LKB1-AMPK激酶异常在乳腺癌发生及侵袭转移中的作用机制研究

能量代谢紊乱是肿瘤细胞区别于正常细胞的特征性改变。LKB1-AMPK激酶是细胞能量代谢的关键感应及调节激酶，在维持上皮细胞极性中也起着重要作用。临床资料证实LKB1基因在乳腺癌细胞常发生杂合性缺失，其表达与乳腺癌恶性度呈负相关，然而目前对LKB1-AMPK激酶通路在乳腺癌发生发展中的细节机制尚不清楚。我们的前期研究结果显示,LKB1下游激酶AMPK参与调控细胞纺锤体检查点蛋白BUB1及上皮细胞标志物E-Cadherin,从而与维持染色质稳定性及上皮细胞特性有关。因此，我们设想：LKB1-AMPK激酶异常可导致细胞染色质不稳定；同时引起细胞极性丢失及上皮间皮化并导致肿瘤侵袭转移。我们拟以乳腺癌为研究对象，对LKB1-AMPK激酶异常在乳腺癌发生发展中的作用进行研究。该项目的完成，将阐明LKB1-AMPK激酶异常在乳腺癌恶性进程中的全新作用机制，并为筛选抗肿瘤药物的新靶点提供理论依据。

Deregulation of cellular energy metabolism is one of the cancer hallmarks. LKB1-AMPK kinase pathway plays a pivotal role in sensing and regulating cell energy metabolism and in maintaining cell polarity. Clinical data has shown loss of heterozygosity of LKB1 in breast cancer and negative correlation of LKB1 expression with the histological grade of breast cancer. However, the mechanism underlying the role of LKB1-AMPK kinase pathway dysfunction in the malignant progression of breast cancer is still unclear. Our preliminary data have shown that LKB1-AMPK kinase pathway may play an important role in regulating spindle checkpoint protein BUB1 and epithelial marker E-cadherin, which may indicate that LKB1-AMPK kinase pathway may be related to the maintenance of chromosome integrity and epithelial characteristics. Based on our preliminary data and previous literature reports, we hypothesize that dysfunction of LKB1-AMPK kinase pathway may lead to cell chromosome instability and epithelial-messenchymal transition (EMT), and consequently, give rise to breast cancer metastasis. Based on our preliminary data, we plan to conduct research on the effects of deregulated LKB1-AMPK kinase pathway on the malignant progression in human breast cancer, and to clarify a novel mechanism by which LKB1-AMPK kinase pathway affects the malignant progression of breast cancer.This project is expected to provide a theoretical basis for screening a novel anti-tumor target.