大豆异黄酮调控结肠肿瘤细胞增殖和间质转化的作用机制研究

In recent years, with the changes in the dietary patterns of Chinese people, the incidence of colon cancer which is the representative of "lifestyle cancer" becomes higher and higher. High fat diet induced obesity, exponentially increases the risk of colon cancer. Soy isoflavones (SI) has been found to have significant inhibitory effects on kinds of cancers and the mechanism has also been a hot topic in many researches. However few focuses are put on the relationships between SI and colon cancer.SI has been reported that can suppressed the proliferation and invasion of some cancer cells by reversing the process of epithelial mesenchymal transitions (EMT).Our previous study found that the Lipid Droplets (LD) significantly increased in colon cancer cells treated by Epidermal Growth Factor Receptor（EGFR）, at the same time, the expressive activity of the tumor suppressor protein Forkhead Box O3（FOXO3） was decreased. We also found that SI can potentially inhibit EGFR induced process. Therefore,the effects of SI on the proliferation and EMT of colon cancer will be discussed in this research. Meanwhile, the mechanisms of the SI acting on LD accumulation and its induced cell proliferation will be further explained. This study will be helpful for the scientific and rational use of soybean and its products, and benefit the prevention and control of nutrition-related diseases such as obesity and colon cancer.

随着近几年我国居民膳食结构的转变，以结肠癌为代表的"生活方式癌"发病率越来越高。高脂肪饮食引起肥胖，成倍增加了患结肠癌的风险。大豆异黄酮（Soy isoflavones ,SI）已被发现具有显著的癌症抑制作用，其抑癌机理也一直是人们研究的热点，而关于SI与结肠癌之间关系和调控机制的研究非常有限。已有报道表明SI可通过对某些癌细胞间质转化(EMT)的逆转作用抑制其增殖和转移。我们前期研究发现，细胞表皮生长因子受体（EGFR）可引起结肠癌细胞中脂滴（Lipid Droplets, LD）的聚积和叉形头转录因子蛋白（FOXO3）表达活性的降低，而SI可削弱EGFR的这一作用。基于此，本研究将利用分子营养学手段，探讨SI对结肠癌细胞增殖和间质转化过程的影响，并揭示SI在LD聚集及其诱导的结肠肿瘤增殖过程中的调控机制。本研究将为科学合理的利用大豆制品，预防和控制肥胖及结肠肿瘤等营养相关疾病提供帮助。

结肠癌是一种世界性的恶性肿瘤。近几年我国居民饮食结构的变化，导致结肠癌发病率日益增高。高脂肪饮食引起肥胖，成倍增加了患结肠癌的风险。大豆异黄酮抑制癌症机理一直是人们研究的热点，而关于大豆异黄酮调控结肠癌的作用机理研究相对较少。本项目通过细胞和小鼠模型实验，研究了大豆异黄酮通过抑制脂滴（LDs）积累和间质转化（EMT）过程，影响结肠肿瘤细胞增殖的调控机制。研究结果表明：大豆染料木素（Genistein）可以通过上调E-cadherin蛋白的表达，下调N- cadherin蛋白的表达，同时通过调节slug、zeb1、twist1等基因mRNAs的表达活性，来抑制结肠肿瘤HT-29细胞的EMT过程。另一方面，Genistein通过下调Notch-1、NF-κB 和p-NF-κB等蛋白的表达，并通过上调Bax/Bcl-2, Caspase-8和Caspase-3等蛋白的表达，即通过Notch1/NF-κB/slug/ Cadherin信号通路和Caspase家族蛋白的级联反应，诱导结肠肿瘤细胞的凋亡。同时，通过对这些蛋白表达的调控，进一步抑制EMT活性，形成一个相互关联的分子信号通路。此外，本研究还首次发现大豆染料木素（Genistein）和大豆素（Daidzein）可通过调控LDs积累相关蛋白（包括perilipin-1，ADRP和Vimentin）和基因（包括PPAR-γ、Fas、FABP、GPAT3、MTTP和UCP2等）的表达活性，抑制LDs的积累，从而切断结肠肿瘤细胞的能量来源，抑制其增殖活性；同时通过调控PI3K/AKt/FOXO3a途径相关蛋白的表达，进一步诱导肿瘤细胞的凋亡。本研究揭示了大豆异黄酮抑制结肠癌增殖的新机制，这对于基于大豆异黄酮类物质的结肠癌抑制和治疗类药物开发，以及大豆健康食品的合理加工和科学消费都具有重要的参考价值和推动作用。