AMPK对Bmi-1表达的调控在抑制胃癌转移中的作用

The objective of this grant proposal is to investigate the relationship between suppression of AMPK and overexpression of Bmi-1 and implication of their changes in progression and prognosis in gastric cancer. Bmi-1 belongs to the poly-com family of transcriptional regulators that promote self-renewal and EMT processes of cancer cells. It has been show that the invasion and metastasis of gastric cancer is closely associated with Bmi-1 overexpression. Previous studies and our preliminary results revealed that the activity of AMPK was suppressed in multiple tumors including gastric cancer and that AMPK activation could repress Bmi-1 expression, which was mediated by upregulation of LITAF, an AMPK downstream target. Therefore, we hypothesize that AMPK can attenuate progression of gastric cancer by downregulation of may lead to upregulation of Bmi-1. To test the hypothesis, we will examine clinical specimens of gastric cancer to compare levels of Bmi-1 and AMPK in different stages of cancer and explore the underlying molecular mechanisms. To our knowledge, this is the first study to link AMPK, an emerging important tumor suppressor and Bmi-1, a critical prometastatic factor. Hence, the proposed study will add important knowledge to tumor biology and provide a strong rationale to target AMPK for prevention and treatment of gastric cancer progression, a devastating disease in our country.

本课题旨在探讨AMPK活性、Bmi-1过表达及胃癌转移之间的关系。Bmi-1属于PcG家族转录抑制因子，对肿瘤转移发挥重要作用，在胃癌及多种癌症中过表达，但其调控机制不明。我们前期研究显示激活AMPK（公认的抑癌基因）能在体外试验中抑制Bmi-1表达和细胞迁移，Bmi-1水平的调节与AMPK下游靶分子LITAF有关，而胃癌细胞中AMPK活性下降。据此，我们假设： Bmi-1水平受AMPK调控；受肿瘤微环境影响，AMPK活性下降，失去对Bmi-1抑制，使Bmi-1表达过度。为此，我们拟以病理实验探讨胃癌进展中Bmi-1升高与AMPK活性的关系；以细胞实验研究AMPK活性对Bmi-1水平和功能的影响，探讨AMPK调控Bmi-1水平的机制；以动物肿瘤模型验证AMPK活性、Bmi-1表达与胃癌三者间的关系。该研究首次将AMPK和Bmi-1的相互作用与胃癌的进展联系在一起，为靶向治疗提供新的切入点。

5’单磷酸腺苷活化蛋白激酶（AMP-activated protein kinase，AMPK）一直以来被称为细胞内的“能量感受器与调节器”，AMPK的抑癌功能已经得到研究者们的广泛认可。AMPK可通过一系列信号通路影响细胞的增殖、侵袭和迁移从而发挥其抑癌功能。Bmi-1属于多疏基因家族成员，不仅能维持肿瘤干细胞的自我更新，还在EMT进程中发挥着极为重要的作用。我们的前期试验表明：1. AMPK活性升高，Bmi-1表达下降；而降低AMPK活性后，Bmi-1的表达反而升高，即AMPK能够抑制Bmi-1的表达。2. LITAF为AMPK下游，受AMPK正调控，且我们的microarray分析结果显示LITAF可以调控部分miRNA，而其中的miRNA-15a/128/194可调控Bmi-1的表达。所以我们猜想AMPK是否能通过LITAF抑制Bmi-1的表达。因此，本研究旨在探究胃癌中Bmi-1的表达是否受AMPK抑制，并探索AMPK影响Bmi-1表达的分子机制。为进一步研究AMPK的抑癌功能提供实验依据。