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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 / Copyright

    Affiliations: Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara 634‑8522, Japan
    Copyright: © Kawahara et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 122
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    Published online on: September 21, 2020
       https://doi.org/10.3892/etm.2020.9250
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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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1 

Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F (eds): GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. IARC CancerBase No. 11. International Agency for Research on Cancer, Lyon, 2013.

2 

Tsuchiya A, Sakamoto M, Yasuda J, Chuma M, Ohta T, Ohki M, Yasugi T, Taketani Y and Hirohashi S: Expression profiling in ovarian clear cell carcinoma: Identification of hepatocyte nuclear factor-1 beta as a molecular marker and a possible molecular target for therapy of ovarian clear cell carcinoma. Am J Pathol. 163:2503–2512. 2003.PubMed/NCBI View Article : Google Scholar

3 

Shigetomi H, Sudo T, Shimada K, Uekuri C, Tsuji Y, Kanayama S, Naruse K, Yamada Y, Konishi N and Kobayashi H: Inhibition of cell death and induction of G2 arrest accumulation in human ovarian clear cells by HNF-1β transcription factor: Chemosensitivity is regulated by checkpoint kinase CHK1. Int J Gynecol Cancer. 24:838–843. 2014.PubMed/NCBI View Article : Google Scholar

4 

Ito F, Yoshimoto C, Yamada Y, Sudo T and Kobayashi H: The HNF-1β-USP28-Claspin pathway upregulates DNA damage-induced Chk1 activation in ovarian clear cell carcinoma. Oncotarget. 9:17512–17522. 2018.PubMed/NCBI View Article : Google Scholar

5 

Senkel S, Lucas B, Klein-Hitpass L and Ryffel GU: Identification of target genes of the transcription factor HNF1beta and HNF1alpha in a human embryonic kidney cell line. Biochim Biophys Acta. 1731:179–190. 2005.PubMed/NCBI View Article : Google Scholar

6 

Tanaka T, Tomaru Y, Nomura Y, Miura H, Suzuki M and Hayashizaki Y: Comprehensive search for HNF-1beta-regulated genes in mouse hepatoma cells perturbed by transcription regulatory factor-targeted RNAi. Nucleic Acids Res. 32:2740–2750. 2004.PubMed/NCBI View Article : Google Scholar

7 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real time quantitative PCR and the 2 (Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar

8 

Johnston ST, Shah ET, Chopin LK, Sean McElwain DL and Simpson MJ: Estimating cell diffusivity and cell proliferation rate by interpreting IncuCyte ZOOM™ assay data using the Fisher-Kolmogorov model. BMC Syst Biol. 9(38)2015.PubMed/NCBI View Article : Google Scholar

9 

Wilson W III and Baldwin AS: Maintenance of constitutive IkappaB kinase activity by glycogen synthase kinase-3α/β in pancreatic cancer. Cancer Res. 68:8156–8163. 2008.PubMed/NCBI View Article : Google Scholar

10 

Ougolkov AV, Fernandez-Zapico ME, Savoy DN, Urrutia RA and Billadeau DD: Glycogen synthase kinase-3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells. Cancer Res. 65:2076–2081. 2005.PubMed/NCBI View Article : Google Scholar

11 

Kajihara H, Yamada Y, Kanayama S, Furukawa N, Noguchi T, Haruta S, Yoshida S, Sado T, Oi H and Kobayashi H: Clear cell carcinoma of the ovary: Potential pathogenic mechanisms (Review). Oncol Rep. 23:1193–1203. 2010.PubMed/NCBI View Article : Google Scholar

12 

Yamaguchi K, Mandai M, Toyokuni S, Hamanishi J, Higuchi T, Takakura K and Fujii S: Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress. Clin Cancer Res. 14:32–40. 2008.PubMed/NCBI View Article : Google Scholar

13 

Niiro E, Kawahara N, Yamada Y, Yoshimoto C, Shimada K, Sudo T and Kobayashi H: Immunohistochemical expression of CD44v9 and 8-OHdG in ovarian endometrioma and the benign endometriotic lesions adjacent to clear cell carcinoma. J Obstet Gynaecol Res. 45:2260–2266, Epub ahead of print. 2019.PubMed/NCBI View Article : Google Scholar

