Research Abstract

While cytosine methylation in CpG-island, located usually regulatory region of many genes, is well recognized as an inhibitory epigenetic regulator, biological significance of the cytosine methylation other than CpG-island is unclear. By focusing morphology-oriented microscopic dissection methods, we investigated cytosine methylation status in the gene promoter, and found that some of the cytosine methylation outside of the CpG-island have major contributions during cancer progression.

Research Products

• [Journal Article] BAMBI gene is epigenetically silenced in a subset of high-grade bladder cancer (2009)
  • Author(s): Sann Sanda Khin, Kitazawa R, Win N, Than TA, Mori K, Kondo T, Kitazawa S
  • Journal Title: Int J Cancer 125 Pages: 328-338
  • Peer Reviewed
• [Journal Article] BAMBI gene is epigenetically silenced in a subset of high-grade bladder cancer. (2009)
  • Author(s): Sann Sanda Khin, et al.
  • Journal Title: Int J Cancer 125 Pages: 328-338
  • Peer Reviewed
• [Journal Article] Ce promotes intestinal tumorigenesis of ApcMin/+ mice through augmentation of inflammation and angiogenesis. (2009)
  • Author(s): Li M., et al.
  • Journal Title: Carcinogenesis 30 Pages: 1424-1432
  • Peer Reviewed
• [Journal Article] Thioredoxin-1 overexpression in transgenic mice attenuates streptozotocin-induced diabetic osteopenia. (2009)
  • Author(s): Hamada Y., et al.
  • Journal Title: Bone 44 Pages: 936-941
  • Peer Reviewed
• [Journal Article] Dexamethasone Promotes Osteoclastogenesis by Inhibiting Osteoprotegerin through Multiple Levels (2008)
  • Author(s): Kondo T, Kitazawa R, Yamaguchi A, Kitazawa S
  • Journal Title: J Cell Biochem 103 Pages: 335-345
  • Peer Reviewed
• [Journal Article] Hypermethylation of Epithelial-cadherin Gene Promoter is Associated with Epstein-Barr Virus in Nasopharyngeal (2008)
  • Author(s): Niemhom S, Kitazawa S, Kitazawa R, Maeda S, Leopairat J
  • Journal Title: Carcinoma, Cancer Detect Prev 32 Pages: 127-134
  • Peer Reviewed
• [Journal Article] FSP27 Contributes to Efficient Energy Storage in Murine White Adipocytes by Promoting the Formation of Unilocular Lipid Droplets (2008)
  • Author(s): Nishino N, Tamori Y, Tateya S, Kawaguchi T, Shibakusa T, Mizunoya W, Inoue K, Kitazawa R, Kitazawa S, Matsuki Y, Hiramatsu R, Masubuchi S, Omachi A, Kimura K, Saito M, Amo T, Ohta S, Yamaguchi T, Osumi T, Cheng J, Fujimoto T, Nakao H, Nakao K, Aiba A, OkaNishino N, Tamori Y, Tateya
  • Journal Title: J Clin Invest 118 Pages: 2808-2821
  • Peer Reviewed
• [Journal Article] Lipopolysaccharide Suppresses RANK Gene Expression in Macrophages by Down-Regulating PU. 1 and MITF (2008)
  • Author(s): shii J, Kitazawa R, Mori K, McHugh K.P., Morii E, Kondo T, Kitazawa S
  • Journal Title: J Cellular Biochem 105 Pages: 896-904
  • Peer Reviewed
• [Journal Article] MeCP2 Expression and Promoter Methylation of Cyclin D1 Gene Are Associated with Cyclin D1 (2008)
  • Author(s): Darwanto A, Kitazawa R, Kondo T, Kitazawa S
  • Journal Title: Expression in Developing Rat Epididymal Duct Acta Histochem Cytochem 41 Pages: 135-142
  • Peer Reviewed
• [Journal Article] Modulation of Mouse RANKL Gene Expression by Runx2 and Vitamin D3 (2008)
  • Author(s): Kitazawa R, Mori K, Yamaguchi A, Kondo T, Kitazawa S
  • Journal Title: J Cellular Biochem 105 Pages: 289-1297
  • Peer Reviewed
• [Journal Article] Hepatic failure and enhanced oxidative stress in mitochondrial diabetes (2008)
  • Author(s): Takahashi Y, Iida K, Takeno R, Kitazawa R, Kitazawa S, Kitamura H, Fujioka Y, Yamada H, Kanda F, Ohta S, Nishimaki K, Fujimoto M, Kondo T, Iguchi G, Takahashi K, Kaji H, Okimura Y, Chihara K
