Dexamethasone inhibits stemness maintenance and enhances chemosensitivity of hepatocellular carcinoma stem cells by inducing deSUMOylation of HIF‑1α and Oct4

Jiang,Zhongmin; Zhang,Chunyan; Liu,Xiaozhi; Ma,Xiaofang; Bian,Xiyun; Xiao,Xiaolin; Gao,Rui; Sun,Yajing; Wu,Wenhan; Zhao,Po

doi:10.3892/ijo.2020.5097

Dexamethasone inhibits stemness maintenance and enhances chemosensitivity of hepatocellular carcinoma stem cells by inducing deSUMOylation of HIF‑1α and Oct4

Authors:
- Zhongmin Jiang
- Chunyan Zhang
- Xiaozhi Liu
- Xiaofang Ma
- Xiyun Bian
- Xiaolin Xiao
- Rui Gao
- Yajing Sun
- Wenhan Wu
- Po Zhao
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Affiliations: Department of Pathology, Chinese People's Liberation Army (PLA) General Hospital, Beijing 100853, P.R. China, Department of Pharmacy, Binhai New Area Hospital of Traditional Chinese Medicine, Tianjin 300450, P.R. China, Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm Infants, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China, Department of Pathology, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China, Department of Pathology, Chinese People's Liberation Army (PLA) General Hospital, Beijing 100853, P.R. China
Published online on: July 8, 2020 https://doi.org/10.3892/ijo.2020.5097
Pages: 780-790
Copyright: © Jiang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

It has been controversial whether patients with hepatocellular carcinoma (HCC) should receive glucocorticoid therapy during chemotherapy. Recent studies have demonstrated that glucocorticoids increase the therapeutic sensitivity of tumors to some chemotherapeutic drugs, but the specific mechanism remains unclear. In the present study, dexamethasone (Dex) was used to treat HCC stem cells. The results demonstrated that Dex reduced stemness maintenance and self‑renewal of HCC stem cells, promoted epithelial‑to‑mesenchymal transition, inhibited migration and angiogenesis and, more importantly, increased cell sensitivity to the herpes simplex virus thymidine kinase/ganciclovir drug system in vitro and in vivo. Further mechanistic analyses demonstrated that Dex inhibited small ubiquitin‑like modifier (SUMO) modification of several proteins in HCC stem cells, including hypoxia‑inducible factor (HIF)‑1α, an important hypoxia tolerance protein, and octamer‑binding transcription factor 4 (Oct4), a crucial stemness maintenance protein. Inducing deSUMOylation of HIF‑1α and Oct4 reduced their accumulation in the nucleus, thereby inhibiting tumor angiogenesis and stemness maintenance. These findings provide a new perspective to the study of the mechanism underlying the anti‑hepatocarcinogenesis effects of Dex. Due to the few side effects of glucocorticoids at low doses and their anti‑inflammatory effects, the appropriate combination of glucocorticoids and chemotherapeutic drugs is expected to improve the survival of HCC patients and their prognosis.

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