黄芩素介导miR-7/FAK/Akt信号通路抑制胃癌演进的分子机制研究

Gastric cancer is the most common malignant tumor in the digestive system. The mortality rate of gastric cancer in China is 2 times more than the world average. At present, commonly used anti-cancer drugs have some disadvantages such as expensive, toxic and drug resistance. Thus, it is important to study traditional Chinese medicine as antitumor drug due to its inexpensive, low toxicity and high efficiency for treatment of gastric cancer. Studies demonstrated that baicalein (BAI), the main active ingredient of Scutellaria, inhibit the proliferation of various tumor cells such as gastric cancer, but the specific mechanism is not yet clear. MiR-7 targets focal adhesion kinase (FAK) to inhibit the proliferation and metastasis of cancers, which is associated with PI3K/Akt signaling pathway. Our previous studies have showed that, BAI regulates the expression of miR-7 and FAK protein in gastric cancer cells, and inhibits the cell proliferation and migration, induces apoptosis and autophagy, inhibits expression of p-PI3K and p-AKT protein. These suggest that BAI may effect progression of gastric cancer mediate miR-7/FAK/Akt signal transduction pathway. Therefore, this project uses miR-7 over-expression cell line and low-expression cell line of gastric cancer, in vitro and in vivo to investigate the molecular mechanism and effects of BAI inhibiting progression of gastric cancer mediating miR-7/FAK/Akt signaling pathway. This will provide not only a new gene target for gastric cancer therapy, but also the experimental data and theoretical basis for the development and application of BAI, a traditional Chinese medicine.

胃癌是最常见的消化系统恶性肿瘤，我国胃癌死亡率是世界平均水平的2倍以上。目前常用抗癌药存在价贵、毒性大、易耐药等缺点。研究价廉、低毒、高效的抗肿瘤中药对具有重要意义。研究表明，黄芩素（BAI）为黄芩的主要活性成分，可抑制胃癌等多种肿瘤细胞增殖，但具体机制尚不明确。miR-7靶向局部黏着斑激酶（FAK）抑制肿瘤增殖和转移，并与PI3K/Akt信号通路相关。前期研究发现，BAI调控胃癌细胞miR-7和FAK蛋白表达，抑制细胞增殖和迁移，诱导凋亡和自噬，抑制p-PI3K和p-AKT蛋白表达。提示，BAI可能介导miR-7/FAK/Akt信号转导通路影响胃癌进展。因此，本项目用miR-7高表达和低表达胃癌细胞株，利用分子生物学和动物实验学等方法，在体外和体内探讨BAI介导miR-7/FAK/Akt信号通路抑制胃癌演进的作用及分子机制，为胃癌靶向治疗及BAI的开发应用提供新实验数据和理论依据。

胃癌是最常见的消化系统恶性肿瘤，我国胃癌死亡率是世界平均水平的2倍以上。目前常用抗癌药存在价贵、毒性大、易耐药等缺点。研究价廉、低毒、高效的抗肿瘤中药对具有重要意义。研究表明，黄芩素（baicalein，BAI）为黄芩的主要活性成分，可抑制胃癌等多种肿瘤细胞增殖，但具体机制尚不明确。miR-7靶向局部黏着斑激酶（focal adhesion kinase， FAK）抑制肿瘤增殖和转移，并与PI3K/Akt信号通路相关。项目组用BAI处理胃癌细胞，并制备FAK和miR-7的高表达和低表达胃癌细胞系，通过体内外实验研究了BAI抑制胃癌细胞增殖、迁移和EMT进程，诱导细胞凋亡和自噬体的形成并抑制自噬流的作用和分子机制。我们的研究结果提示：1. BAI通过PI3K/AKT/mTOR信号通路抑制胃癌细胞的增殖、迁移和EMT进程，诱导自噬体的形成和抑制自噬流的发生；2. FAK，又名蛋白酪氨酸激酶 2（protein tyrosine kinase 2, PTK2），在胃癌中高表达，BAI抑制FAK诱导的胃癌细胞增殖、迁移和EMT进程；3.miR-7在胃癌组织中低表达，并与胃癌不良预后相关， BAI可上调胃癌细胞的miR-7的表达，并通过miR-7/FAK/AKT信号通路抑制胃癌的生物学过程。本项目结果为BAI在临床胃癌的治疗提供了可靠的理论依据，也为miR-7在临床胃癌诊断和治疗中的可行性奠定了理论基础。