  • Journal Title: Endocr J 55 Pages: 509-14
  • NAID: 10021266426
  • Peer Reviewed
• [Journal Article] Modulation of Mouse RANKL Gene Expression by Runx2 and Vitamin D3 (2008)
  • Author(s): Kitazawa R, Mori K, Yamaguchi AKondo T, Kitazawa S
  • Journal Title: J CellularBiochem 105 Pages: 1289-1297
  • Peer Reviewed
• [Journal Article] MeCP2 Expression and Promoter Methylation of Cyclin D1 Gene are Associated with Cyclin D1 Expression in Developing Rat Epididymal Duct (2008)
  • Author(s): Darwanto A, Kitazawa R, Kondo T, Kitazawa S
  • Journal Title: Acta Histochem Cytochem 41 Pages: 135-142
  • NAID: 130000070760
  • Peer Reviewed
• [Journal Article] Lipopolysaccharide Suppresses RANK Gene Expression in Macrophages by Down-Regulating PU.1 and MITF (2008)
  • Author(s): Ishii J, Kitazawa R, Mori K, McHugh K.P., Morii E, Kondo T, Kitazawa S
  • Journal Title: J Cellular Biochem 105 Pages: 896-904
  • Peer Reviewed
• [Journal Article] FSP27 Contributes to Efficient Energy Storage in Murine White Adipocytes by Promoting the Formation of Unilocular Lipid Droplets (2008)
  • Author(s): Nishino N, Tamori Y, Tateya S, Kawaguchi T, Shibakusa T, Mizunoya W,Inoue K, Kitazawa R, Kitazawa S,Matsuki Y, Hiramatsu R, Masubuchi S, Omachi A, Kimura K, Saito M, Amo T, Ohta S, Yamaguchi T, Osumi T, Cheng J, Fujimoto T, Nakao H, Nakao K, Aiba A, Okamura H, Fushiki T, Kasuga M
  • Journal Title: J Clin Invest 118 Pages: 2808-2821
  • Peer Reviewed
• [Journal Article] Leopairat J, Hypermethylation of Epithelial-cadherin Gene Promoter is Associated with Epstein-Barr Virus in Nasopharyngeal Carcinoma (2008)
  • Author(s): Niemhom S, Kitazawa S, Kitazawa R, Maeda S
  • Journal Title: Cancer Detect Prev 32 Pages: 127-134
  • Peer Reviewed
• [Journal Article] Lipopolysaccharide suppresses RANK gene expression by macrophage through the down-regulation of PU. 1 and MITF. (2008)
  • Author(s): Ishii J., et al.
  • Journal Title: J Cell Biochem 105 Pages: 896-904
  • Peer Reviewed
• [Journal Article] Modulation of mouse RANKL gene expression by Runx2 and vitamin D3 pathway. (2008)
  • Author(s): Kitazawa R., et al.
  • Journal Title: J Cell Biochem 105 Pages: 1289-1297
  • Peer Reviewed
• [Journal Article] MeCP2 expression and promoter methylation of cyclin D1 gene are associated with cyclin D1 expression in developing rat epididymalduct. (2008)
  • Author(s): Darwanto A., et al.
  • Journal Title: Acta Histochem Cytochem 41 Pages: 135-142
  • Peer Reviewed
• [Journal Article] Methylation Status of a Single CpG Locus 3 Bases Upstream of TATA-box of RANKL Gene Promoter Modulates Cell-and Tissue-specific RANKL Expression and Osteoclastogenesis (2007)
  • Author(s): Kitazawa R, Kitazawa S
  • Journal Title: Mol Endocrinology 21 Pages: 148-158
  • Peer Reviewed
• [Journal Article] Methylation Status of a Single CpG Locus 3 Bases Upstream of TATA-box of RANKL Gene Promoter Modulates Cell- and Tissue-specific RANKL Expression and Osteoclastogenesis (2007)
  • Author(s): Kitazawa R, Kitazawa S,
  • Journal Title: Mol Endocrinology 21 Pages: 148-158
  • Peer Reviewed
• [Journal Article] Dexamethasone Promotes Osteoclastogenesis by Inhibiting Osteoprotegerin through Multiple Levels. (2007)
  • Author(s): Kondo T., et. al.
  • Journal Title: J Cell Biochem 103 Pages: 335-345
  • Peer Reviewed
• [Journal Article] Histomorphometric Analysis of Diabetic Osteopenia in Streptozotocin-induced Diabetic Mice: a Possible Role of Oxidative Stress. (2007)
  • Author(s): Hamada Y., et. al.
