Analysis of the mechanisms of induction of cancer initiation/progression by abnormal peripheral circadian rhythm using cancer mouse models

• Project/Area Number: 20K21651
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
• Research Institution: Kanazawa University
• Principal Investigator: Daikoku Takiko 金沢大学, 疾患モデル総合研究センター, 教授 (30767249)
• Co-Investigator(Kenkyū-buntansha): 水本 泰成 金沢大学, 附属病院, 講師 (00420331) ; 藤原 浩 金沢大学, 医学系, 教授 (30252456) ; 安藤 仁 金沢大学, 医学系, 教授 (50382875)
• Project Period (FY): 2020-07-30 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2021: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2020: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: マウスモデル / 子宮がん / 概日リズム / 子宮体癌 / 子宮肉腫 / 時計遺伝子

Outline of Research at the Start

本研究では、申請者らが作製した、100%のマウスが子宮体癌を自然発症しさらに筋層浸潤、リンパ節転移する、子宮間質も含めてPten遺伝子が欠損したPten-PRcre、100%のマウスが過形成までの病変を自然発症するがリンパ節転移はしない、上皮細胞のみPten遺伝子が欠損するPten-LTFcre、および100%のマウスが子宮肉腫を自然発症する、プロゲステロンを連続投与したPten-Rcreマウスを用いて、末梢概日リズムの異常が、がんの発症や進展に関与するという新たな仮説を検証する。

Outline of Final Research Achievements

In the present study, we found that disruption of peripheral circadian rhythms may be involved the initiation and progression of endometrial cancer by regulating angiogenesis through the deletion of the Bmal1 gene in mouse models that spontaneously develops endometrial hyperplasia or endometrial cancer.

Academic Significance and Societal Importance of the Research Achievements

これまでの知見からは、子宮体癌発生が段階的な遺伝子変異の蓄積だけでは説明が困難であるが、末梢時計の乱れが、子宮体癌発症・進展に関与する可能性をマウスモデルを用いて示唆した点が学術的に意義がある。また、新しい機序の解明により臨床の新しい診断法や治療法の開発に繋がる点で社会的に意義がある。

Research Products

• [Journal Article] Mucinous, endometrioid, and serous ovarian cancers with peritoneal dissemination are potent candidates for P-cadherin targeted therapy: a retrospective cohort study (2021)
  • Author(s): Kayahashi Kayo、Mizumoto Yasunari、Matsuoka Ayumi、Obata Takeshi、Iwadare Junpei、Nakamura Mitsuhiro、Daikoku Takiko、Fujiwara Hiroshi
  • Journal Title: BMC Cancer Volume: 21 Issue: 1 Pages: 1-9
  • DOI: 10.1186/s12885-020-07737-w
  • Peer Reviewed / Open Access
• [Journal Article] Brown adipocyte-specific knockout of Bmal1 causes mild but significant thermogenesis impairment in mice (2021)
  • Author(s): Hasan Nazmul、Nagata Naoto、Morishige Jun-ichi、Islam Md Tarikul、Jing Zheng、Harada Ken-ichi、Mieda Michihiro、Ono Masanori、Fujiwara Hiroshi、Daikoku Takiko、Fujiwara Tomoko、Maida Yoshiko、Ota Tsuguhito、Shimba Shigeki、Kaneko Shuichi、Fujimura Akio、Ando Hitoshi
  • Journal Title: Molecular Metabolism Volume: 49 Pages: 101202-101202
  • DOI: 10.1016/j.molmet.2021.101202
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Adolescent Dietary Habit-induced Obstetric and Gynecologic Disease (ADHOGD) as a New Hypothesis?Possible Involvement of Clock System (2020)
  • Author(s): Fujiwara Tomoko, Ono Masanori, Mieda Michihiro, Yoshikawa Hiroaki, Nakata Rieko, Daikoku Takiko, Sekizuka-Kagami Naomi, Maida Yoshiko, Ando Hitoshi, Fujiwara Hiroshi
  • Journal Title: Nutrients Volume: 12 Issue: 5 Pages: 1294-1294
  • DOI: 10.3390/nu12051294
  • Peer Reviewed / Open Access
• [Journal Article] Hypertensive disorders of pregnancy are associated with dysmenorrhea in early adulthood: A cohort study (2020)
  • Author(s): Nakayama Midori, Ono Masanori, Iizuka Takashi, Kagami Kyosuke, Fujiwara Tomoko, Sekizuka‐Kagami Naomi, Maida Yoshiko, Obata Takeshi, Yamazaki Rena, Daikoku Takiko, Fujiwara Hiroshi
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 46 Issue: 11 Pages: 2292-2297
  • DOI: 10.1111/jog.14431
  • Peer Reviewed / Open Access
• [Journal Article] The lack of terminal tubule cells in the submandibular gland of mice deficient in submandibular gland protein C (2020)
  • Author(s): Nakata H, Terakawa J, Horike S, Daikoku T, Iseki S
  • Journal Title: Cell and Tissue Research Volume: 381(2) Issue: 2 Pages: 229-237
  • DOI: 10.1007/s00441-020-03205-w
  • Peer Reviewed / Open Access