The Role of Hepatocyte Nuclear Factor-1Beta in the Pathogenesis of Endometriosi-Associated Ovarian Cancer

2010 Fiscal Year Final Research Report

• Project/Area Number: 20591958
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Nara Medical University
• Principal Investigator: KOBAYASHI Hiroshi Nara Medical University, 医学部, 教授 (40178330)
• Co-Investigator(Kenkyū-buntansha): KANAYAMA Seiji 奈良県立医科大学, 医学部, 博士研究員 (10423914) ; ITO Takahiro 奈良県立医科大学, 医学部, 助教 (60285369)
• Project Period (FY): 2008 – 2010
• Keywords: 子宮内膜症 / 卵巣癌 / 転写因子 / HNF-1beta

Research Abstract

Problem Clear cell carcinoma of the ovary (CCC) has a number of features distinguishing it from other epithelial ovarian carcinomas (EOC) because of its characteristic histology and biology, frequent concurrence with endometriotic lesion, and highly chemoresistant nature resulting in an extremely poor prognosis. The incidence of CCC has been steadily increasing in Japan. They comprise approximately 20% of all EOC. Understanding the mechanisms of CCC development and elucidating pathogenesis and pathophysiology are intrinsic to prevention and effective therapies for CCC. Method We have investigated the role of hepatocyte nuclear factor-1beta (HNF-1beta) for biology, pathogenesis, and pathophysiological studies on endometriosis-associated EOC. Several data are discussed in the context of endometriosis and CCC biology. Results Here, we show that 1) the expression of the genes involved in transcription, signaling, cell cycle, adhesion, matrix, proteinase, and detoxification was greatly incr eased in the CCC carcinogenesis ; 2) upregulation of HNF-1beta and Polo-like kinase (PLK)-Early mitotic inhibitor-1 (Emi1) as well as their downstream targets are specifically found in most CCC. The promising molecular targeting approach will emerge in the context of HNF-1beta and PLK-Emi1 biology ; and 3) several significant common pathways observed in CCC of the ovary overlap the datasets identified in CCC of the kidney. To improve the outcome in CCC therapy, we must learn various adaptive treatment strategies for renal CCC, although it is not supported by any preliminary clinical data. These studies based on genome-wide expression analysis technology have noted specific expression of transcription factor genes, HNF-1beta, in endometriosis and CCC, suggesting that early differentiation into the clear cell lineage takes place in the endometriosis. The HNF-1beta-dependent pathway of CCC will be discussed, which are providing new insights into regulation of apoptosis and glycogen synthesis and resistance of CCC to anticancer agents. Conclusion This study demonstrates recent advances in the HNF-1beta and its target genes, the potential challenges to the understanding of carcinogenesis, pathogenesis and pathophysiology of CCC, and a possible novel model is proposed. The inhibitors that target HNF-1beta and PLK-Emi1 and their downstream signaling molecules would be evaluated. The challenges accompanying the recent advance are described in this article.

Research Products

• [Journal Article] Mechanisms of Soybean-Derived Protease Inhibitors, Bowman-Birk Inhibitor and Kunitz Trypsin Inhibitor, in Preventing the Development of Cancer and Inflammation. (2010)
  • Author(s): Kobayashi H, Oi H, Kanayama S, Kawaguchi R, Sado T, Sakata M, Yoshida S, Yamada Y.
  • Journal Title: Frontiers in Bioscience
• [Journal Article] Nidogen-2 : A new serum biomarker for ovarian cancer. (2010)
  • Author(s): Kuk C, Gunawardana CG, Soosaipillai A, Kobayashi H, Li L, Zheng Y, Diamandis EP
  • Journal Title: Clin Biochem. 43(4-5) Pages: 355-361
• [Journal Article] Screening, epidemiology, molecular biology, and treatment strategies for endometriosis-associated ovarian cancer. (2010)
  • Author(s): Kobayashi H.
  • Journal Title: Reprod.Med.Biol. 9(1) Pages: 17-22
• [Journal Article] A case of intravenous leiomyomatosis with high levels of hyaluronan. (2010)
  • Author(s): Yaguchi C, Oi H, Kobayashi H, Miura K, Kanayama N.
