子宮内膜細胞の老化逸脱へのゲノム多様性の関与

• Project/Area Number: 23249075
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Kyushu University
• Principal Investigator: 和氣 徳夫 九州大学, 学内共同利用施設等, 研究員 (60091584)
• Co-Investigator(Kenkyū-buntansha): 浅野間 和夫 九州大学, 医学(系)研究科(研究院), 准教授 (30380413) ; 劉 格 九州大学, 学内共同利用施設等, 研究員 (50647998) ; 恒松 良祐 九州大学, 医学(系)研究科(研究院), 助教 (20380529) ; 高尾 知佳 九州大学, 環境発達医学研究センター, 学術研究員 (40612429) ; 井上 貴史 九州大学, 大学病院, 助教 (70380417)
• Project Period (FY): 2011-11-18 – 2016-03-31
• Project Status: Declined (Fiscal Year 2015)
• Budget Amount: ¥30,160,000 (Direct Cost: ¥23,200,000、Indirect Cost: ¥6,960,000); Fiscal Year 2015: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2014: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000); Fiscal Year 2013: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000); Fiscal Year 2012: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: Genome diversity / Endometrial cancer / MDM2 309 G/T SNP / AhR -130bp C/T SNP / AhR transcription / serum IL24 concentration / MDM2 / SNP / AHR / NF1C / 子宮体癌 / MDM2型 / シグナロソーム / -130C/T多型 / NFIC

Outline of Annual Research Achievements

1)子宮内膜細胞の老化逸脱へのゲノム多様性の関与
MDM2 SNP309 G/G＋G/TとTP53コドン72Arg/Argの組み合わせは子宮体癌発症odds比2.53(1.03-6.21)と両遺伝子間に統計学的有意な相互作用を示し、子宮体癌発症リスクを増大する。
2)AhR-130 C/T SNPによる転写制御
AhR-130 T/T遺伝子型はC/C遺伝子型に比しmRNAレベルで1.7倍、蛋白レベルで2倍のAhR発現亢進を示した。NF1C転写抑制因子結合サイトがC/C型では維持されT/T型で消失するためである。AhR T/T型の頻度は全体の10%程度であるが進行子宮体癌で有意に高頻度に検出される。AhRが癌細胞にEpithelial Mesenchymal Transition(EMT)を誘発し癌の進展に関与するためである。
マイクロアレイ法にてAhR下流でTCDD応答性発現変化する遺伝子を同定した。そのうちIL24遺伝子はT/T遺伝子型でC/C遺伝子型に比しTCDD非存在下の発現が有意に亢進しており、TCDD非存在性、AhR依存性AhR転写制御の存在が強く示唆された。TCDD存在下でのIL24発現もT/T型で有意に高値であった。ダイオキシン類高濃度被曝例として、油症患者の血中IL24濃度を測定した。T/T遺伝子型油症患者の血中IL24濃度はC/C遺伝子型と比較し有意に高値であった。これらの結果から、AhR-130bp C/T SNP及びIL24血中濃度はダイオキシン類による病態発症を予知出来るバイオマーカーとして使用可能であることが示唆された。

