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

作者全名："Pu, Chunyun; Tian, Shaorong; He, Sanxiu; Chen, Weihong; He, Yuanyuan; Ren, Hongyan; Zhu, Jing; Tang, Jun; Huang, Xiaolan; Xiang, Ying; Fu, Yixiao; Xiang, Tingxiu"

作者地址："[Pu, Chunyun; Tian, Shaorong; He, Sanxiu; Chen, Weihong; Tang, Jun; Xiang, Ying; Xiang, Tingxiu] Chongqing Med Univ, Key Lab Mol Oncol & Epigenet, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [He, Yuanyuan] Chongqing Med Univ, Dept Resp & Crit Care Med, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Ren, Hongyan] Chongqing Med Univ, Dept Urinary Surg, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Zhu, Jing] Chongqing Med Univ, Dept Oncol, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Huang, Xiaolan] Chongqing Med Univ, PhD Res Ctr Med & Social Dev, Chongqing 400016, Peoples R China; [Fu, Yixiao] Chongqing Med Univ, Dept Psychiat, Affiliated Hosp 1, Chongqing 400016, Peoples R China"

通信作者："Xiang, TX (通讯作者)，Chongqing Med Univ, Key Lab Mol Oncol & Epigenet, Affiliated Hosp 1, Chongqing 400016, Peoples R China."

来源：GENES & DISEASES

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000811818600019

JCR分区：Q1

影响因子：6.8

年份：2022

卷号：9

期号：4

开始页：1024

结束页：1037

文献类型：Article

关键词：Cancer; Chronic unpredictability mild stress; CpG methylation; Depression; Hypocretin

摘要："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 depressi on 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. Copyright 2020, Chongqing Medical University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/)."

基金机构：National Natural Science Foundation of China (NSFC) [81872380]; Opening Foundation of Chongqing Key Laboratory of Mo-lecular Oncology and Epigenetics

基金资助正文：The study was supported by the National Natural Science Foundation of China (NSFC) (No.#81872380) ; and the Opening Foundation of Chongqing Key Laboratory of Mo-lecular Oncology and Epigenetics.