Identification of molecular mechanisms and the targets using in vitro carcinogenesis model of endometrial cancer.

• Project/Area Number: 20390432
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Kanazawa University
• Principal Investigator: KYO Satoru Kanazawa University, 医学系, 講師 (50272969)
• Co-Investigator(Kenkyū-buntansha): MIZUMOTO Yasunari 金沢大学, 附属病院, 助教 (00420331)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000); Fiscal Year 2010: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2009: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2008: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
• Keywords: 子宮内膜癌 / 癌化モデル / 分子標的

Research Abstract

In the present study, we investigated the molecular targets of KRAS signals using tumorigenic cells with oncogenic KRAS mutation established from TERT-immortalized endometrial epithelial cells. We first confirmed that the Raf-Erk pathway, but not the PI3K-Akt pathway, was activated in KRAS-tumorigenic cells. However, the introduction of constitutively active MEK into immortalized cells to mimic Raf-Erk activation failed to obtain tumorigenic phenotypes, indicating the existence of other carcinogenic pathways triggered by KRAS Recent evidence suggestive of linkage with KRAS signals prompted us to examine the involvement of NF-κB in endometrial carcinogenesis. We found that the DNA binding activity of NF-κB was markedly elevated in KRAS-tumorigenic cells compared to TERT-immortalized cells. Furthermore, the ability of NF-κB to activate the target gene promoters significantly increased in KRAS-tumorigenic cells. Introduction of a mutant IκB that is resistant to degradation and thereby enhances the inhibitory effect on NF-κB largely abrogated the transformed phenotypes of KRAS-tumorigenic cells. Thus, oncogenic KRAS signals contributed to the tumorigenic phenotypes of endometrial cells by activating the transcription function of NF-κB. These findings clearly show that NF-κB activation is a novel target of oncogenic KRAS in endometrial carcinogenesis, implying the potential utility of NF-κB inhibitors for endometrial cancer chemoprevention, especially with KRAS mutation.

Research Products

• [Journal Article] Activation of NF-κB is a novel target of KRAS induced endometrial careinogenesis. (2011)
  • Author(s): Mizumoto Y, Kyo S, Kiyono T, Takakura M, Nakamura M, Maida Y, Mori N, Bono Y, Sakurai H, Inoue M.
  • Journal Title: Clin.Cancer Res. 17 Pages: 1341-1350
  • Peer Reviewed
• [Journal Article] Dianogest, a synthetic progestine, inhibits prostaglandin E2 production and aromatase expression by human endometrial epithelial cells in a sheroid culture system. (2011)
  • Author(s): Shimizu Y, Mita S, Takeuchi T, Notsu T, Mizuguchi K, Kyo S.
  • Journal Title: Steroids 76 Pages: 60-67
  • Peer Reviewed
• [Journal Article] Forkhead transcription factor FOXO1 is a direct target of progestin to inhibit endometrial epithelial cell growth. (2011)
  • Author(s): Kyo S, Sakaguchi J, Kiyono T, Shimizu Y, Maida Y, Mizumoto Y, Mori N, Nakamura M, Takakura M, Miyake M, Sakamoto M, Inoue M.
  • Journal Title: Clin.Cancer Res. 17 Pages: 525-537
  • Peer Reviewed
• [Journal Article] Activation of NF-{kappa}B Is a Novel Target of KRAS-Induced End ometrial Carcinoaenesis. (2011)
  • Author(s): Mizumoto Y, Kyo S, et al.
  • Journal Title: Clin Cancer Res Volume: 17 Pages: 1341-1350
  • Peer Reviewed
• [Journal Article] KLF4 contributes to maintenance of telomerase activity in stem cells. (2010)
  • Author(s): Wong CW, Hou PS, Tseng SF, Chien CL, Wu KJ, Chen HF, Ho HN, Kyo S, Teng SC.
  • Journal Title: Stem Cells 28 Pages: 1510-1517
  • Peer Reviewed
• [Journal Article] In vivo biological purging for lymph node metastasis of human colorectal cancer by telomerase-specific incolytic virotherapy. (2010)
  • Author(s): Kojima T, Watanabe Y, Hashimoto Y, Kuroda S, Yamasaki Y, Yano S, Ouchi M, Tazawa H, Uno F, Kagawa S, Kyo S, Mizuguchi H, Urata Y, Tanaka N, Fujiwara T.