  • Journal Title: Bone 40 Pages: 938-943
  • Peer Reviewed
• [Journal Article] Unsuspected Uterine Leiomyosarcoma: MR Imaging Findings before and after Focused Ultrasound Surgery(FUS) (2007)
  • Author(s): Fukunishi H., et. al.
  • Journal Title: Int J Gynecolog Cancer 17 Pages: 724-728
  • Peer Reviewed
• [Journal Article] Methylation status of a single CpG locus 3 bases upstream of TATA-box of RANKL gene promoter modulates cell- and tissue-specific RANKL expression and osteoclastogenesis (2007)
  • Author(s): Kitazawa R, et al.
  • Journal Title: Mol Endocrnol 21・1 Pages: 148-158
• [Journal Article] Growth hormone reverses nonalcoholic steatohepatitis in a patient with adult growth hormone deficiency. (2007)
  • Author(s): Takahashi Y, et al.
  • Journal Title: Gastroenterology (in press)
• [Journal Article] In situ Detection of Specific Gene Expression During and Immediately After Transcription at Electron (2006)
  • Author(s): Kitazawa S, Kitazawa R
  • Journal Title: Microscopic Level J Struct Biol 153 Pages: 64-72
  • Peer Reviewed
• [Journal Article] Expression Profiles of Genes Related to Osteoclastogenesis in Mouse Growth Plate and Articular Cartilage (2006)
  • Author(s): Kishimoto K, Kitazawa R, Kurosaka M, Maeda S, Kitazawa S
  • Journal Title: Histochem Cell Biol 125 Pages: 592-602
  • Peer Reviewed
• [Journal Article] DNA Methylation of Multiple Tumor-related Genes in Association with Overexpression of DNA Methyltransferase 1 (DNMT1) during Multistage Carcinogenesis of the Pancreas (2006)
  • Author(s): Peng DF, Kanai Y, Sawada M, Ushijima S, Hiraoka N, Kitazawa S, Hirohashi S
  • Journal Title: Carcinogenesis 27 Pages: 1160-1168
  • Peer Reviewed
• [Journal Article] Modulation of Mouse RANKL Gene Expression by Runx2 and PKA Pathway (2006)
  • Author(s): Mori K, Kitazawa R, Kondo T, Maeda S, Yamaguchi A, Kitazawa S
  • Journal Title: J Cell Biochem 98 Pages: 1629-1644
  • Peer Reviewed
• [Journal Article] MCP-1 Contributes to Macrophage Infiltration into Adipose Tissue, Insulin Resistance, and Hepatic Steatosis in Obesity (2006)
  • Author(s): Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M
  • Journal Title: J Clin Invest 116 Pages: 1494-1505
  • Peer Reviewed
• [Journal Article] Protruding Disordered Loop of gC1qR is Specifically Exposed and Related to Antiapoptotic Property in Germ Cell Lineage (2006)
  • Author(s): Kitazawa S, Takenaka A, Kondo T, Mizoguchi A, Kitazawa R
  • Journal Title: Histochem Cell Biol 126 Pages: 665-677
  • Peer Reviewed
• [Journal Article] Miyachi H, Maeda S, Egashira K, KasugaM, MCP-1 Contributes to Macrophage Infiltration into Adipose Tissue, Insulin Resistance, and Hepatic Steatosis in Obesity (2006)
  • Author(s): Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S
  • Journal Title: J Clin Invest 116 Pages: 1494-1505
• [Journal Article] Modulation of Mouse RANKL Gene Expression by Runx2 and PKA Pathway (2006)
  • Author(s): Mori K, Kitazawa R, Kondo T, Maeda S, Yamaguchi AKitazawa S
  • Journal Title: J Cell Biochem 98 Pages: 1629-1644
  • Peer Reviewed
• [Journal Article] DNA Methylation of Multiple Tumor-related Genes in Association with Overexpression of DNA Methyltransferase 1 (DNMT1) during Multistage Carcinogenesis of the Pancreas (2006)
  • Author(s): Peng DF, Kanai Y, Sawada M, UshijimaS, Hiraoka N, Kitazawa S, Hirohashi S
  • Journal Title: Carcinogenesis 27 Pages: 1160-1168
  • Peer Reviewed
• [Journal Article] In situ Detection of Specific Gene Expression During and Immediately After Transcription at Electron Microscopic Level (2006)
  • Author(s): Kitazawa S, Kitazawa R
  • Journal Title: J Struct Biol 153 Pages: 64-72
  • Peer Reviewed
• [Journal Article] Protruding disordered loop of gC1qR is specifically exposed and related to antiapoptotic property in germ cell lineage. (2006)
  • Author(s): Kitazawa S, et al.
