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Full Length Article | Open Access

Depression and stress levels increase risk of liver cancer through epigenetic downregulation of hypocretin

Chunyun Pua,1, Shaorong Tiana,1, Sanxiu Hea, Weihong Chena, Yuanyuan Heb, Hongyan Renc, Jing Zhud, Jun Tanga, Xiaolan Huange, Ying Xianga, Yixiao Fuf, Tingxiu Xianga( )
Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China
Department of Urinary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China
Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China
Ph.D Research Center for Medical and Social Development, Chongqing Medical University, Chongqing 400016, PR China
Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China

Peer review under responsibility of Chongqing Medical University.

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Abstract

Recent studies suggest that Hypocretin (HCRT, Orexin) are involved in stress regulation of depression through the hypothalamic-pituitary-adrenal (HPA) axis. However, the molecular mechanism by which Hypocretin regulate neurobiological responses is unknown. Herein, the effects of chronic stress on the epigenetic modification of HCRT and its association with depression were explored with regard to a potential role in cancer progression. In the study, Sprague Dawley (SD) rats were used to establish an animal model of cancer with depression by administrating n-nitrosodiethylamine (DEN) and chronic unpredictable mild stress (CUMS). RNA-sequencing was used to detect differentially expressed genes in the hippocampus of rats and quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the results of RNA-sequencing. The status of HCRT promoter methylation was assessed by methylation specific polymerase chain reaction. Behavioral tests showed that rats exposed to CUMS had significant depressive-like behaviors. The number of liver tumors and tumor load in depressed rats exposed to CUMS was higher than in SD rats without CUMS. RNA-sequencing revealed that HCRT was one of the most siginificantly downregulated gene in the hippocampus of SD rats with CUMS compared to non-stressed group, which was validated by qRT-PCR. HCRT mRNA expression was downregulated and the promoter for HCRT was hyper-methylated in those with depression. These results identified a critical role for chronic psychological stressors in tumorigenesis and cancer progression, via epigenetic HCRT downregulation. Such epigenetic downregulation may be the molecular basis for the association of cancer with depression.

Keywords

DepressionCancerChronic unpredictability mild stressCpG methylationHypocretin

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Genes & Diseases
Volume 9 Issue 4,
July 2022
Pages 1024-1037
DOI: 10.1016/j.gendis.2020.11.013
Cite this article:
Pu C, Tian S, He S, et al. Depression and stress levels increase risk of liver cancer through epigenetic downregulation of hypocretin. Genes & Diseases, 2022, 9(4): 1024-1037. https://doi.org/10.1016/j.gendis.2020.11.013

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Received: 25 August 2020
Accepted: 24 November 2020
Published: 02 December 2020
© 2020, Chongqing Medical University.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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