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 

作者机构：Key Laboratory of Molecular Oncology and EpigeneticsThe First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016PR China Department of Respiratory and Critical Care MedicineThe First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016PR China Department of Urinary SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016PR China Department of OncologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016PR China Ph.D Research Center for Medical and Social DevelopmentChongqing Medical UniversityChongqing 400016PR China Department of PsychiatryThe First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016PR China 

出 版 物：《Genes & Diseases》 (基因与疾病（英文）)

年 卷 期：2022年第9卷第4期

页      面：1024-1037页

核心收录：

学科分类：0710[理学-生物学] 0831[工学-生物医学工程（可授工学、理学、医学学位）] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100214[医学-肿瘤学] 0703[理学-化学] 10[医学] 

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. 

主　　题：Cancer Chronic unpredictability mild stress CpG methylation Depressi on 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 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.