瑞香狼毒黄酮类活性成分通过调节TGF-beta-Smad2/3通路抑制肿瘤侵袭转移的功能及分子机制研究

Cancer invasion and metastasis represents the major problem in cancer treatment clinically and experimentally.It is also a crucial determinant for the survival of cancer patients.Through recent studies, it is widely accepted that TGF-beta-Smad2/3 signal pathway plays key role in the regulation of Epithelial-Mesenchymal Transition(EMT) and metastasis procedures. However, the research and development of new drugs targeting cancer metastasis has attracted little attention. It has long been recorded that Stellera chamaejasme L. can been used for anti-cancer treatment in the history of chinese medicine. However，its clinical application is largely limited due to its high cytotoxicity against normal cells.Our previous study has clearly identified the anti-tumor effects for the extracts from Stellera chamaejasme L.(ESC) in various kinds of tumor types. Interestingly, low-dose Stellera chamaejasme L. flavonoids also play key roles in the inhibition of TGF-beta-Smad2/3 pathway and EMT for cancer cells. Based on this indication, we plan to fully test the activity of Stellera chamaejasme L.flavonoids in cancer EMT regulation and metastasis inhibition. We will further reveal its molecular targets and the potential mechanism of ESC during the regulation of TGF-beta-Smad2/3 pathway in cancer cells. Our study will be helpful for the clear understanding of ESC activity for cancer treatment pharmacologically, and provide basic evidence for the research and development of anti-tumor drugs in clinical practice.

肿瘤侵袭和转移是医学关注和研究的重大科学问题，同时也是肿瘤患者生存的决定要素。近年研究证明，肿瘤的上皮间质变迁是调节肿瘤运动、侵袭及转移的核心机制，而TGF-beta/Smads通路是调控肿瘤EMT的核心通路。但与肿瘤转移的机制研究相比，以其为干预靶点的药物较少。狼毒抗癌自古便有记载，但其高毒性限制了其临床应用。本课题前期研究表明，瑞香狼毒提取物具有多样的抗癌功效，特别是黄酮类组分在低浓度下对肿瘤TGFbeta-Smad2/3通路具有明确的抑制作用，继而功能性的抑制肿瘤运动、迁移能力。本课题拟通过分子药理学等研究方法,进一步确证其在较低浓度下对肿瘤EMT和侵袭转移的抑制作用，分析其调节EMT活性的动力学特征，揭示其影响TGF-beta-Smad2/3通路的分子机制。本研究将拓展对瑞香狼毒抗癌机制的认识，并为肿瘤抗转移药物的研发提供基础研究证据，具有药理研究和临床应用的双重价值。