  • Journal Title: J.Obstet.Gynaecol.Res. 36(2) Pages: 454-458
• [Journal Article] Anti-inflammatory actions of serine protease inhibitors containing the Kunitz domain. (2010)
  • Author(s): Shigetomi H, Onogi A, Kajiwara H, Yoshida S, Furukawa N, Haruta S, Tanase Y, Kanayama S, Noguchi T, Yamada Y, Oi H, Kobayashi H.
  • Journal Title: Inflamm Res. 59(9) Pages: 679-687
• [Journal Article] Fatal Factors of Clinical Manifestations and Laboratory Testing in Patients with Amniotic Fluid Embolism. (2010)
  • Author(s): Oi H, Naruse K, Noguchi T, Sado T, Kimura S, Kanayama N, Terao T, Kobayashi H.
  • Journal Title: Gynecol Obstet Invest. 70(2) Pages: 138-144
• [Journal Article] Clear cell carcinoma of the ovary : potential pathogenic mechanisms (Review). (2010)
  • Author(s): Kajihara H, Yamada Y, Kanayama S, Furukawa N, Noguchi T, Haruta S, Yoshida S, Sado T, Oi H, Kobayashi H.
  • Journal Title: Oncol Rep. 23(5) Pages: 1193-1203
• [Journal Article] Beta blocker infusion decreases the magnitude of core hypothermia after anesthesia induction. (2010)
  • Author(s): Inoue S, Abe R, Kawaguchi M, Kobayashi H, Furuya H.
  • Journal Title: Minerva Anestesiol. 76(12) Pages: 1002-1009
• [Journal Article] The role of iron in the pathogenesis of endometriosis. (2009)
  • Author(s): Kobayashi H, Yamada Y, Kanayama S, Furukawa N, Noguchi T, Haruta S, Yoshida S, Sakata M, Sado T, Oi H.
  • Journal Title: Gynecol Endocrinol. 25(1) Pages: 39-52
• [Journal Article] Oxytocin Hypersensitivity in Pregnant P-LAP Deficient Mice. (2009)
  • Author(s): Ishii M, Naruse K, Hattori A, Tsujimoto M, Ishiura S, Numaguchi Y, Murohara T, Kobayashi H, Mizutani S.
  • Journal Title: Life Sci. 84(19-20) Pages: 668-672
• [Journal Article] The urokinase plasminogen activator (tPA) system in uterine natural killer cells in the placental bed during early pregnancy. (2009)
  • Author(s): Naruse K, Lash GE, Bulmer JN, Innes BA, Otun HA, Searle RF, Robson SC
  • Journal Title: Placenta 30(5) Pages: 398-404
• [Journal Article] The role of hepatocyte nuclear factor-1beta in the pathogenesis of clear cell carcinoma of the ovary. (2009)
  • Author(s): Kobayashi H, Yamada Y, Kanayama S, Furukawa N, Noguchi T, Haruta S, Yoshida S, Sakata M, Sado T, Oi H.
  • Journal Title: Int J Gynecol Cancer. 19(3) Pages: 471-479
• [Journal Article] A Neonate with Umbilical Arteriovenous Malformation Showing Hemorrhagic Shock from Massive Umbilical Hemorrhage. (2009)
  • Author(s): Shibata M, Kanehiro H, Shinkawa T, Fujita Y, Yada K, Kamamoto T, Arai I, Nishikubo T, Sakata M, Kobayashi H, Takeda M, Nonomura A, Takahashi Y.
  • Journal Title: Am J Perinatol. 26(8) Pages: 583-586
• [Journal Article] Molecular pathogenesis of endometriosis-associated clear cell carcinoma of the ovary (Review). (2009)
  • Author(s): Kobayashi H, Kajiwara H, Kanayama S, Yamada Y, Furukawa N, Noguchi T, Haruta S, Yoshida S, Sakata M, Sado T, Oi H.
  • Journal Title: Oncol.Rep. 22 Pages: 233-240
• [Journal Article] Ab initio molecular orbital calculations on specific interactions between urokinase-type plasminogen activator and its receptor. (2009)
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• [Journal Article] The effect of recombinant aminopeptidase A (APA) on hypertension in pregnant spontaneously hypertensive rats (SHRs). (2009)
  • Author(s): Ishii M, Hattori A, Numaguchi Y, Ma X, Nagasaka T, Tsujimoto M, Murohara T, Kobayashi H, Mizutani S.