Research Progress Status

翌年度、交付申請を辞退するため、記入しない。

Strategy for Future Research Activity

翌年度、交付申請を辞退するため、記入しない。

Research Products

• [Journal Article] Aryl hydrocarbon receptor SNP -130 C/T associates with dioxins susceptibility through regulating its receptor activity and downstream effectors including interleukin 24. (2015)
  • Author(s): Liu G, Asanoma K, Takao T, Tsukimori K, Uchi H, Furue M, Kato K, Wake N
  • Journal Title: Toxicology Letters Volume: 232 Pages: 384-392
  • DOI: 10.1016/j.toxlet.2014.11.025
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A definitive haplotype of structural variations determined by microarray analysis of duplicated haploid genomes. (2014)
  • Author(s): Tomoko T, Koji Y, Yoji K, Koichiro H, Kiyoko K, Norio W, Kenshi H
  • Journal Title: Genoomics Data Volume: 2 Pages: 55-59
  • Peer Reviewed
• [Journal Article] Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment. (2014)
  • Author(s): Court F, Tayama C, Romanelli V, Martin-Trujillo A, Iglesias-Platas I, Okamura K, Sugahara N, Simon C, Moore H, Harness J, Keirstead H, Vicente Sanchez-Mut J, Kaneki E, Lapunzina P, Soejima H, Wake N, Esteller M, Ogata T, Hata K, Nakabayashi K, Monk D
  • Journal Title: Genome Reserch. Volume: 24 (4) Pages: 554-569
  • DOI: 10.1101/gr.164913.113
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Correlation between regular mouthing movements and heart rate patterns during non-rapid eye movement periods in normal human fetuses between 32 and 40 weeks of gestation. (2013)
  • Author(s): Yuka O, Seiichi M, Kotaro F, Norio W, Kiyoko K,
  • Journal Title: Early Hum Dev. Volume: 89(6) Pages: 381-386
  • DOI: 10.1016/j.earlhumdev.2012.12.007
  • Peer Reviewed
• [Journal Article] Association of MDM2 SNP309 and TP53 Arg72Propolymorphisms with risk of endometrial cancer. (2013)
  • Author(s): Tomoko Y, Ayumi K, Kiyoko K, Tatsuhiro O, Kanako O, Toshiaki S, and Norio W,
  • Journal Title: Oncology Reports. Volume: 30 Pages: 25-34
  • DOI: 10.3892/or.2013.2433
• [Journal Article] Establishment of a new diagnostic method for hydropic villi by using TSSC3 antibody. (2013)
  • Author(s): Wake N, Takao T, Asanoma K, Kato H
  • Journal Title: J Obstet Gynaecol Res Volume: 39(7) Pages: 1230-1235
  • DOI: 10.1111/jog.12100
  • Peer Reviewed
• [Journal Article] Clinical utility of augmentation index as a new parameter of peripheral circulation in human fetuses. (2013)
  • Author(s): Fujita Y, Satoh S, Sugitani M, Yumoto Y, Fukushima K, Wake N,
  • Journal Title: Early Hum Dev. Volume: 89(8) Pages: 601-605
  • DOI: 10.1016/j.earlhumdev.2013.03.004
• [Journal Article] Doppler sonographic evaluation of arteriovenous shunt flow in a fetus with dural sinus malformation. (2013)
  • Author(s): Sato Y, Fujita Y, Anami A, Yumoto Y, Fukushima K, Wake N.
  • Journal Title: J Obstet Gynaecol Res. Volume: 39(5) Pages: 1081-1084
  • DOI: 10.1111/jog.12023
• [Journal Article] Well-Differentiated Villoglandular Adenocarcinoma of the Uterine Cervix : Assessment of Cytological Features by Histological Subtypes (2013)
  • Author(s): Hagiwara T, Kaku T, Kobayashi H, Wake N, Saito T.
  • Journal Title: Acta Cytologica Volume: 57(1) Pages: 61-68
  • DOI: 10.1159/000342917
  • Peer Reviewed
• [Journal Article] Oxidative stress produced by xanthine oxidase induces apoptosis in human extravillous trophoblast cells. (2013)
  • Author(s): Murata M, Fukushima K, Takao T, Seki H, Takeda S, Wake N.
  • Journal Title: J Reprod Dev. Volume: 59(1) Pages: 7-13
  • NAID: 10031156805
