Depression and stress levels increase risk of liver cancer through epigenetic downregulation of hypocretin.
Depression and stress levels increase risk of liver cancer through epigenetic downregulation of hypocretin.
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抑郁和压力水平通过下丘脑分泌素的表观遗传下调增加患肝癌的风险
DOI：
10.1016/j.gendis.2020.11.013
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发表时间：
2022-07
期刊：
影响因子：
6.8
通讯作者：
Xiang, Tingxiu
中科院分区：
文献类型：
--
作者：
Pu, Chunyun;Tian, Shaorong;He, Sanxiu;Chen, Weihong;He, Yuanyuan;Ren, Hongyan;Zhu, Jing;Tang, Jun;Huang, Xiaolan;Xiang, Ying;Fu, Yixiao;Xiang, Tingxiu
最近的研究表明，下丘脑分泌素（HCRT, Orexin）通过下丘脑-垂体-肾上腺（HPA）轴参与抑郁症的应激调节。然而，下丘脑泌素调节神经生物学反应的分子机制尚不清楚。本文探讨了慢性应激对HCRT表观遗传修饰的影响及其与抑郁症的关系，以及其在癌症进展中的潜在作用。本研究采用SD大鼠（Sprague Dawley， SD）给药n-亚硝基二乙胺（DEN）和慢性不可预测轻度应激（CUMS），建立癌症伴抑郁动物模型。采用rna测序法检测大鼠海马区差异表达基因，采用实时定量聚合酶链反应（qRT-PCR）对rna测序结果进行验证。通过甲基化特异性聚合酶链反应评估HCRT启动子甲基化状态。行为测试表明，暴露于CUMS的大鼠有明显的抑郁样行为。暴露于CUMS的抑郁大鼠的肝脏肿瘤数量和肿瘤负荷高于未暴露于CUMS的SD大鼠。rna测序结果显示，与非应激组相比，HCRT是CUMS SD大鼠海马中下调最显著的基因之一，qRT-PCR证实了这一点。抑郁症患者HCRT mRNA表达下调，HCRT启动子超甲基化。这些结果确定了慢性心理压力源在肿瘤发生和癌症进展中的关键作用，通过表观遗传HCRT下调。这种表观遗传下调可能是癌症与抑郁症关联的分子基础。
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.
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影响因子：
5.3
作者：
Cattaneo A;Macchi F;Plazzotta G;Veronica B;Bocchio-Chiavetto L;Riva MA;Pariante CM
通讯作者：
Pariante CM
影响因子：
4.8
作者：
Irie, M;Miyata, M;Kasai, H
通讯作者：
Kasai, H
影响因子：
82.9
作者：
Johnson, Philip L.;Truitt, William;Fitz, Stephanie D.;Minick, Pamela E.;Dietrich, Amy;Sanghani, Sonal;Traskman-Bendz, Lil;Goddard, Andrew W.;Brundin, Lena;Shekhar, Anantha
通讯作者：
Shekhar, Anantha
影响因子：
3.4
作者：
Grafe LA;Eacret D;Dobkin J;Bhatnagar S
通讯作者：
Bhatnagar S
影响因子：
3
作者：
Abbas MG;Shoji H;Soya S;Hondo M;Miyakawa T;Sakurai T
通讯作者：
Sakurai T