  • Journal Title: Ann. Surg. 251 Pages: 1079-1086
  • Peer Reviewed
• [Journal Article] Expression of HER-2 impacts patient survival and paclitaxel sensitivity in endometrial cancer. (2010)
  • Author(s): Mori N, Kyo S, Nakamura M, Hashimoto M, Maida Y, Mizumoto Y, Takakura M, Ohno S, Kiyono T, Inoue M.
  • Journal Title: Br.J.Cancer 103 Pages: 889-898
  • Peer Reviewed
• [Journal Article] Prognostic impact of CD133 expression as a tumor intiating marker in endometrial cancer. (2010)
  • Author(s): Nakamura M, Kyo S, Zhang B, Zhang X, Mizumoto Y, Takakura M, Maids Y, Mori N, Hashimoto M, Ohno S, Inoue M.
  • Journal Title: Hum.Pathol. 41 Pages: 1516-1529
  • Peer Reviewed
• [Journal Article] A novel translational approach for human Malignant pleural mesothelioma : paranase-assisted dual virotherapy. (2010)
  • Author(s): Watanabe Y, Kojima T, Kagawa S, Uno F, Hashimoto Y, Kyo S, Mizuguchi H, Tanaka N, Kawamura H, Ichimaru D, braid Y, Fujiwara T.
  • Journal Title: Oncogene 29 Pages: 1145-1154
  • Peer Reviewed
• [Journal Article] Kruppel-like factor 4 mediates anti-proliferative effects of progesterone with GO/G1 arrest in huma endometrial epithelia cells. (2010)
  • Author(s): Shimizu Y, Takeuchi T, Mita S, Nost T, Mizoguchi K ans Kyo S.
  • Journal Title: J.Endocr.Invest. 33 Pages: 745-750
  • Peer Reviewed
• [Journal Article] WT1 expression correlates with angiogenesis in endometrial cancer tissues. (2010)
  • Author(s): Dohi A, Ohno S, Ohno Y, Kyo S, Soma G, Sugiyama H, Tnoue M.
  • Journal Title: Anti cancer Res. 30 Pages: 3187-3192
  • Peer Reviewed
• [Journal Article] Intraperitoneal administration of telomerase-specific oncolytic adenovirus sensitizes ovarian cancer cells to cisplatin and affects survival in a xenograft model with peritoneal dissemination (2010)
  • Author(s): Takakura M, Nakamura M, Kyo S, Hashimoto M, Mori N, Ikoma T, Mizumoto Y, Fujiwara T, Urata Y, Inoue M.
  • Journal Title: Cancer Gene Ther. 17 Pages: 11-19
  • Peer Reviewed
• [Journal Article] Forkhead transcription factor FOXO1 is a direct target of progestin to inhibit endometrial epithelial cell growth. (2010)
  • Author(s): Kyo S, Sakaguchi J, et al.
  • Journal Title: Clin Cancer Res Volume: 17 Pages: 525-537
  • Peer Reviewed
• [Journal Article] Wilms' Tumor 1 (WT1) Peptide Immunotherapy for Gynecological Malignancy (2009)
  • Author(s): Ohno S, Kyo S, Myojo S, Dohi S, Ishizaki J, Miyamoto K, Morita S, Sakamto J.
  • Journal Title: Anti cancer Res. 29 Pages: 4779-4784
  • Peer Reviewed
• [Journal Article] A simple biological imaging system for detecting viable human circulating tumor cells. (2009)
  • Author(s): Kojima T, Hashimoto Y, Watanabe Y, Kagawa S, Uno F, Kuroda S, Tazawa H, Kyo S, Mizuguchi H, Urata Y, Tanaka N, Fujiwara T.
  • Journal Title: J.Clin.Invest. 119 Pages: 3172-3181
  • NAID: 120004724430
  • Peer Reviewed
• [Journal Article] Experience and efficacy of a bipolar vessel sealing system for radical abdominal hysterectomy. (2009)
  • Author(s): Kyo S, Mizumoto Y, Takakura M, Hashimoto M, Mori N, Ikoma T, Nakamura M, Tnoue M
  • Journal Title: Int J Gynecol Cancer. 19 Pages: 1658-1661
  • Peer Reviewed
• [Journal Article] Correlation between WT1 Expression and Cell Proliferation in Endometrial Cancer. (2009)
  • Author(s): Dohi S, Ohno S, Ohno Y, Soma G, KKyo S, Inoue M.