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• [Journal Article] Theoretical model of treatment strategies for clear cell carcinoma of the ovary : Focus on perspectives. (2009)
  • Author(s): Yoshida S, Furukawa N, Haruta S, Tanase Y, Kanayama S, Noguchi T, Sakata M, Yamada Y, Oi H, Kobayashi H.
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• [Journal Article] Expression profiles of genes involved in poor prognosis of epithelial ovarian carcinoma : a review. (2009)
  • Author(s): Yoshida S, Furukawa N, Haruta S, Tanase Y, Kanayama S, Noguchi T, Sakata M, Yamada Y, Oi H, Kobayashi H.
  • Journal Title: Int J Gynecol Cancer. 19(6) Pages: 992-997
• [Journal Article] A neonate with umbilical arteriovenous malformation showing hemorrhagic shock from massive umbilical hemorrhage. (2009)
  • Author(s): Shibata M, Kanehiro H, Shinkawa T, Fujita Y, Yada K, Kamamoto T, Arai I, Nishikubo T, Sakata M, Kobayashi H, Takeda M, Nonomura A, Takahashi Y.
  • Journal Title: Am J Perinatol. 26(8) Pages: 583-586
• [Journal Article] Localisation of matrix metalloproteinase (MMP)-2, MMP-9, and tissue inhibitors for MMPs (TIMPs) in uterine natural killer cells in early human pregnancy. (2009)
  • Author(s): Naruse K, Lash GE, Innes BA, Otun HA, Searle RF, Robson SC, Bulmer JN
  • Journal Title: Hum Reprod. 24(3) Pages: 553-561
• [Journal Article] Ovarian cancer in endometriosis : epidemiology, natural history, and clinical diagnosis. (2009)
  • Author(s): Kobayashi H.
  • Journal Title: Int J Clin Oncol. 14(5)(Review) Pages: 378-382
• [Journal Article] Ovarian endometrioma-Risks factors of ovarian cancer development. (2008)
  • Author(s): Kobayashi H, Sumimoto K, Kitanaka T, Yamada Y, Sado T, Sakata M, Yoshida S, Kawaguchi R, Kanayama S, Shigetomi H, Haruta S, Tsuji Y, Ueda S, Terao T.
  • Journal Title: Eur J Obstet Gynecol Reprod Biol. 138(2) Pages: 187-193
• [Journal Article] A randomized study of screening for ovarian cancer : a multicenter study in Japan. (2008)
  • Author(s): Kobayashi H, Yamada Y, Sado T, Sakata M, Yoshida S, Kawaguchi R, Kanayama S, Shigetomi H, Haruta S, Tsuji Y, Ueda S, Kitanaka T.
  • Journal Title: Int J Gynecol Cancer. 18(3) Pages: 414-420
• [Journal Article] Prevalence of Ovarian Cancer among Women with a CA125 Level of 35 U/ml or Less. (2008)
  • Author(s): Kobayashi H, Yamada Y, Sado T, Sakata M, Yoshida S, Kawaguchi R, Kanayama S, Shigetomi H, Haruta S, Tsuji Y, Ueda S, Kitanaka T.
  • Journal Title: Gynecol.Obstet.Invest. 65(2) Pages: 133-138
• [Journal Article] Massive ovarian edema in pregnancy after ovulation induction using clomiphene citrate. (2008)
  • Author(s): Kawaguchi R, Ueda S, Tsuji Y, Haruta S, Kanayama S, Yamada Y, Ooi H, Kobayashi H.
  • Journal Title: Arch Gynecol Obstet. 277(4) Pages: 375-378
• [Journal Article] Giant abdominal tumor of the ovary. (2008)
  • Author(s): Ueda S, Yamada Y, Tsuji Y, Kawaguchi R, Haruta S, Shigetomi H, Kanayama S, Yoshida S, Sakata M, Sado T, Kitanaka K, Kobayashi H.