14 

Yamada Y, Shigetomi H, Onogi A, Haruta S, Kawaguchi R, Yoshida S, Furukawa N, Nagai A, Tanase Y, Tsunemi T, et al: Redox-active iron-induced oxidative stress in the pathogenesis of clear cell carcinoma of the ovary. Int J Gynecol Cancer. 21:1200–1207. 2011.PubMed/NCBI View Article : Google Scholar

15 

Shigetomi H, Higashiura Y, Kajihara H and Kobayashi H: A potential link of oxidative stress and cell cycle regulation for development of endometriosis. Gynecol Endocrinol. 28:897–902. 2012.PubMed/NCBI View Article : Google Scholar

16 

Schmidt KN, Amstad P, Cerutti P and Baeuerle PA: The roles of hydrogen peroxide and superoxide as messengers in the activation of transcription factor NF-κ B. Chem Biol. 2:13–22. 1995.PubMed/NCBI View Article : Google Scholar

17 

Zhang Y, Huang N, Yan F, Jin H, Zhou S, Shi J and Jin F: Diabetes mellitus and Alzheimer's disease: GSK-3β as a potential link. Behav Brain Res. 339:57–65. 2018.PubMed/NCBI View Article : Google Scholar

18 

Llorens-Martín M, Jurado J, Hernández F and Avila J: GSK-3β, a pivotal kinase in Alzheimer disease. Front Mol Neurosci. 7(46)2014.PubMed/NCBI View Article : Google Scholar

19 

Llorens-Martín M, Blazquez-Llorca L, Benavides-Piccione R, Rabano A, Hernandez F, Avila J and DeFelipe J: Selective alterations of neurons and circuits related to early memory loss in Alzheimer's disease. Front Neuroanat. 8(38)2014.PubMed/NCBI View Article : Google Scholar

20 

Llorens-Martín M, Fuster-Matanzo A, Teixeira CM, Jurado-Arjona J, Ulloa F, Defelipe J, Rábano A, Hernández F, Soriano E and Avila J: Alzheimer disease-like cellular phenotype of newborn granule neurons can be reversed in GSK-3β-overexpressing mice. Mol Psychiatry. 18:395–95. 2013.PubMed/NCBI View Article : Google Scholar

21 

Llorens-Martín M, Fuster-Matanzo A, Teixeira CM, Jurado-Arjona J, Ulloa F, Defelipe J, Rábano A, Hernández F, Soriano E and Avila J: GSK-3β overexpression causes reversible alterations on postsynaptic densities and dendritic morphology of hippocampal granule neurons in vivo. Mol Psychiatry. 18:451–460. 2013.PubMed/NCBI View Article : Google Scholar

22 

Lim NK, Hung LW, Pang TY, Mclean CA, Liddell JR, Hilton JB, Li QX, White AR, Hannan AJ and Crouch PJ: Localized changes to glycogen synthase kinase-3 and collapsin response mediator protein-2 in the Huntington's disease affected brain. Hum Mol Genet. 23:4051–4063. 2014.PubMed/NCBI View Article : Google Scholar

23 

Gray JE, Infante JR, Brail LH, Simon GR, Cooksey JF, Jones SF, Farrington DL, Yeo A, Jackson KA, Chow KH, et al: A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin. Invest New Drugs. 33:1187–1196. 2015.PubMed/NCBI View Article : Google Scholar

24 

Rizzieri DA, Cooley S, Odenike O, Moonan L, Chow KH, Jackson K, Wang X, Brail L and Borthakur G: An open-label phase 2 study of glycogen synthase kinase-3 inhibitor LY2090314 in patients with acute leukemia. Leuk Lymphoma. 57:1800–1806. 2016.PubMed/NCBI View Article : Google Scholar

25 

Wang Z, Smith KS, Murphy M, Piloto O, Somervaille TC and Cleary ML: Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy. Nature. 455:1205–1209. 2008.PubMed/NCBI View Article : Google Scholar

26 

Suzuki E, Kajita S, Takahashi H, Matsumoto T, Tsuruta T and Saegusa M: Transcriptional upregulation of HNF-1β by NF-κB in ovarian clear cell carcinoma modulates susceptibility to apoptosis through alteration in bcl-2 expression. Lab Invest. 95:962–972. 2015.PubMed/NCBI View Article : Google Scholar

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Copy and paste a formatted citation
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
Copy and paste a formatted citation
x
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
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