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

作　　者：Chunyun Pu Shaorong Tian Sanxiu He Weihong Chen Yuanyuan He Hongyan Ren Jing Zhu Jun Tang Xiaolan Huang Ying Xiang Yixiao Fu Tingxiu Xiang 

机构地区：[1]Key Laboratory of Molecular Oncology and Epigenetics,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,PR China [2]Department of Respiratory and Critical Care Medicine,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,PR China [3]Department of Urinary Surgery,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,PR China [4]Department of Oncology,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,PR China [5]Ph.D Research Center for Medical and Social Development,Chongqing Medical University,Chongqing 400016,PR China [6]Department of Psychiatry,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,PR China

出　　处：《Genes & Diseases》2022年第4期1024-1037,共14页基因与疾病（英文）

基　　金：The study was supported by the National Natural Science Foundation of China (NSFC) (No.#81872380);the Opening Foundation of Chongqing Key Laboratory of Molecular Oncology and Epigenetics.

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 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.

关 键 词：Cancer Chronic unpredictability mild stress CpG methylation Depressi on HYPOCRETIN 

分 类 号：R730[医药卫生—肿瘤]