基于ADRB2-Hh/Gli1-Par3通路探讨抑郁促进结肠癌进展的机制研究及和厚朴酚的干预作用

研究发现，抑郁等中枢神经系统功能紊乱因素可经脑-肠轴调控肠道粘膜微环境进而促进结肠癌的进展，但其作用机制尚不明确。我们在前期研究中对抑郁模型小鼠结肠粘膜组织进行iTRAQ蛋白质组学分析，发现β2肾上腺素能受体（ADRB2）信号异常激活，而Gli1是差异表达蛋白互作网络的关键因子，并受ADRB2信号调控。Hh/Gli1通路可通过负向调控Par3增强结肠癌的增殖及转移能力；和厚朴酚是一种兼具抗抑郁抗肿瘤的中药活性成分，可降低抑郁模型小鼠结肠粘膜组织ADRB2表达并抑制结肠癌的发展，但其分子机制尚不明确。因此，我们设想，和厚朴酚可通过ADRB2-Hh/Gli1-Par3通路抑制抑郁相关性结肠癌的进展；本项目以抑郁模型小鼠、APCmin/+小鼠及结肠癌细胞系为研究对象，通过体内外实验，阐明抑郁等中枢神经功能紊乱因素促进结肠癌进展的具体机制及和厚朴酚的抑癌作用机制，为结肠癌的中药治疗提供新的理论依据

It has been found that depression and other central nervous system dysfunction factors can regulate intestinal mucosal microenvironment via the brain-gut axis and promote the progression of colon cancer, but the mechanism remains unclear.In our previous study, iTRAQ proteomics analysis was performed on colonic mucosal tissues of depressed mice, and we found that β2 adrenergic receptor (ADRB2) signaling was abnormally activated. Gli1 is a key factor in the differentially expressed protein interaction network and is regulated by ADRB2 signaling.Hh/Gli1 pathway can promote the proliferation and metastasis of colon cancer through negatively regulating the expression of Par3. Honokiol is both anti-depression and anti-tumor active components of Traditional Chinese medicine, which can reduce the expression of ADRB2 in colon mucosa and inhibit the development of colon cancer in depressed mice. However, the molecular mechanism of this activity remains unclear.Therefore, we hypothesized that honokiol inhibits the progression of depression-associated colon cancer through the ADRB2-Hh/gli1-Par3 pathway.In this study, depression model mice, APCmin/+ mice and colon cancer cell lines were used as research objects. In vitro and in vivo experiments were conducted to clarify the specific mechanism of depression and other central nervous system dysfunction factors promoting the progression of colon cancer and the mechanism of the inhibitory effect of honokiol, so as to provide a new theoretical basis for the treatment of colon cancer with Traditional Chinese medicine.