HIF-1α/SDF-1α轴调控Warburg效应在蟾灵膏抑制结直肠癌肝转移中的作用机制

The probability of liver metastasis of colorectal cancer is more than 50%, inhibition of liver metastasis is the key point to determine the prognosis of patients with colorectal cancer, and it also fits the traditional Chinese medicine theory of ‘preventive treatment of disease’ that prevents disease prior to pathogen attack. Warburg effect is an important feature of tumor cell energy metabolism, and there are many key points to be solved urgently. The Warburg effect on tumor metastasis has become a research hotspot. In aerobic glycolysis, the activation of AKT, Warburg kinase, can promote the transcription and translation of HIF1α, HIF1α can promote tumor cell proliferation, tumor angiogenesis and escape apoptosis program to promote tumor metastasis through signal transduction under hypoxic microenvironment. Previous studies show that the Chanling Gao can support the down regulation of the expression levels of HIF-1α, SDF-1 and CXCR4 protein. It can be inferred that HIF-1 α/SDF-1α signal axis may exist and play an important role in tumor metastasis under the Warburg effect. On the basis of previous work, this project will be further confirm the presence of HIF-1α/SDF-1α signal axis and its mechanism of Warburg effect regulation on inhibition of liver metastasis from colorectal cancer in Chanling Gao.

结直肠癌发生肝转移的概率在50%以上，抑制肝转移是决定结直肠癌患者预后的关键点，也正契合中医治未病“先安未受邪之地”的预防理念。Warburg效应是肿瘤细胞能量代谢的重要特征，其中各关键点还有很多疑问亟待解决，Warburg效应对肿瘤转移的作用逐渐成为研究热点。在有氧糖酵解中，在缺氧微环境下Warburg激酶AKT的活化会促进HIF1α的转录和翻译，HIF1α通过信号传导促进肿瘤细胞增殖、启动肿瘤血管新生和躲避细胞凋亡程序等来促进肿瘤转移。前期研究表明，蟾灵膏可下调HIF-1a、SDF-1α和CXCR4蛋白的表达水平。由此推测，Warburg效应下可能存在HIF-1α/SDF-1α信号轴并在介导肿瘤转移中有着重要作用。本项目将在前期工作基础上进一步证实HIF-1α/SDF-1α轴的存在及其调控Warburg效应在蟾灵膏抑制结直肠癌肝转移中的作用机制。

结直肠癌发生肝转移的概率在50%以上，抑制肝转移是决定结直肠癌患者预后的关键点，也正契合中医治未病“先安未受邪之地”的预防理念。近年来结直肠癌的诊疗水平不断提高，但 5 年生存率仍徘徊在 50%左右，其根本原因就在于结直肠癌的转移和复发尚未得到有效控制。由此可以看出，肝转移是结直肠癌治疗的主要障碍，而预防和抑制肝转移则是决定结直肠癌患者预后的关键因素；中医药在结直肠癌肝转移防治方面有着不可忽视的重要作用且越来越受到重视。若能发现有效的防治药物，其临床意义重大。前期的实验研究中证明了蟾灵膏的安全性及有效性，可抑制结直肠癌细胞的生长。本课题组为了进一步探讨其治疗结直肠癌的机制，通过4年的研究工作，主要完成了以下内容：①完成了蟾灵膏对人结肠癌 LOVO-luc 细胞及人结肠癌SW480 细胞有氧糖酵解相关代谢产物及关键激酶的影响；②探讨了蟾灵膏对人结肠癌 LOVO-luc 细胞及人结肠癌SW480 细胞建立的原位裸鼠模型移植瘤的生长、转移作用及肿瘤微环境血管新生的情况的影响；③分析了蟾灵膏对人结肠癌LOVO-luc 细胞及人结肠癌SW480 细胞的粘附、运动与迁移等生物学行为的影响；④揭示蟾灵膏影响结直肠肿瘤生物学行为的改变与 Warburg 效应的相关性；⑤揭示了HIF-1α/SDF-1信号轴调控Warburg效应在蟾灵膏抑制结直肠癌肝转移中的作用机制；⑥培养硕士研究生3名；⑦发表论文6篇，其中在 SCI 收录期刊上发表论文5篇；⑧申请专利 3 项；