FoxM1在二甲双胍抑制胰腺癌发生发展中的作用与机制研究

Pancreatic cancer brings huge public health burden to the society. Metformin is a first-line drug for type 2 diabetes. It can inhibit cancer cell proliferation and invasiveness in several human malignancies including pancreatic cancer. AMPK/mTOR signaling pathway plays a vital role during this process. FoxM1 is a kind of transcription factor which accelerates the development of pancreatic cancer. Our preliminary data shows that the expression of FoxM1 is reduced when metformin activates AMPK, and FoxM1 can potentially target mTOR. This suggests that FoxM1 functions in the AMPK/mTOR signaling pathway which is activated by metformin. Following studies will be carried out in current project:1. To verify the prerequisite function of AMPK when metformin regulates FoxM1. 2. To determine AMPK as an upstream suppressor of FoxM1. 3. To determine the transcriptional regulation of FoxM1 to mTOR. 4. To verify the existence and significance of AMPK/FoxM1/mTOR signaling pathway. Through these studies, we will determine the molecular mechanisms of FoxM1 during the inhibition effect on pancreatic cancer by metformin and raise the hypothesis of the existence of AMPK/FoxM1/mTOR signaling pathway for the first time.

胰腺癌给社会带来巨大公共医疗负担。二甲双胍是针对2型糖尿病的临床一线用药，能够抑制胰腺癌等多种人体恶性肿瘤细胞的增殖和侵袭，AMPK/mTOR信号通路在其中发挥重要作用。FoxM1是一种转录因子，对胰腺癌的发生发展起促进作用。申请人针对胰腺癌进行前期研究，发现二甲双胍激活AMPK后FoxM1的表达受到抑制，且FoxM1对mTOR具有潜在的靶向调控作用，提示FoxM1在由二甲双胍激活的AMPK/mTOR信号通路中具有一定的生物学功能。本项目拟开展下述研究：1）验证AMPK在二甲双胍调节FoxM1过程中的必要性；2）明确AMPK对FoxM1的上游调控作用；3）明确FoxM1对mTOR的转录调节作用；4）验证AMPK/FoxM1/mTOR信号通路的有效性。通过上述研究，力图阐明FoxM1在二甲双胍抑制胰腺癌发生发展中的作用机制，并创新性提出AMPK/FoxM1/mTOR信号通路假说。