  • Journal Title: Anticancer Res. 29 Pages: 4887-4891
  • Peer Reviewed
• [Journal Article] Deregulated glycogen synthase kinase-3β sustains gastrointestinal cancer Cells survival by modulating human telomerase reverse transcriptase and telomerase (2009)
  • Author(s): Mai W, Kawakami K, Shakoori A, Kyo S, Miyashita K, Yokoi K, Jin M, Shimasaki T, Motoo Y, Minomoto T.
  • Journal Title: Clin.Caner Res. 15 Pages: 6810-6819
  • Peer Reviewed
• [Journal Article] Dienogest, a synthetic progestin, inhibits the proliferation of immortalized human endometrial epithelial cells with suppression of cyclin D1 gene expression (2009)
  • Author(s): Shimizu Y, Takeuchi T, Mizuguchi K, Kiyono T, Inoue M, Kyo S.
  • Journal Title: Mot.Hum.Reprod. 15 Pages: 693-701
  • Peer Reviewed
• [Journal Article] Bone marrow-derived cells from male donors can compose endometrial glands in female transplant recipients. (2009)
  • Author(s): Ikoma T, Kyo S, Maida Y, Ozaki S, Takakura M, Nakao S, Inoue M.
  • Journal Title: Am.J.Obstet.Gynecol. 201
  • Peer Reviewed
• [Journal Article] Activation of telomerase by human cytomegalovirus. (2009)
  • Author(s): Straat K, Liu C, Rahbar A, Zhu Q, Liu L, Wolmer-Solberg N, Lou F, Liu Z, Shen J, Jib J, Kyo S, Bjorkholm M,Sjlberg J, Soderberg-Naucl er C, Xu D.
  • Journal Title: J Natl Cancer Inst. 101 Pages: 488-497
  • Peer Reviewed
• [Journal Article] Telomerase-Specific Virotheranostics for Human Head and Neck Cancer. (2009)
  • Author(s): Kurihara Y, Watanabe Y, Onimatsu H, Kojima T, Shirota T, Hatori M, Liu D, Kyo S, Mizuguchi H, Urata Y, Shintani S, Fujiwara T.
  • Journal Title: Clin Cancer Res. 15 Pages: 2335-2343
  • Peer Reviewed
• [Journal Article] Hypoxia-specific stabilization of HIF-1・・by human pappilomaviruses (2009)
  • Author(s): Nakamura M, Bodily J, Beglin M, Kyo S, Inoue M, Laimins L.
  • Journal Title: Virology 387 Pages: 442-448
  • Peer Reviewed
• [Journal Article] Stathmin, a microtubule regulatory protein is associated with hypoxia-inducible factor-la levels in human endometrial and endothelial cells. (2009)
  • Author(s): Yoshie M, Miyajima F, Kyo S, Tamura K.
  • Journal Title: Endocrinology 150 Pages: 2413-2418
  • Peer Reviewed
• [Journal Article] Immunohistochemical detection of WT1 protein in endometrial cancer. (2009)
  • Author(s): Ohno S, Dohi S, Ohno Y, Kyo S, Sugiyama H, Suzuki N, Inoue M.
  • Journal Title: Anti Cancer Res. 29 Pages: 1691-1695
  • Peer Reviewed
• [Journal Article] Diagnostic potential and limitation of imaging cancer cell in cytological sample using telomerase-specific replicative adenovirus. (2009)
  • Author(s): Maida Y, Kyo S, Sakaguchi J, Mizumoto Y, Hashimoto M, Mori M, Ikoma T, Nakamura M, Takakura M, Urata Y, Fujiwara T, Tnoue M.