  • Journal Title: J Obstet Gynaecol Res. 34(1) Pages: 108-111
• [Journal Article] Hepatocyte growth factor induces anoikis resistance by up-regulation of cyclooxygenase-2 expression in uterine endometrial cancer cells. (2008)
  • Author(s): Kanayama S, Yamada Y, Kawaguchi R, Tsuji Y, Haruta S, Kobayashi H.
  • Journal Title: Oncol Rep. 19(1) Pages: 117-122
• [Journal Article] Molecular structure and function analysis of bikunin on down-regulation of tumor necrosis factor-alpha expression in activated neutrophils. (2008)
  • Author(s): Kanayama S, Yamada Y, Onogi A, Shigetomi H, Ueda S, Tsuji Y, Haruta S, Kawaguchi R, Yoshida S, Sakata M, Sado T, Kitanaka T, Oi H, Yagyu T, Kobayashi H.
  • Journal Title: Cytokine 42 Pages: 191-197
• [Journal Article] Peritoneal disseminated recurrence and lung metastasis after surgery for stage IA uterine papillary serous carcinoma of the endometrium : a case report. (2008)
  • Author(s): Kanayama S, Yamada Y, Haruta S, Naruse K, Furukawa N, Kawaguchi R, Yoshida S, Sakata M, Sado T, Kitanaka T, Oi H, Kobayashi H.
  • Journal Title: Arch Gynecol Obstet. 278(3) Pages: 277-280
• [Journal Article] New insights into the importance of aminopeptidase A in hypertension. (2008)
  • Author(s): Mizutani S, Ishii M, Hattori A, Nomura S, Numaguchi Y, Tsujimoto M, Kobayashi H, Murohara T, Wright JW
  • Journal Title: Heart Fail.Rev. 13 Pages: 273-284
• [Journal Article] Two cases of pregnant women with ovarian endometrioma mimicking a malignant ovarian tumor. (2008)
  • Author(s): Yoshida S, Onogi A, Shigetomi H, Tsuji Y, Haruta S, Naruse K, Kanayama S, Noguchi T, Sakata M, Furukawa N, Sado T, Yamada Y, Kitanaka T, Oi H, Kobayashi H.
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• [Journal Article] The Effect of Recombinant Aminopeptidase A on Hypertension in Spontaneously Hypertensive Rats : Its Effect in Comparison with Candesartan. (2008)
  • Author(s): Ishii M, Hattori A, Numaguchi Y, Tsujimoto M, Ishiura S, Kobayashi H, Murohara T, Wright JW, Mizutani S.
  • Journal Title: Horm Metab Res. 40(12) Pages: 887-891
• [Journal Article] Clinicopathologic features of ovarian cancer in patients with ovarian endometrioma. (2008)
  • Author(s): Kawaguchi R, Tsuji Y, Haruta S, Kanayama S, Sakata M, Yamada Y, Fujita H, Saito H, Tsuneto K, Kobayashi H.
  • Journal Title: J Obstet Gynaecol Res. 34(5) Pages: 872-877
• [Journal Article] Iron-dependent oxidative stress as a pathogenesis for preterm birth. (2008)
  • Author(s): Sakata M, Sado T, Kitanaka T, Naruse K, Noguchi T, Yoshida S, Shigetomi H, Onogi A, Oi H, Kobayashi H.
  • Journal Title: Obstet Gynecol Surv. 63(10) Pages: 651-660
• [Journal Article] Malignancy and thrombosis. Recent advanced in thrombosis and hemostasis 2008.
  • Author(s): Kobayashi H, Kawaguchi R, Tsuji Y, Yamada Y. Sakata M, Kanayama S, Haruta S, Oi H.
  • Journal Title: Editor. Tanaka K and Davie EW. Pages: 536-550
• [Presentation] Effects of Adiponectin in Differentiation (2009)
  • Author(s): Onogi A, Naruse K, Shigetomi H, Yoshizawa Y, Noguchi H, Sado T, Kitanaka T, Oi H, Kobayashi H.