• [Journal Article] Successful management of cervico-isthmic pregnancy delivered at term. (2013)
  • Author(s): Sakai A, Fujita Y, Yumoto Y, Fukushima K, Kobayashi H, Wake N.
  • Journal Title: 10.1111/j.1447-0756.2012.01967.x. Epub 2012 Jul 29. Volume: 39(1) Pages: 371-374
• [Journal Article] The predictive value of anti-SS-A antibodies titration in pregnant women with fetal congenital heart block. (2013)
  • Author(s): Anami A, Fukushima K, Takasaki Y, Sumida T, Waguri M, Wake N, Murashima A.
  • Journal Title: Mod Rheumatol. Volume: 23(4) Pages: 653-658
  • DOI: 10.1007/s10165-012-0704-z
  • NAID: 10031189158
• [Journal Article] Characterization of placental transfer of polychlorinated dibenzo-p-dioxins, dibenzofurans and polychlorinated biphenyls in normal pregnancy. (2013)
  • Author(s): Tsukimori K, Morokuma S, Hori T, Takahashi K, Hirata T, Otera Y, Fukushima K, Kawamoto T, Wake N
  • Journal Title: J Obstet Gynaecol Res. Volume: 39(1) Pages: 83-90
  • DOI: 10.1111/j.1447-0756.2012.01906.x
  • Peer Reviewed
• [Journal Article] Ultrasound evaluation of fetal brain dysfunction based on behavioral patterns (2013)
  • Author(s): Morokuma S, Fukushima K, Otera Y, Yumoto Y, Tsukimori K, Ochiai M, Hara T, Wake N.
  • Journal Title: Brain & development Volume: 35(1) Pages: 61-67
  • DOI: 10.1016/j.braindev.2012.01.007
  • NAID: 40017369136
  • Peer Reviewed
• [Journal Article] Characterization of placental transfer of polychlorinated dibenzo-p-dioxins, dibenzofurans and polychlorinated biphenyls in normal pregnancy. (2013)
  • Author(s): Kiyomi T, Seiichi M, Tsuguhide H, Koji T,Teruaki H, Yuka O, Kotaro F, Toshihiro K and Norio W
  • Journal Title: Obstetrics and Gynaecology Research Volume: 39 Pages: 83-90
  • Peer Reviewed
• [Journal Article] Inhibin-α and synaptophysin immunoreactivity in synovial sarcoma with granular cell features. (2012)
  • Author(s): Setsu N, Kohashi K, Endo M, Yamamoto H, Ohishi Y, Sueyoshi K, Iwamoto Y, Tsuneyoshi M, Motoi T, Kumagai A, Oda Y.
  • Journal Title: Hum Pathol. Volume: 43(6) Pages: 850-857
  • Peer Reviewed
• [Journal Article] Ultrasound and MR images of prenatally diagnosed bilateral congenital diaphragmatic hernia, a rare variation of CDH☆. (2012)
  • Author(s): Kana Ishibashi Hiasa, Yasuyuki Fujita, Kotaro Fukushima, Kouji Nagata, Tomoaki Taguchi, Norio Wake.
  • Journal Title: Clinical Imaging. Volume: 36(5) Pages: 639-642
  • Peer Reviewed
• [Journal Article] Successful management of cervico-isthmic regnancy delivered at term. (2012)
  • Author(s): Atsuhiko Sakai, Yasuyuki Fujita, Yasuo Yumoto, Kotaro Fukushima, Hiroaki Kobayashi and Norio Wake.
  • Journal Title: Obstetrics and Gynaecology Research. Volume: 39(1) Pages: 371-374
  • Peer Reviewed
• [Journal Article] A retrospective chart review of the perinatal period in 22 pregnancies of 16 women with Moyamoya disease. (2012)
  • Author(s): Fukushima K, Yumoto Y, Kondo Y, Fujita Y, Morokuma S, Tsukimori K, Wake N.
  • Journal Title: Clinical neuroscience. Volume: 19(10) Pages: 1358-1362
  • Peer Reviewed
• [Journal Article] Characterization of placental transfer of polychlorinated dibenzo-p-dioxins, dibenzofurans and polychlorinated biphenyls in normal pregnancy. (2012)
  • Author(s): Tsukimori K, Morokuma S, Hori T, Takahashi K, Hirata T, Otera Y, Fukushima K, Kawamoto T, Wake N.
  • Journal Title: Obstetrics and Gynaecology Research. Volume: 39(1) Pages: 83-90
  • Peer Reviewed
