能量代谢感受器AMPK在乳腺癌转移中的作用及分子机制

AMP-activated protein kinase (AMPK) plays a critical role in cellular energy homeostasis. In recent years, studies demonstrate that AMPK has an important role in cancer cell growth and survival. However, whether AMPK is involved in cancer metastasis is still largely unclear. Furthermore, a large number of studies have focused on the activity regulation of AMPK, while the gene expression of AMPK is rarely studied. In our preliminary studies show that the expression of AMPKa1, AMPK catalytic subunit, is significantly down-regulated in advanced breast cancers; inhibition of AMPK dramatically increases cell invasion; oncogenic PI3K/Her2/Ras markedly inhibits AMPKa1 mRNA expression. Based on these data, we hypothesized that (1) AMPK plays a pivotal role in regulating breast cancer metastasis; (2) oncogenic PI3K/Her2/Ras regulates transcription of AMPKa1 whcih in turn plays a critical role in PI3K/Her2/Ras-induced cancer metastasis; (3) AMPK activator inhibits breast cancer metastasis. Together, we aim to elucidate the role of AMPK in cancer metastasis and establish that AMPK is a valid target for cancer diagnosis and treatment.

腺苷酸激活蛋白激酶(AMPK)在维持细胞能量代谢稳态过程中起着关键作用。近来研究表明，AMPK在调控肿瘤细胞生长及生存过程中扮演着重要的角色。但AMPK是否在肿瘤转移过程中也起着作用，目前尚不清楚。此外，大量研究集中于AMPK的活性调控，而AMPK的基因表达研究甚少。本项目的前期研究表明AMPK催化亚基AMPKa1的mRNA和蛋白水平在高恶性的乳腺癌中显著降低；基因沉默AMPKa1明显增加乳腺癌细胞的侵袭能力；PI3K/Her2/Ras信号通路的激活显著抑制AMPKa1的mRNA表达。基于此，本项目拟探索（1）AMPK在乳腺癌转移中的作用及机制；（2）PI3K/Her2/Ras转录调控AMPKa1的分子机制及与肿瘤转移的相关性；（3）AMPK激活剂对乳腺癌转移的干预作用。本项目的实施为理解AMPK在肿瘤转移中的作用提供理论基础，进一步为乳腺癌的治疗提供理论和临床指导意义。

腺苷酸激活蛋白激酶(AMPK)在维持细胞能量代谢稳态过程中起着关键作用。近来研究表明，AMPK在调控肿瘤细胞生长及生存过程中扮演着重要的角色。但AMPK是否在肿瘤转移过程中也起着作用，目前尚不清楚。此外，大量研究集中于AMPK的活性调控，而AMPK的基因表达研究甚少。本项目在分子、细胞、动物及临床层面阐明了转录抑制AMPK是乳腺癌转移的关键驱动力，并揭示了AMPK调控乳腺癌转移的具体分子机理。本项目主要研究内容包括：（1）AMPK催化亚基AMPKα1的mRNA和蛋白水平在高恶性的乳腺癌中显著降低；（2）抑制AMPK通过增加Twist1表达，从而抑制细胞粘附因子E-cadherin转录，最终扰乱乳腺癌细胞粘附及增加乳腺癌转移；（3）p53家族蛋白p63是AMPKα1的直接转录因子，p63可直接结合到AMPKα1基因启动子的-1382到-1209；（4）PI3K/HER2信号通路的激活通过抑制p63的蛋白表达，从而抑制AMPKα1的转录，进而促进乳腺癌转移；（5）AMPK激活剂可显著抑制乳腺癌转移。综上，本项目原创性的发现PI3K/HER2-p63-AMPK-Twist1-E-cadherin是调控乳腺癌转移的关键信号通路。本项目的实施为理解AMPK在肿瘤转移中的作用提供理论基础，为乳腺癌的治疗提供了新靶点和新方法。