  • Organizer: Invasion and Migration of Human Trophoblastic Cells 15^<Th> World Congress of International Federation of Placenta Association (IFPA).(Poster)
  • Place of Presentation: Adelaide, Austraria
  • Year and Date: 20091006-20091009
• [Presentation] Angiopoietin-like Protein 2 (AngPTL2) in Human Maternal Serum, Amniotic Fluid and Term Placental Trophoblast in Pregnancy. (2009)
  • Author(s): Naruse K, Endo M, Onogi A, Shigetomi H, Yoshizawa Y, Sado T, Oi H, Oike Y, Kobayashi H.
  • Organizer: 15^<Th> IFPA.(Poster)
  • Place of Presentation: Adelaide, Austraria
  • Year and Date: 20091006-20091009
• [Presentation] Adipocyte-derived cytokines in hypertensive pregnancy : A trigger for systemic inflammation. (2009)
  • Author(s): Naruse K, Onogi A, Sado T, Shigetomi H, Yoshida S, Kitanaka T, Oi H, Kobayashi H.
  • Organizer: Europian branch of International Society for Study of Hypertension in Pregnancy (ESSHP).(Poster)
  • Place of Presentation: Oxford, England
  • Year and Date: 20090910-20090914
• [Presentation] Increase of High Molecular Weight/Active Form Adiponectin in Preeclampsia is Induced by Brain-type Natriuretic Peptide on Adipocyte. (2009)
  • Author(s): Naruse K, Onogi A, Sado T, Sakata M, Yoshizawa Y, Noguchi H, Yoshida S, Sakata M, Oi H, Kobayashi H.
  • Organizer: 56^<th> Annual Meeting of the Society for Gynecologic Investigation (SGI).
  • Place of Presentation: Glasgow, Scotland
  • Year and Date: 20090317-20090321
• [Presentation] Better management for cesarean scar pregnancy : Review of literatures and our three cases. (2009)
  • Author(s): Onogi A, Shigetomi H, Naruse K, Kanayama S, Noguchi T, Yoshida S, Furukawa N, Sakata M, Sado T, Yamada Y, Kitanaka T, Oi H, Kobayashi H.
  • Organizer: 56^<th> SGI.(Poster)
  • Place of Presentation: Glasgow, Scotland
  • Year and Date: 20090317-20090321
• [Presentation] High Molecular Weight-Adiponectin and Brain-type Natriuretic Peptide in Preeclamptic Maternal Serum and Cultured Adipocyte (2008)
  • Author(s): Naruse K, Oonogi A, Sado T, Sakata M, Noguchi T, Yamasaki Y, Kitanaka T, Kobayashi H.
  • Organizer: 16^<th> World congress of the International Society for the Study of Hypertension (ISSHP)(Young Investigators Award受賞:口演)
  • Place of Presentation: Washington DC, USA
  • Year and Date: 20080920-20080924
• [Presentation] High Adiponectin and Low Oxygen Culture of Term Placental Tropholast : Effects on Cytokine/Protease Secretion (2008)
  • Author(s): Naruse K, Oonogi A, Noguchi H, Yoshida S, Sakata M, Sado T, Kitanaka T, Oi H, Kobayashi H.
  • Organizer: 14^<Th> World Congress of IFPA
  • Place of Presentation: Austria
  • Year and Date: 20080910-20080913
• [Presentation] Ultrasonic CTAR and PLI Indices Predict Neonatal Congestive Heart Failure in Monochorionic Twin Pregnancies (2008)
  • Author(s): Sakata M, Shigetomi H, Utsu M, Kobayashi H, Maeda K.
  • Organizer: The Fetus as a Patient XXIV International
  • Place of Presentation: Congress Germany
  • Year and Date: 20080612-20080614
• [Presentation] A Case Report of the Hydrops Fetalis Associated with Chorioanginoma (2008)
  • Author(s): Oonogi A, Shigetomi H, Yoshida S, Sakata M, Sado T, Oi H, Kobayashi H.
  • Organizer: The Fetus as a Patient XXIV International
  • Place of Presentation: Congress Germany
  • Year and Date: 20080612-20080614
• [Presentation] Live-birth deliveries of dichorionic triplet pregnancy (2008)
  • Author(s): Shigetomi H, Oonogi A, Yoshida S, Sakata M, Sado T, Oi H, Kobayashi H.
  • Organizer: The Fetus as a Patient XXIV International
  • Place of Presentation: Congress Germany
  • Year and Date: 20080612-20080614