Molecular mechanism for predisposition to develop oral cancer based on epigenome modification in utero

• Project/Area Number: 19K10052
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57010:Oral biological science-related
• Research Institution: Kyushu University
• Principal Investigator: Kawakubo-Yasukochi Tomoyo 九州大学, 歯学研究院, 准教授 (70507813)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: DOHaD / 口腔癌 / エピゲノム / 炎症 / 葉酸 / 皮膚癌 / 扁平上皮がん / 癌 / エピジェネティクス / 扁平上皮

Outline of Research at the Start

近年、生活習慣病胎児期起源説（DOHaD: Developmental Origins of Health and Disease）、すなわち妊娠母体の栄養状態が児の将来の生活習慣病発症リスクを規定していることが様々な疫学調査によって実証されつつある。
申請者は最近、妊娠母体の葉酸欠乏が胎児の発がん遺伝子にメチル化異常を誘導すること明らかにした。
そこで本研究では、妊娠母体が摂取するOne carbon metabolism 関連栄養素の摂取量に着目した動物実験を行うことで、扁平上皮癌発症素因が胎内で規定されている可能性をエピジェネティックな観点から検証する。

Outline of Final Research Achievements

In this research, the effect of maternal folic acid intake in the gestational period on the carcinogenic susceptibility of the next generation was elucidated.
As a result of research, maternal folic acid shortage in pregnancy caused methylation abnormalities in the deubiquitinating enzyme gene(s) in the fetal, causing abnormal expression of the gene(s), and the epigenomic change lasts even after the offspring had matured. It was demonstrated that the sensitivity to induction of inflammation was increased, and its tendency was particularly remarkable in the squamous epithelial tissue. Furthermore, it was revealed that maternal folic acid shortage in pregnancy increases the carcinogenic susceptibility of offspring to oral squamous cell cancer. This suggests that proper maternal intake of folic acid contributes to the suppression of oral cancer carcinogenesis in the offspring.

Academic Significance and Societal Importance of the Research Achievements

こでまでに、がんにおけるエピゲノム制御については、詳細な検討がなされてきたが、母体(因)と仔 (果)の因果関係について総合的把握を行った研究は非常に少ない。本研究課題では、がんの発症素因として胎内の栄養状態によるエピゲノム変異（先天的環境要因）の提示を行った。口腔癌発症素因が、母体の妊娠期栄養状態によって胎内で既定されうることをその分子基盤を以て実証したことにより、栄養学を通して予防歯学の基盤確立に貢献した。また、現在まで環境素因が主な原因とされてきた口腔癌の病因論に一石を投じることになった。

