抑郁经脑肠轴激活β2-AR-eEF2/eEF2K-MYH9通路促进结直肠癌进展的机制研究

Studies have confirmed that central nervous system disorders such as depression could promote the progression of colorectal cancer (CRC). Central nervous system could regulate the colon microenvironment via brain-gut axis. However, the specific mechanism of brain-gut axis regulating the progress of CRC remains unclear. Recently, we have found that β2-adrenergic receptor (β2-AR) signaling pathway was activated in the iTRAQ proteomics which was conducted in the intestinal tissue of depressed mice model. And eEF2, which could be regulated by the β2-AR signaling pathway, is the key gene in the interaction network of differentially expressed proteins. eEF2/eEF2K could regulate the progression of CRC by promoting MYH9. Thus, we proposed that depression could promote CRC progression through the β2-AR-eEF2/eEF2K-MYH9 pathway. In order to verify our hypothesis, depression mice model, APCmin/+ mice and CRC cell lines will be utilized in this study. Denervation, blocking of adrenergic signal, western blot and many other techniques will be used to clarify the specific mechanism of central nervous system disorders promoting CRC progression, and a novel theoretical basis for the treatment of CRC will be proposed.

研究证实，抑郁等中枢神经系统不良因素可促进结直肠癌（CRC）的进展。中枢神经系统主要通过脑肠轴调控肠道微环境的变化，而脑肠轴在调控CRC进展中的具体机制尚不明确。申请人在前期研究中对抑郁模型小鼠肠道组织行iTRAQ蛋白质组分析，发现β2-肾上腺素受体（β2-AR）信号通路受到激活，此外受β2-AR信号通路调控的eEF2是差异表达蛋白互作网络的关键基因。eEF2/eEF2K可通过MYH9影响CRC的进展。由此，我们提出抑郁可通过β2-AR-eEF2/eEF2K-MYH9这一通路促进CRC的进展。为验证以上假设，我们将以抑郁模型小鼠、APCmin/+小鼠及结肠癌细胞系为研究对象，采用神经离断、信号阻滞、western blot等多种实验技术，阐明抑郁等中枢神经不良因素促进CRC进展的具体机制，为CRC的治疗提供新的理论依据。

抑郁、压力等中枢神经系统不良因素可通过脑肠轴通路调控结直肠癌（CRC）的进展，其具体机制可为CRC的治疗提供新的理论依据。为探究脑肠轴通路调控CRC的具体机制，我们首先通过对抑郁模型小鼠以AOM+DSS构建CRC模型，在抑郁模型小鼠血清中检测肾上腺相关激素的水平，初步确定肾上腺素是脑肠轴通路的关键作用因子。继而通过裸鼠成瘤、肺转移模型及APCmin/+小鼠模型确定肾上腺素对CRC的促进作用。为研究肾上腺素促进CRC的具体机制，我们利用CRC细胞系，经肾上腺素刺激后，研究其生物学行为。我们发现肾上腺素可促进CRC细胞的增殖、迁移、耐药及干细胞成球，并降低其凋亡。继而我们通过转录组测序及蛋白组学分析，探索肾上腺素促进CRC的分子机制，证实肾上腺素可通过TRIM21降低eEF2K的表达，促进CRC的自噬，且肾上腺素可通过TRIM2影响P53的稳定性，促进CRC的EMT和干性。