自噬可诱导肿瘤细胞凋亡逃避，致使化疗耐药。AMPK/mTOR激活是自噬发生的重要分子事件。课题组发现SHMT2在结肠癌中表达上调，并与肿瘤预后及化疗耐药相关。过表达SHMT2抑制5-FU引发的凋亡，增强自噬; 此外发现AMPK/mTOR是SHMT2潜在的下游靶标。我们推测SHMT2可能通过促进AMPK磷酸化直接或间接抑制mTOR活性诱导自噬；自噬清除化疗产生的破损细胞器等有害成分，导致化疗诱导的凋亡耐受，从而降低化疗敏感性。本项目拟采用CRISP/Cas9等基因操作技术，验证SHMT2在结肠癌化疗敏感性中的作用；透射电镜及流式细胞仪等观察SHMT2通过诱导自噬抵抗凋亡影响肿瘤耐药；激光共聚焦等技术探讨SHMT2调控AMPK/mTOR增强自噬的分子机制；公共数据库验证SHMT2与自噬的相关性及AMPK/mTOR与化疗预后的联系，结合大样本组织验证其临床意义，为逆转肿瘤化疗耐受提供新思路。

Autophagy can induce tumor cells to escape apoptosis, resulting in resistance to chemotherapy. Activation of AMPK/mTOR signaling is an important molecular events of autophagy. Our previous study found that SHMT2 was upregulated in colon cancer and was associated with tumor prognosis and resistance to chemotherapy. Overexpression of SHMT2 inhibited apoptosis induced by 5-FU and enhanced autophagy in colon cancer cells. Besides, AMPK/mTOR was found to be the downstream target of SHMT2. Thus we suggested SHMT2 may promote phosphorylation of AMPK, then suppress the activity of mTOR directly or indirectly, inducing autophagy in colon cancer cells. Autophagy mediated by SHMT2 can eliminate the harmful products such as damaged organelles, thereby resulting in cell apoptosis tolerance and reducing chemotherapy sensitivity. To validate the hypothesis, in this project, CRISP/Cas9 knockout methods is used to elucidate the relationship between SHMT2 and chemotherapy sensitivity; Transmission electron microscopy and flow cytometry are used to investigate the drug resistance function of SHMT2 in regulating apoptosis tolerance by inducing autophagy; confocal laser scanning technology is applied to explore the underlying molecular mechanism of autophagy caused by SHMT2 through AMPK/mTOR signaling pathway; public databases are mined to verify the association between SHMT2 and autophagy, and the relationship between AMPK/mTOR and prognosis within chemotherapy; a large sample of tissue is used to verify their clinical significance. All these together would provide a new approach to reversal the resistance to chemotherapy.