• [Journal Article] "Piling up" clear cells in müllerian-type mucinous and mixed cell-type borderline tumor do not represent concomitant clear cell neoplasms. (2012)
  • Author(s): Ohishi Y, Kurihara S, Aman M, Takeuchi T, Imamura H, Kaku T, Kobayashi H, Wake N, Oda Y.
  • Journal Title: Human Pathology Volume: 43(10) Pages: 1618-1626
  • Peer Reviewed
• [Journal Article] A comparing the Effects of Kamishoyosan or HRT on Climacteric Disorders in Postmenopausal Women. (2012)
  • Author(s): Higuchi T, Iino K, Tarakida A, Abe K, Taniguchi R, Mizunuma H, Mikami Y, Katagiri S, Hashimoto T, Hasuo Y, et al
  • Journal Title: Results from a Randomized Controlled Trial. Menopause & Women’s Health Jpn. Volume: 20 Pages: 305-312
  • Peer Reviewed
• [Journal Article] The maternally expressed gene Tssc3 regulates the expression of MASH2 transcription factor in mouse trophoblast stem cells through the AKT-Sp1 signaling pathway. (2012)
  • Author(s): Takao T, Asanoma K, Tsunematsu R, Kato K, Wake N.
  • Journal Title: Journal of biological chemistry. Volume: 287(51) Pages: 42685-42694
  • Peer Reviewed
• [Journal Article] Maternal exposure to high levels of dioxins in relation to birth weightin women affected by Yusho disease (2012)
  • Author(s): Tsukimori K, Uchi H, Mitoma C, Yasukawa F, Chiba T, Todaka T, Kajiwara J, Yoshimura T, Hirata T, Fukushima K, Wake N, Furue M
  • Journal Title: Environ Int Volume: 38(1) Pages: 79-86
  • Peer Reviewed
• [Journal Article] SATB Homeobox Protenis Regulate Trophoblast Stem Cell Renewal and Differentiation (2012)
  • Author(s): Asanoma K, Kubota K, Chakraborty D, Renaud SJ, Wake N, Fukushima K, Soares MJ, Rumi MA
  • Journal Title: J Biol Chem Volume: 287(3) Pages: 2257-2268
  • Peer Reviewed
• [Journal Article] Comparison of the concentrations of polychlorinated biphenyls and dioxins in mothers affected by the Yusho incident and their children (2011)
  • Author(s): Tsukimori K, Uchi H, Mitoma C, Yasukawa F, Fukushima K, Kajiwara J, Yoshimura T, Hirata T, Wake N, Furue M
  • Journal Title: Chemosphere Volume: 84(7) Pages: 928-935
  • Peer Reviewed
• [Journal Article] Sodium butyrate inhibits the self-renewal capacity of endometrial tumor side-population cells by inducing a DNA damage response (2011)
  • Author(s): Kato K, Kuhara A, Yoneda T, Inoue T, Takao T, Ohgami T, Dan L, Kuboyama A, Kusunoki S, Takeda S, Wake N
  • Journal Title: MolCancer Ther Volume: 10(8) Pages: 1430-1439
  • Peer Reviewed
• [Journal Article] Lsolation and Characterization of Human Trophoblast Side-Population (SP) Cells in Primary Villous Cytotrophoblasts and HTR-8/SVneo Cell Line (2011)
  • Author(s): Takao T, Asanoma K, Kato K, Fukushima K, Tsunematsu R, Hirakawa T, Matsumura S, Seki H, Takeda S, Wake N
  • Journal Title: PLoS One Volume: 6(7)
  • Peer Reviewed
• [Journal Article] Effects of S-equol and natural S-eqol supplement(SE5-OH) on the growth of MCF-7 in vitro and as tumors implanted into ovariectomized athymic mice (2011)
  • Author(s): Onda A, Ueno T, Uchiyama S, Hayashi S, Kato K, Wake N
  • Journal Title: Food Chem Toxicol Volume: 49(9) Pages: 2279-2284
  • Peer Reviewed
• [Journal Article] FGF4-dependent stem cells derived from rat blastocycts differentiate alone the trophoblast lines (2011)
  • Author(s): Asanoma K, Rumi MA, Kent LN, Chakraborty D, Renaud SJ, Wake N, Lee DS, Kubota K, soares MJ,
  • Journal Title: Dev Biol Volume: 351(1) Pages: 110-119
  • Peer Reviewed
• [Presentation] のう胞化絨毛の研究-基礎からの臨床- (2011)
  • Author(s): 和気徳夫
  • Organizer: 日本産婦人科学会
  • Place of Presentation: 大阪(招待講演)
  • Year and Date: 2011-08-30