Research Products

• [Int'l Joint Research] Auckland University(ニュージーランド)
• [Journal Article] Hepatic glycogenolysis is determined by maternal high-calorie diet via methylation of Pygl and it is modified by oteocalcin administration in mice (2021)
  • Author(s): Kawakubo-Yasukochi Tomoyo、Yano Ena、Kimura Soi、Nishinakagawa Takuya、Mizokami Akiko、Hayashi Yoshikazu、Hatakeyama Yuji、Ohe Kenji、Yasukochi Atsushi、Nakamura Seiji、Jimi Eijiro、Hirata Masato
  • Journal Title: Molecular Metabolism Volume: 54 Pages: 101360-101360
  • DOI: 10.1016/j.molmet.2021.101360
  • Peer Reviewed / Open Access
• [Journal Article] Anthracenyl functionalization of half-sandwich carbene complexes: In vitro anticancer activity and reactions with biomolecules (2021)
  • Author(s): Lee BYT, Sullivan MP, Yano E, Tong KKH, Hanif M, Kawakubo-Yasukochi T, Jamieson SMF, Soehnel T, Goldstone DC, Hartinger CG.
  • Journal Title: Inorg Chem Volume: 60(19) Issue: 19 Pages: 14636-14644
  • DOI: 10.1021/acs.inorgchem.1c01675
  • Peer Reviewed / Open Access
• [Journal Article] Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis (2021)
  • Author(s): Mukai Satoru、Mizokami Akiko、Otani Takahito、Sano Tomomi、Matsuda Miho、Chishaki Sakura、Gao Jing、Kawakubo-Yasukochi Tomoyo、Tang Ronghao、Kanematsu Takashi、Takeuchi Hiroshi、Jimi Eijiro、Hirata Masato
  • Journal Title: Journal of Biological Chemistry Volume: 296 Pages: 100274-100274
  • DOI: 10.1016/j.jbc.2021.100274
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The roles of osteocalcin in lipid metabolism in adipose tissue and liver (2020)
  • Author(s): Otani Takahito、Mizokami Akiko、Kawakubo-Yasukochi Tomoyo、Takeuchi Hiroshi、Inai Tetsuichiro、Hirata Masato
  • Journal Title: Advances in Biological Regulation Volume: 78 Pages: 100752-100752
  • DOI: 10.1016/j.jbior.2020.100752
  • Peer Reviewed / Open Access
• [Journal Article] GLP-1 signaling is required for improvement of glucose tolerance by osteocalcin. J. Endocrinol. (2020)
  • Author(s): Mizokami, A., Mukai, S., Gao, J., Kawakubo-Yasukochi, T., Otani, T., Takeuchi, H., Jimi, E., Hirata, M.
  • Journal Title: Journal of Endocrinology Volume: 244 Issue: 2 Pages: 285-296
  • DOI: 10.1530/joe-19-0288
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of IC50 levels immediately after treatment with anticancer reagents using a real-time cell monitoring device (2019)
  • Author(s): Hazekawa M, Nishinakagawa T, Kawakubo-Yasukochi T, Nakashima M.
  • Journal Title: Exp Ther Med Volume: 18(4) Pages: 3197-3205
  • DOI: 10.3892/etm.2019.7876
  • Peer Reviewed / Open Access
• [Journal Article] Maternal folic acid depletion during early pregnancy increases sensitivity to squamous tumor formation in the offspring in mice (2019)
  • Author(s): Kawakubo-Yasukochi T, Morioka M, Ohe K, Yasukochi A, Ozaki Y, Hazekawa M, Nishinakagawa T, Ono K, Nakamura S, Nakashima M.
  • Journal Title: J Dev Orig Health Dis Volume: 10(6) Issue: 6 Pages: 683-691
  • DOI: 10.1017/s2040174419000217
  • Peer Reviewed
• [Journal Article] Regulation of collagen type XVII expression by miR203a-3p in oral squamous cell carcinoma cells (2019)
  • Author(s): Yasukochi A, Kawakubo-Yasukochi T, Morioka M, Hazekawa M, Nishinakagawa T, Ono K, Nakashima M, Nakamura S.
  • Journal Title: J Biochem Volume: in press Issue: 2 Pages: 163-173
  • DOI: 10.1093/jb/mvz024
  • Peer Reviewed
• [Journal Article] Glypican-3 gene silencing for ovarian cancer using siRNA-PLGA hybrid micelles in a murine peritoneal dissemination model (2019)
  • Author(s): Hazekawa M, Nishinakagawa T, Kawakubo-Yasukochi T, Nakashima M.
  • Journal Title: J Pharmacol Sci Volume: 139(3) Issue: 3 Pages: 231-239
  • DOI: 10.1016/j.jphs.2019.01.009
  • Peer Reviewed
• [Presentation] Maternal high calorie diet during pregnancy induces abnormal hepatic glycogenolysis in the offspring and it is mitigated by osteocalcin (2022)
  • Author(s): Kawakubo-Yasukochi T, Yano E, Kimura S, Mizokami A, Hayashi Y, Yasukochi A, Nakamura S, Jimi E, Hirata M.
  • Organizer: 第95回日本薬理学会年会
• [Presentation] Association of maternal folic acid shortage during early pregnancy with carcinogenic risk in the offspring (2021)
  • Author(s): Kawakubo-Yasukochi T, Yano E, Kimura S, Nakamura S, Jimi E.
  • Organizer: The 23rd Korea-Japan Joint Seminar on Pharmacology
  • Int'l Joint Research
• [Presentation] Distinctive non-cording RNA profile in the serum of IgG4-related disease patient (2021)
  • Author(s): Kimura S, Kawakubo-Yasukochi T, Hayashi Y, Yano E, Moriyama M, Nakamura S, Jimi E.
  • Organizer: The 23rd Korea-Japan Joint Seminar on Pharmacology
  • Int'l Joint Research
• [Presentation] Physiological and Pathological Roles of Inhibitor of Differentiation 4 in the Salivary Gland (2021)
  • Author(s): Kimura S, Kawakubo-Yasukochi T, Hayashi Y, Yano E, Moriyama M, Nakamura S, Jimi E.
  • Organizer: KOB & OBT 5th Joint International Symposium 2021
  • Int'l Joint Research
• [Presentation] 胎内栄養環境に基づく糖脂質代謝制御と オステオカルシンの関与 (2020)
  • Author(s): 安河内（川久保） 友世、溝上顕子、木村 宗惟、中村 誠司、 自見 英治郎、 平田 雅人
  • Organizer: 第62回歯科基礎医学会学術大会
• [Presentation] 脂肪細胞表面受容体GPRC6Aの食事誘発性肥満における役割 (2020)
  • Author(s): 溝上 顕子, 大谷 崇仁, 松田 美穂、安河内（川久保） 友世、竹内 弘, 自見 英治郎, 平田 雅人
  • Organizer: 第62回歯科基礎医学会学術大会
• [Presentation] 口腔扁平上皮癌におけるBP180の発現制御機構 (2020)
  • Author(s): 安河内 篤、安河内（川久保）友世、中村 誠司
  • Organizer: 第62回歯科基礎医学会学術大会
• [Presentation] IgG4関連疾患病態形成における非コードRNAの役割 (2020)
  • Author(s): 木村宗惟、安河内（川久保）友世、中村誠司、自見英治郎
  • Organizer: 第62回歯科基礎医学会学術大会
• [Presentation] miR-200c-3pによる口腔扁平上皮癌の浸潤制御機構 (2019)
  • Author(s): 安河内（川久保）友世、森岡政彦、櫨川舞、西中川拓也、安河内篤、中村誠司、中島学
  • Organizer: 第92回日本薬理学会年会
• [Presentation] 妊娠母体の葉酸不足は仔の皮膚および舌において扁平上皮の発癌感受性を増強させる (2019)
  • Author(s): 安河内（川久保）友世、森岡政彦、安河内篤、櫨川舞、西中川拓也、中村誠司、中島学
  • Organizer: 第92回日本生化学会大会
• [Presentation] The effect of maternal uncarboxylated osteocalcin on the metabolic properties of next generation (2019)
  • Author(s): Kawakubo-Yasukochi T, Kondo A, Mizokami A, Hirata M
  • Organizer: The 11th DOHaD World Congress
  • Int'l Joint Research
• [Presentation] The effect of maternal folic acid deficiency during early pregnancy on the carcinogen sensitivity of offspring in mice (2019)
  • Author(s): Kawakubo-Yasukochi T, Morioka M, Atsushi Yasukochi, Hazekawa M, Nishinakagawa T, Ono K, Nakamura S, Nakashima M
  • Organizer: The 11th DOHaD World Congress
  • Int'l Joint Research