  • Journal Title: Histochem Cell Biol 126・6 Pages: 665-677
• [Journal Article] MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. (2006)
  • Author(s): Kanda H, et al.
  • Journal Title: J Clin Invest 116・6 Pages: 1494-1505
• [Journal Article] Modulation of mouse RANKL gene expression by Runx2 and PKA pathway. (2006)
  • Author(s): Mori K, et al.
  • Journal Title: J Cell Biochem 98・6 Pages: 1629-1644
• [Journal Article] Lung carcinosarcoma with liposarcoma element. an autopsy case. (2006)
  • Author(s): Kitazawa R, et al.
  • Journal Title: Pathol Int 56・8 Pages: 449-452
  • NAID: 10020332518
• [Presentation] マウスRANK遺伝子転写におけるNFATの機能解析 (2009)
  • Author(s): 北澤理子, 他
  • Organizer: 第98回日本病理学会総会
  • Place of Presentation: 国立京都国際会館(京都府)
  • Year and Date: 2009-05-03
• [Presentation] 転写早期の新生mRNAの電子顕微鏡による動態解析 (2008)
  • Author(s): 北澤荘平, 他
  • Organizer: 第49回日本組織細胞化学会総会シンポジウム
  • Place of Presentation: 長崎
  • Year and Date: 2008-10-05
• [Presentation] 日本、ミャンマー両国の膀胱腫瘍発生に関するエヒジェネティクス解析 (2007)
  • Author(s): Sann Sanda Khin
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Presentation] タイタンエイ, ネウイン, 北澤荘平, 日本とミャンマーにおける膀胱腫瘍進展過程におけるBAMBI遺伝子のエピジェネティクス制御の変化 (2007)
  • Author(s): サンサンダキン, 北澤理子, 近藤武史, 森清
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] 日本とミャンマ-における膀胱腫瘍進展過程におけるBAMBI 遺伝子のエピジェネティクス制御の変化 (2007)
  • Author(s): サン サンダキン, 北澤理子, 近藤武史, 森清, タイタンエイ, ネウイン, 北澤荘平
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Regulation of Osteoclastogenesis by CpG Methylation of Mouse Receptor Activator of NF-kB Ligand(RANKL)Gene Promoter Region (2006)
  • Author(s): Kitazawa R, Mori K, Kondo T, Kitazawa S
  • Organizer: ASBMR 28th Annual Meeting
  • Place of Presentation: Pennsylvania Convention Center Philadeophia, USA
• [Presentation] In Situ of Specific Gene Expression During and Immediately After Transcription at Electron Microscopic Level (2006)
  • Author(s): Kitazawa S, Kitazawa R, Fujimoto M, Mori K, Sann Sanda Khin, Ishii J, Kondo T
  • Organizer: The 16th International Microscoy Congress
  • Place of Presentation: Sapporo Convention Center, Sapporo
• [Book] 組織細胞化学2010-組織細胞化学イメージングの基礎と最前線:生体内分子局在と機能を探る- (2010)
  • Author(s): 北澤荘平,森清,近藤武史,北澤理子
  • Publisher: 日本組織細胞化学会編集
• [Book] DNA Methylation Research Trends, Epigenetic roles of CpG methylation at non-CpG-islands revealed by morphology-oriented epigenetic research (Editor; Kobayashi TB) (2007)
  • Author(s): Kitazawa S, Mori K, kondo T, Fujimoto M, Kitazawa R
  • Publisher: Nova Science Publishers, New York
• [Book] DNA Methylation Research Trends, Epigenetic roles of CpG methylation at non-CpG-islands revealed by morphology-oriented epigenetic research (2007)
  • Author(s): Kitazawa S, Mori K, kondo T, Fujimoto M, Kitazawa R
  • Publisher: Nova Science Publishers,(Editor ; Kobayashi TB)
• [Book] DNA Methylation Research Trends (2007)
  • Author(s): T. B. Kobayashi
  • Total Pages: 200
  • Publisher: Nova Science Publishers Inc
• [Book] Epigenetic roles of CpG methylation at non-CpG-islands revealed by morphology-oriented epigenetic research. In ; DNA Methylation Research (2007)
  • Author(s): Kitazawa S, et al.
  • Total Pages: 240
  • Publisher: Nova Science Publishers, Inc. Hauppauge, New York
• [Remarks]
  • URL: http://www.med.kobe-u.ac.jp/patho2/index.html