GSK-3β mediates the effects of HNF-1β overexpression in ovarian clear cell carcinoma.

• Material Type: 博士論文
• Title: GSK-3β mediates the effects of HNF-1β overexpression in ovarian clear cell carcinoma.
• Author/Editor: Kawahara, Naoki; Mizutani, Ayano; Matsubara, Sho; Takeda, Yoshinori; Kobayashi, Hiroshi
• Author Heading: Kawahara, Naoki; Mizutani, Ayano; Matsubara, Sho; Takeda, Yoshinori; Kobayashi, Hiroshi
• Publication, Distribution, etc.: Spandidos
• Publication Date: 2020-11
• Publication Date (W3CDTF): 2020-11
• Alternative Title: HNF-1β過剰発現を呈する卵巣明細胞癌においてGSK-3βは新たなシグナル伝達経路を介在する
• Periodical title: Experimental and therapeutic medicine
• No. or year of volume/issue: 20 5
• Volume: 20
• Issue: 5
• Pages: Article No.122-
• ISSN (Periodical Title): ISSN : 1792-0981
• Degree grantor/type: 奈良県立医科大学
• Date Granted: 2021-03-15
• Dissertation Number: 甲第785号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: ovarian clear cell carcinoma; glycogen synthase kinase-3β; hepatocyte nuclear factor-1β; nuclear factor-κB
• Target Audience: 一般
• Note (General): type:Thesis; Deubiquitinase USP28 is a target gene of the transcription factor HNF1 homeobox β (HNF-1β), which promotes the survival of ovarian clear cell carcinoma (OCCC) cell lines. However, the pharmacological inhibition of HNF-1β can cause several adverse effects as it is abundantly expressed in numerous organ systems, including the kidney, liver, pancreas and digestive tract. Therefore, small interfering RNA (siRNA) screening was performed in the current study to identify other potential downstream targets of the HNF-1β-mediated pathway. The results revealed that glycogen synthase kinase-3β (GSK-3β) may be a potential downstream target affecting cell viability. To further clarify the effects of GSK-3β, two human OCCC cell lines, TOV-21G (HNF-1β overexpressing line) and ES2 (HNF-1β negative) were transfected with siRNA targeting GSK-3β or control vectors. Loss-of-function studies using RNAi-mediated gene silencing indicated that HNF-1β facilitated GSK-3β expression, resulting in the loss of phosphorylated nuclear factor-κB (p-NFκB) and the reduction of TOV-21G cell proliferation. The cell proliferation assay also revealed that GSK-3β inhibitors rescued the effects of HNF-1β silencing on cell viability in a dose-dependent manner. Furthermore, the GSK-3β inhibitor, AR-A014418, effectively inhibited tumor cell proliferation in a xenograft mouse model. In conclusion and to the best of our knowledge, the current study was the first to determine that GSK-3β is a target gene of HNF-1β. In addition, the results of the present study revealed the novel HNF-1β-GSK-3β-p-NFκB pathway, occurring in response to DNA damage. Targeting this pathway may therefore represent a putative, novel, anticancer strategy in patients with OCCC.; 博士（医学）・甲第785号・令和3年3月15日; Copyright: © Kawaharaet al. This is an open access article distributed under theterms of CreativeCommons Attribution License(https://creativecommons.org/licenses/by-nc-nd/4.0/).; identifier:Experimental and therapeutic medicine Vol.20 No.5 Article No.122 (2020 Nov); identifier:17920981; identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/3909; identifier:Experimental and therapeutic medicine, 20(5): Article No.122
• Access Restrictions: インターネット公開
• Related Material (DOI): 10.3892/etm.2020.9250
• Data Provider (Database): 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）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 奈良県立医科大学 : 奈良県立医科大学機関リポジトリ GINMU

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http://ginmu.naramed-u.ac.jp/dspace/bitstream/10564/3909/1/01%e7%94%b2785%e6%9c%ac%e6%96%87%e3%81%ae%e8%a6%81%e6%97%a8.pdf fulltext

http://ginmu.naramed-u.ac.jp/dspace/bitstream/10564/3909/2/02%e7%94%b2785%e5%af%a9%e6%9f%bb%e8%a6%81%e6%97%a8.pdf fulltext

http://ginmu.naramed-u.ac.jp/dspace/bitstream/10564/3909/3/03%e7%94%b2785%e6%9c%ac%e6%96%87.pdf fulltext