Depression And Stress Levels Increase Risk Of Liver Cancer Through Epigenetic Downregulation Of Hypocretin

OBJECTS: Recent studies suggest that Hypocretin(HCRT,Orexin)are involved in stress regulation of depression through the hypothalamicpituitary-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.METHODS: In the study,male Sprague Dawley(SD)rats were selected to establish an animal model of cancer with dpression.Depression-like behaviors were induced by chronic unpredictability mild stress(CUMS),N-nitrosodiethylamine(DEN)was used to induce Hepatocellular carcinoma(HCC).Firstly,RNA-Sequencing was used to detect differentially expressed genes(DEGs)in hippocampus and liver tissues of rats,analyzing enrichment functions and signal pathways of DEGs.Secondly,q RT-PCR was used to determined the expression of HCRT mRNA in hippocampus and liver tissues of rats to validated the result of RNA-Seq.Meanwhile,clinical depression cases and whole blood samples were collected to measure HCRT mRNA expression for clinical verification.Lastly,the status of HCRT promoter methylation in samples of rats and clinical subjects were assayed by MSP.RESULTS: Behavioral tests showed that the 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 those in rats without CUMS.RNA-Seq revealed that the HCRT was differentially expressed in comparison of hippocampus in depression vs.control rats,and it was a down-regulated gene.Moreover,the signaling pathways enriched by these DEGs include long-term depression.Signaling pathways such as inflammation-mediated regulation of TRP channels and Renin secretion were found to be significantly enriched in comparison of HCC vs.HCC with depression DEGs.q RT-PCR validation results showed that HCRT mRNA expression was downregulated in depressed tissue samples,consistented with RNA-Seq results.In addition,HCRT mRNA expression was also down-regulated in liver cancer tissue,and was further more decreased in that with depression.Importantly,a higher level of promoter methylation was found in samples of depressive tissues in rats and clinical cases.CONCLUSION: 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.