子宮内膜細胞の老化逸脱へのゲノム多様性の関与と癌幹細胞における不死化能獲得機構

2010 Fiscal Year Annual Research Report

• Project/Area Number: 20390435
• Research Institution: Kyushu University
• Principal Investigator: 和氣 徳夫 九州大学, 医学研究院, 教授 (60091584)
• Co-Investigator(Kenkyū-buntansha): 小林 裕明 九州大学, 医学研究院, 准教授 (70260700) ; 福嶋 恒太郎 九州大学, 大学病院, 講師 (40304779)
• Keywords: Endometrial cancer / SNP / AED / 細胞老化誘導シグナロソーム / cancer stem cells / EMT

Research Abstract

本研究は細胞老化誘導シグナロソーム(Ras/MDM2/ERα/p21)の機能破綻にゲノム多様性がいかに関与し子宮体癌発生に至るか解明することを目的とした。さらに子宮体癌幹細胞を同定し生物学的特性を解明した。
1)MDM2 SNP309 G/T多型
子宮体癌患者125例及び福岡コホート研究参加者200例をそれぞれケース及びコントロールとした。p53,ERα,p21SNPsと子宮体癌の関連は認めなかった。しかしMDM2 SNP309G/Gは子宮体癌オッズ比の高まりをしめした(OR1.76,95%G1 0.93-3.30)。さらに309T/G,G/G多型はp53codou72 Arg/Argと遺伝子間相互作用を示し、有意な子宮体癌オッズ比の上昇を示した(OR2.53 95%/C 1.03-6.21)。
2)MDM2対立遺伝子間発現量差異(Allelic Expression Difference:AED)
MDM2プロモータ領域内のSNPがその発現量に及ぼす影響について解析した。正常子宮内膜36例、子宮体癌組織38例についてMDM2 exon 1 SNP(rs937283,A/G)多型を用い、CDNAを増幅した。SSCP法により対立遺伝子間のAEDを定量した。ゲノムDNAをコントロールとした。正常子宮内膜、体癌、組織でのA/G検体はそれぞれ18,17例で、そのうち4例及び3例に顕著なAEDが認められた。
3)子宮体癌幹細胞の生物学的特性
子宮体癌細胞株からそれぞれSP,non SP細胞を採取し、増殖特性及び造腫瘍性について解析した。SP細胞はnon SP細胞に比し、高い増殖を示し未分化な腫瘍形成を示した。さらに腫瘍間質の形成に参加するというEMT表現型を示した。

Research Products

• [Journal Article] Expression and localization of E-cadherin and catenin in uterine carcinosarcoma (2011)
  • Author(s): Nishimura I, Ohishi Y, Oda Y, Kishimoto J, Yasunaga M, Okuma E, Kobayashi H, Wake N, Tsuneyoshi M
  • Journal Title: Virchows Arch Volume: 458(1) Pages: 85-94
  • Peer Reviewed
• [Journal Article] Incidence of postmolar gestational trophoblastic disease in androgenetic moles and the morphological features associated with low risk postmolar gestational trophoblastic disease (2011)
  • Author(s): Kaneki E, Kobayashi H, Hirakawa T, Matsuda T, Kato H, Wake N
  • Journal Title: Cancer Sci Volume: 101(7) Pages: 1717-1721
  • Peer Reviewed
• [Journal Article] Cytoplasmic and stromal expression of laminin 2 chain correlates with infiltrative invasion in ovarian mucinous neoplasms of gastro-intestinal type (2011)
  • Author(s): Okuma E, Ohishi Y, Oda Y, Aishima S, Kurihara S, Nishimural, Yasunaga M, Kobayashi H, Wake N, Tsuneyoshi M
  • Journal Title: Oncol Rep Volume: 24(6) Pages: 1569-1576
  • Peer Reviewed
• [Journal Article] Nuclear localization of E-cadherin but not beta-catenin in human ovarian granulosa cell tumours and normal ovarian follicles and ovarian stroma (2011)
  • Author(s): Ohishi Y, Oda Y, Kurihara S, Kaku T, Kobayashi H, Wake N, Tsuneyoshi M
  • Journal Title: Histopathology Volume: 58(3) Pages: 423-432
  • Peer Reviewed
• [Journal Article] Sentinel node detection with (99m)Tc phytate alone is satisfactory for cervical cancer patients undergoing radical hysterectomy and pelvic lymphadenectomy (2010)
  • Author(s): Ogawa S, Kobayashi H, Amada S, Yahata H, Sonoda K, Abe K, Baba S, Sasaki M, Kaku T, Wake N
  • Journal Title: Int J Clin Oncol Volume: 15(1) Pages: 52-58
  • Peer Reviewed
• [Journal Article] Comparative study of peripheral neurotoxicity after injection of two different paclitaxel formulations in rats (2010)
  • Author(s): Nakamura I, Ichimura E, Kobayashi H, Mashiba H, Nagai H, Ebara K, Hayashi H, Okamoto K, Wake N, Nishikawa K
  • Journal Title: Arzneimittel Forschung Drug Research Volume: 60(4) Pages: 205-209
  • Peer Reviewed
• [Journal Article] A Definitive Haplotype Map as Determined by Genotyping Duplicated Haploid Genomes Finds a Predominant Haplotype Preference at Copy-Number Variation Events (2010)
  • Author(s): Kukita Y, Yahara K, Tahira T, Higasa K, Sonoda M, Yamamoto K, Kato K, Wake N, Hayashi K
  • Journal Title: The American journal of human genetics Volume: 86 Pages: 918-928
  • Peer Reviewed
• [Journal Article] Coincident expression of beta-catenin and cyclin D1 in endometrial stromal tumors and related high-grade sarcomas (2010)
  • Author(s): Kurihara S, Oda Y, Ohishi Y, Kaneki E, Kobayashi H, Wake N, Tsuneyoshi M
  • Journal Title: Mod Pathol Volume: 23(2) Pages: 225-234
  • Peer Reviewed
• [Journal Article] Endometrial cancer side-population cells show prominent migration and have a potential to differentiate into the mesenchymal cell lineage (2010)
  • Author(s): Kato K, Takao T, Kuboyama A, Tanaka Y, Ohgami T, Yamaguchi S, Adachi S, Yoneda T, Ueoka, Y, Kato Keiji, Hayashi S, Asanoma K, Wake N
  • Journal Title: The American Journal of Pathology Volume: 176(1) Pages: 381-392
  • Peer Reviewed
• [Journal Article] Receptor-binding cancer antigen expressed on SiSo cells induces apoptosis via ectodomain shedding (2010)
  • Author(s): Sonoda K, Miyamoto S, Nakashima M, Wake N
  • Journal Title: Exp Cell Res Volume: 316(11) Pages: 1795-1803
  • Peer Reviewed
• [Journal Article] Low-dose mithramycin exerts its anticancer effect via the p53 signaling pathway and synergizes with nutlin-3 in gynecologic cancers (2010)
  • Author(s): Ohgami T, Kato K, Kobayashi H, Sonoda K, Inoue T, Yamaguchi S, Yoneda T, Wake N :
  • Journal Title: Cancer Sci Volume: 101(6) Pages: 1387-1395
  • Peer Reviewed
• [Journal Article] Three cases of acute fatty liver of pregnancy : Postpartum clinical course depends on interval between onset of symptoms and termination of pregnancy (2010)
  • Author(s): Aso K, Hojo S, Yumoto Y, Fukushima K, Miyazaki M, Kotoh K, Wake N
  • Journal Title: J Matern Fetal Neonatal Med Volume: 23(9) Pages: 1047-1049
  • Peer Reviewed