Establishment of in vitro carcinogenesis model of ovarian low-grade serous carcinoma

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K09229
• 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: Shimane University
• Principal Investigator: Kentaro Nakayama 島根大学, 学術研究院医学・看護学系, 准教授 (70346401)
• Co-Investigator(Kenkyū-buntansha): 京 哲 島根大学, 学術研究院医学・看護学系, 教授 (50272969)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 卵巣癌 / 発癌 / 低異型度 / 漿液性癌 / がん遺伝子

Outline of Final Research Achievements

Serous cystadenoma epithelial cells have been proposed to be the derivation of low grade serous ovarian carcinoma. Whereas several genetic diversifications are known to be involved in development of LGSC, but the fundamental requirements are unclear. We aimed to bracelet oncogenic mutations that responsible for LGSC development in a stepwise model, by using immortalized serous cystadenoma (SCA) epithelial cells. SCA were isolated from clinical sample and immortalized by overexpression of cyclin D1, CDK4R24C and hTERT. Transformed SCA epithelial cells with KRAS MT and PIK3CA MT, formed tumors into nude mouse that were grossly, histologically, and immunohistochemically analogous to human tumor. Thus, KRAS MT and PIK3CA MT were classified as the basal obligation for LGSC development. Current in vitro carcinogenesis model suggested that KRAS MT and PIK3CA MT is responsible for micropapillary stages of LGSC development.

Free Research Field

婦人科悪性腫瘍

Academic Significance and Societal Importance of the Research Achievements

卵巣低異型度漿液性癌は卵巣漿液性嚢胞腺腫を発生起源とする仮説があるがその詳細は不明である。卵巣漿液性嚢胞腺腫の不死化細胞を樹立し、in vitro発癌モデルを構築し、卵巣低異型度漿液性癌の発癌分子機構を明らかにすることを目的とした。HOVcyst1(不死化卵巣漿液性嚢胞腺腫細胞)への変異型PIK3CAおよび変異型KRAS の遺伝子導入により卵巣低異型度漿液性癌のin vitro発癌モデル構築に成功した。卵巣低異型度漿液性癌の発癌経路としてPIK3CA/AKT/mTORおよびKRAS/BRAF/ERK経路の双方の活性化が必要であることが示唆された。