  • Journal Title: Int.J.Oncol. 34 Pages: 1549-1556
  • Peer Reviewed
• [Journal Article] Stathmin, a microtubule regulatory protein is associated with hypoxia-inducible factor-la levels in human endometrial and endothelial cells (2009)
  • Author(s): Yoshie M, Miyajima E, Kyo S, Tamura K
  • Journal Title: Endocrinology 150 Pages: 2413-2418
  • Peer Reviewed
• [Journal Article] Telomerase-Specific Virotheranostics for Human Head and Neck Cancer (2009)
  • Author(s): Kurihara Y, Kyo S, et al
  • Journal Title: Clin Cancer Res 15 Pages: 2335-2343
  • Peer Reviewed
• [Journal Article] Activation of telomerase by human cytomegalovirus (2009)
  • Author(s): Straat K, Kyo S, et al.
  • Journal Title: J Natl Cancer Inst 101 Pages: 488-497
  • Peer Reviewed
• [Journal Article] Early growth response-1 mediates down-regulation of telomerase in cervical cancer. (2008)
  • Author(s): Akutagawa O Nishi H, Kyo S, Terauchi F, Yamazawa K, Higuma C, Inoue M, Isaka K.
  • Journal Title: Cancer Sci 99 Pages: 1401-1406
  • NAID: 10024008633
  • Peer Reviewed
• [Journal Article] Novel Cardiac Precursor-Like Cells from Human Menstrual Blood-Derived Mesenchymal Cells. (2008)
  • Author(s): Hida N, Nishiyama N, Miyoshi S, Kira S, Segawa K, Uyama T, Mori T, Miyado K, Ikegami Y, Cui C, Kiyono T, Kyo S, Shimizu T, Okano T, Sakamoto M, Ogawa S, Umezawa A.
  • Journal Title: Stem Cells. 26 Pages: 1695-1704
  • Peer Reviewed
• [Journal Article] Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers. (2008)
  • Author(s): Kyo S, Takakura M, Fujiwara T, Inoue M.
  • Journal Title: Cancer Sci. 9 Pages: 1528-1538
  • NAID: 10024009430
  • Peer Reviewed
• [Journal Article] Role of menin in the regulation of telomerase activity in normal and cancer cells. (2008)
  • Author(s): Hashimoto M, Kyo S, Hua X, Tahara H, Nakajima M, Takakura M, Saskaguchi J, Maida Y, Nakamura M, Ikoma T, Mori N, Mizumoto Y, Inoue M.
  • Journal Title: Int.J.Oncol. 33 Pages: 333-340
  • Peer Reviewed
• [Journal Article] Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers (2008)
  • Author(s): Kyo S, Takakura M, et al
  • Journal Title: Cancer Sci 9 Pages: 1528-1538
  • NAID: 10024009430
  • Peer Reviewed
• [Journal Article] Role of menin in the regulation of telomerase activity in normal and cancer cells. (2008)
  • Author(s): Hashimoto M, Kyo S, et al.
  • Journal Title: Int. J. Oncol 33 Pages: 333-340
  • Peer Reviewed
• [Journal Article] Novel Cardiac Precursor-Like Cells from Human Menstrual Blood-Derived Mesenchymal Cells (2008)
  • Author(s): Hida H, Kyo S, et al.
  • Journal Title: Stem Cells 26 Pages: 1695-1704
  • Peer Reviewed
• [Presentation] Oncogenic KRAS transforms endometrial cells through NFkR activation independently of IkBa degradation or p65-IkBa dissociation (2009)
  • Author(s): Yasunari Mizumoto Satoru Kyo Masahiro Takakura Mitsuhiro Nakamura, Manabu Hashimoto, Noriko Mori, Tomomi Ikoma, Masaki Inoue
  • Organizer: 第68回日本癌学会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2009-10-01
• [Presentation] The significance of CD133 expression as a potential marker of tumor initiation and proliferation in endometrial cancer cells (2009)
  • Author(s): Nakamura M, Kyo, S, et al.
  • Organizer: American Association for Cancer Research meeting
  • Place of Presentation: Denver, CO, USA
• [Presentation] 子宮内 膜癌において変異型KRASの下流でNFkBが活性化され、癌形質獲得に寄与する (2008)
  • Author(s): 水本泰成 京哲 高倉正博 中村充宏 森紀子 生駒友美 井上正樹
  • Organizer: 第60回日本産科婦人科学会学術講演会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2008-04-12