Open Access

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

  • Authors:
    • Naoki Kawahara
    • Ayano Mizutani
    • Sho Matsubara
    • Yoshinori Takeda
    • Hiroshi Kobayashi
  • View Affiliations

  • Published online on: September 21, 2020     https://doi.org/10.3892/etm.2020.9250
  • Article Number: 122
  • Copyright: © Kawahara et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.
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November-2020
Volume 20 Issue 5

Print ISSN: 1792-0981
Online ISSN:1792-1015

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Copy and paste a formatted citation
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Spandidos Publications style
Kawahara N, Mizutani A, Matsubara S, Takeda Y and Kobayashi H: GSK‑3β mediates the effects of HNF‑1β overexpression in ovarian clear cell carcinoma. Exp Ther Med 20: 122, 2020.
APA
Kawahara, N., Mizutani, A., Matsubara, S., Takeda, Y., & Kobayashi, H. (2020). GSK‑3β mediates the effects of HNF‑1β overexpression in ovarian clear cell carcinoma. Experimental and Therapeutic Medicine, 20, 122. https://doi.org/10.3892/etm.2020.9250
MLA
Kawahara, N., Mizutani, A., Matsubara, S., Takeda, Y., Kobayashi, H."GSK‑3β mediates the effects of HNF‑1β overexpression in ovarian clear cell carcinoma". Experimental and Therapeutic Medicine 20.5 (2020): 122.
Chicago
Kawahara, N., Mizutani, A., Matsubara, S., Takeda, Y., Kobayashi, H."GSK‑3β mediates the effects of HNF‑1β overexpression in ovarian clear cell carcinoma". Experimental and Therapeutic Medicine 20, no. 5 (2020): 122. https://doi.org/10.3892/etm.2020.9250