Elucidation of abnormal metabolic profile of endometrial cancer

• Project/Area Number: 19K09796
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Chiba University
• Principal Investigator: Mitsuhashi Akira 千葉大学, 大学院医学研究院, 特任教授 (40302541)
• Co-Investigator(Kenkyū-buntansha): 羽生 裕二 千葉大学, 医学部附属病院, 助教 (40816162) ; 安西 尚彦 千葉大学, 大学院医学研究院, 教授 (70276054)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 子宮体癌 / 肥満 / メトホルミン / インスリン抵抗性 / 癌代謝 / sgRNAスクリーニング / 糖代謝 / 酸化的リン酸化阻害剤

Outline of Research at the Start

多くの腫瘍では、好気条件下にもかかわらず、酸化的リン酸化を抑制し、乳酸生成に向かう糖代謝(解糖系)およびアミノ酸合成を亢進させている。子宮体癌は疫学的に肥満・インスリン抵抗性・耐糖能異常がリスク因子で、発癌・増殖に糖・アミノ酸代謝異常が関与している可能性があるが、明らかではない。
本研究は、子宮体癌培養細胞株に代謝関連遺伝子のsgRNAライブラリーを導入し、in vivoでゲノム編集を用いた機能喪失スクリーニングを行い、子宮体癌の増殖に関連する代謝プロファイル異常を同定する。さらに、メトホルミンや酸化的リン酸化阻害剤との相互作用を明らかにし、癌局所代謝をターゲットにした新たな治療戦略を構築する。

Outline of Final Research Achievements

Metformin, which is a diabetes drug, has shown to inhibit the growth of endometrial cancer. Metformin was included to cultured endometrial cancer cell lines and examined the changes in gene expression using microarrays.　Microarray analysis revealed the increased expressions of GIF, FAM20A, CDRT15, and BACH2 and decreased expressions of SLC12A7, C8orf37-AS1, and ZCCHC1. Although no common cancer metabolism-related genetic alterations were observed, we obtained certain findings on the action of metformin.We examined the loss-of-function using genome editing and did not obtain any results. However, we will continue to examine cancer metabolism abnormalities as they may be involved in endometrial cancer carcinogenesis and proliferation.

Academic Significance and Societal Importance of the Research Achievements

肥満や糖尿病とも関連し子宮体癌が増加傾向にあるが、癌における糖代謝、アミノ酸代謝と増殖の関連性を解明することは子宮体癌の予防戦略に結びつく.
本研究では、残念ながら子宮体癌に関連する代謝異常に対し有意な見解を得ることはできなかったが、糖尿病治療薬メトホルミンの体癌に対する作用が推測された。

