Investigation of the effect of squalene synthesis pathway on peritoneal dissemination and cancer stem cell trait in epithelial ovarian cancer

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K22978
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0906:Surgery related to the biological and sensory functions and related fields
• Research Institution: Osaka University
• Principal Investigator: Nakae Aya 大阪大学, 医学系研究科, 招へい教員 (60880961)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: 卵巣癌 / 脱ユビキチン化酵素 / ライブラリースクリーニング / スクアレン合成経路 / がん幹細胞

Outline of Final Research Achievements

In vitro and in vivo experiments using human ovarian cancer cell lines showed that USP32 altered significantly cell proliferation capacity, epithelial mesenchymal transition capacity, and especially sphere formation capacity. To catalog the substrates which were targeted by deubiquitinating enzyme USP32, immunoprecipitation-mass spectrometry experiment was conducted. Among the candidates of substrate proteins, we focused on FDFT1, a squalene synthase in the mevalonic acid pathway, which is important for cholesterol biosynthesis. USP32 and FDFT1 expression was high in ovarian cancer spheres. Sphere formation was significantly inhibited by USP32, FDFT1 suppression, FDFT1 inhibitor, and bisphosphonates that inhibit the mevalonic acid pathway, and restored by squalene. Acquisition of sphere-forming potential is essential in the course of peritoneal dissemination of ovarian cancer, suggesting that USP32 and FDFT1 are new therapeutic targets for peritoneal dissemination of ovarian cancer.

Free Research Field

卵巣癌、ユビキチンプロテアソームシステム

Academic Significance and Societal Importance of the Research Achievements

卵巣癌は婦人科悪性腫瘍の中で死亡者数が最も多く、特に腹膜播種を伴うⅢ期以上の進行期症例の予後は不良である。昨今、殺細胞性抗癌剤に替わる選択肢として血管新生阻害剤やPARP阻害剤が導入され予後改善に寄与している。しかし、血管新生阻害剤は腹膜播種を有する患者では腸管穿孔のリスクから使用困難な場合があり、様々な殺細胞性抗癌剤との併用でも無増悪生存期間が3-4ヶ月程度延長するのみである。PARP阻害剤は上皮性卵巣癌の治療においてプラチナ感受性が有効性の主なバイオマーカーであり、複数レジメン終了後のプラチナ抵抗性再発卵巣癌は治療対象とならず、腹膜播種病変を制御しうる新たな治療標的の発見が尚望まれている。