並列タイトル等卵巣明細胞腺癌における転写因子HNF-1βはDNA損傷チェックポイント機構の一つであるCHK1タンパクを制御し、抗癌剤耐性を獲得する
タイトル(掲載誌)International journal of gynecological cancer
一般注記type:Thesis
Objective
Appropriate cell cycle checkpoints are essential for the maintenance of normal cells and chemosensitivity of cancer cells. Clear cell adenocarcinoma (CCA) of the ovary is highly resistant to chemotherapy. Hepatocyte nuclear factor-1β (HNF-1β) is known to be overexpressed in CCA, but its role and clinical significance is unclear. We investigated the role of HNF-1β in regulation of the cell cycle in CCA.
Methods
To clarify the effects of HNF-1β on cell cycle checkpoints, we compared the cell cycle distribution and the expression of key proteins involved in CCA cells in which HNF-1β had been stably knocked down and in vector-control cell lines after treatment with bleomycin. HNF-1β (+) cells were arrested in G2 phase because of DNA damage.
Results
HNF-1β (−) cells died because of a checkpoint mechanism. G2 arrest of HNF-1β (+) cells resulted from sustained CHK1 activation, a protein that plays a major role in the checkpoint mechanism. HNF-1β (+) cells were treated with a CHK1 inhibitor after bleomycin treatment. Flow cytometric analysis of the cell cycle demonstrated that DNA damage–induced G2-arrested cells were released from the checkpoint and killed by a CHK1 inhibitor.
Conclusions
The chemoresistance of CCA may be due to aberrant retention of the G2 checkpoint through overexpression of HNF-1β. This is the first study demonstrating cell cycle regulation and chemosensitization by a CHK1 inhibitor in CCA.
博士(医学)・乙第1345号・平成26年12月3日
© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.
identifier:International journal of gynecological cancer Vol.24 No.5 p.838-843
identifier:1048891X
identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/2749
identifier:International journal of gynecological cancer, 24(5): 838-843
関連情報(DOI)10.1097/IGC.0000000000000136
連携機関・データベース国立情報学研究所 : 学術機関リポジトリデータベース(IRDB)(機関リポジトリ)
提供元機関・データベース奈良県立医科大学 : 奈良県立医科大学機関リポジトリ GINMU