Research Products

• [Journal Article] Time-lapse monitoring of fertilized human oocytes focused on the incidence of 0PN embryos in conventional in vitro fertilization cycles. Kobayashi T, Ishikawa H, Ishii K, Sato A, Nakamura N, Saito Y, Hasegawa H, Fujita M, Mitsuhashi A, Shozu M. (2021)
  • Author(s): Kobayashi T, Ishikawa H, Ishii K, Sato A, Nakamura N, Saito Y, Hasegawa H, Fujita M, Mitsuhashi A, Shozu M.
  • Journal Title: Sci Rep. Volume: 11 Issue: 1 Pages: 18862-18862
  • DOI: 10.1038/s41598-021-98312-1
  • Peer Reviewed / Open Access
• [Journal Article] High prevalence of pulmonary embolism prior to cancer therapies in patients with ovarian and endometrial cancers detected by contrast‐enhanced CT using D‐dimer as an index (2021)
  • Author(s): Habu Yuji、Mitsuhashi Akira、Hanawa Shinsuke、Usui Hirokazu、Horikoshi Takuro、Uno Takashi、Shozu Makio
  • Journal Title: Journal of Surgical Oncology Volume: 124 Issue: 1 Pages: 106-114
  • DOI: 10.1002/jso.26471
  • Peer Reviewed
• [Journal Article] Lymphadenectomy issues in endometrial cancer. (2021)
  • Author(s): Konno Y, Asano H, Shikama A, Aoki D, Tanikawa M, Oki A, Horie K, Mitsuhashi A, Kikuchi A, Tokunaga H, Terao Y, Satoh T, Ushijima K, Ishikawa M, Yaegashi N, Watari H.
  • Journal Title: J Gynecol Oncol Volume: 32 Issue: 2
  • DOI: 10.3802/jgo.2021.32.e25
  • Peer Reviewed / Open Access
• [Journal Article] Differential expression of human papillomavirus 16-, 18-, 52-, and 58-derived transcripts in cervical intraepithelial neoplasia (2020)
  • Author(s): Baba S, Taguchi A, Kawata A, Hara K, Eguchi S, Mori M, Adachi K, Mori S, Iwata T, Mitsuhashi A, Maeda D, Komatsu A, Nagamatsu T, Oda K, Kukimoto I, Osuga Y, Fujii T, Kawana K.
  • Journal Title: Virol J Volume: 17 Issue: 1 Pages: 32-32
  • DOI: 10.1186/s12985-020-01306-0
  • NAID: 120007089054
  • Peer Reviewed / Open Access
• [Journal Article] Propensity score-matched analysis of systemic chemotherapy versus salvage hysterectomy for persistent cervical cancer after definitive radiotherapy/concurrent chemoradiotherapy. (2020)
  • Author(s): Takekuma M, Takahashi F, Mabuchi S, Kudaka W, Horie K, Ikeda M, Shikama A, Mitsuhashi A, Nagao S, Suzuki S, Mizuno M, Nishio S, Tokunaga H, Ota Y, Kasamatsu T, Kitagawa R, Toita T, Kobayashi H, Ishikawa M, Yaegashi N.
  • Journal Title: BMC Cancer Volume: 20 Issue: 1 Pages: 1169-1169
  • DOI: 10.1186/s12885-020-07672-w
  • Peer Reviewed / Open Access
• [Journal Article] Medroxyprogesterone acetate plus metformin for fertility-sparing treatment of atypical endometrial hyperplasia and endometrial carcinoma: trial protocol for a prospective, randomised, open, blinded-endpoint design, dose-response trial (FELICIA trial) (2020)
  • Author(s): Mitsuhashi Akira、Kawasaki Yohei、Hori Makoto、Fujiwara Tadami、Hanaoka Hideki、Shozu Makio
  • Journal Title: BMJ Open Volume: 10 Issue: 2 Pages: e035416-e035416
  • DOI: 10.1136/bmjopen-2019-035416
  • Peer Reviewed / Open Access
• [Journal Article] New therapeutic approaches for the fertility-sparing treatment of endometrial cancer (2020)
  • Author(s): Mitsuhashi Akira、Shozu Makio
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 46 Issue: 2 Pages: 215-222
  • DOI: 10.1111/jog.14155
  • Peer Reviewed
• [Journal Article] Development of localized cul-de-sac endometrioid carcinoma associated with deep infiltrating endometriosis during remission of early endometrial cancer (2020)
  • Author(s): Seki Kumiko、Ishikawa Hiroshi、Hashimoto Rei、Mitsuhashi Akira、Ikeda Jun-ichiro、Shozu Makio
  • Journal Title: Gynecologic Oncology Reports Volume: 31 Pages: 100526-100526
  • DOI: 10.1016/j.gore.2019.100526
  • Peer Reviewed
• [Journal Article] Long-term outcomes of progestin plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer patients (2019)
  • Author(s): Mitsuhashi Akira、Habu Yuji、Kobayashi Tatsuya、Kawarai Yoshimasa、Ishikawa Hiroshi、Usui Hirokazu、Shozu Makio
  • Journal Title: Journal of Gynecologic Oncology Volume: 30 Issue: 6 Pages: 1-11
  • DOI: 10.3802/jgo.2019.30.e90
  • Peer Reviewed / Open Access
• [Presentation] Metformin may attenuate the effect of hyperprolactinemia induced by medroxyprogesterone acetate during fertility-sparing treatment for patients with atypical endometrial hyperplasia and endometrial cancer (2019)
  • Author(s): Mitsuhashi A, Gu W, Habu Y, Kobayashi T, Shozu M.
  • Organizer: ESGO 2019
  • Int'l Joint Research