FOG2调控胰腺癌MAPK/PI3K信号通路对话及PD-L1表达的机制及意义

Activation of MAPK signaling, which is common in pancreatic cancer, plays a key role in the progression and chemotherapy resistance of the cancer. However, drugs targeting the MAPK signaling never take satisfactory effects in pancreatic cancer. In the previous study, we documented that the PI3K signaling would be activated if the MAPK signaling were down regulated in pancreatic cancer, which suggested a crosstalk between the MAPK and PI3K signaling. The crosstalk may contribute greatly to the resistance of pancreatic cancer to the MAPK targeting therapy. The expression of PD-L1 was also showed to be regulated by the crosstalk. The increase of PD-L1 expression may affect the pancreatic cancer cells little in vitro and in animal models, but it lead to the immune escape and progression of the disease in patients. The applicant screened possible molecules that can regulate the crosstalk using bioinformatics methods, and FOG2 was considered to have the potential to be the key molecule. The preliminary experiments also showed that the FOG2 located in both cytoplasm and nucleus of pancreatic cancer cells. In this project, the role of FOG2 in regulating the crosstalk between MAPK and PI3K signaling and the expression of PD-L1 will be studied both in vitro and in vivo. The mechanism of the crosstalk between MAPK and PI3K signal pathway is hopeful to be clarified in this project, and the results will be helpful for the design of effective targeted therapies for pancreatic cancer.

MAPK信号通路活化在胰腺癌中广泛存在，且参与胰腺癌的发生进展，但针对MAPK信号通路的靶向干预在胰腺癌临床治疗中所取得的疗效令人沮丧。在上一个基金研究中，课题组证实在抑制胰腺癌MAPK信号通路活化时会活化PI3K信号通路，提示存在MAPK与PI3K信号通路的对话，该对话可能是胰腺癌耐受MAPK信号通路靶向干预的关键机制，其中对PD-L1分子表达的调控可能导致了MAPK信号通路抑制剂在临床试验中取得的疗效远差于细胞实验和动物实验。项目申请人进而应用生物信息学方法分析出FOG2蛋白可能是两信号通路对话的关键分子，并证实FOG2存在于胰腺癌细胞胞浆中。本项目拟在离体和在体水平基于分子生物学方法与转基因动物验证FOG2调控胰腺癌MAPK与PI3K信号通路对话及下游PD-L1分子表达的推断。若项目成功，有望阐明胰腺癌中MAPK与PI3K信号通路对话的分子机制，并为胰腺癌治疗提供潜在干预靶点。

MAPK信号通路活化在胰腺癌中广泛存在，且参与胰腺癌的发生进展，但针对MAPK信号通路的靶向干预在胰腺癌临床治疗中所取得的疗效令人沮丧。按项目申请书设计，本项目阐明了FOG2在胰腺癌中发挥的生物学效应以及效应机制。对于其对PD-L1表达的影响，研究结果显示FOG2不直接调控PD-L1。目前PD-L1研究进展与临床试验的结果与本研究结果一致。新近针对恶性肿瘤的精准治疗进展显示精准治疗恶性肿瘤能取得优于传统靶向治疗与放化疗的疗效，然而在基础研究与临床研究中也显示出即便是同一组织来源的恶性肿瘤的信号通路都存在极大的差异，实施精准治疗必须依赖恶性肿瘤个体的分子事件特征，否则不能取得预期疗效。因而本研究在完成FOG2调控胰腺癌生物学行为研究的基础上，进一步探索了胰腺癌中MIST1与YBX1等分子在胰腺癌分子事件上的作用。该研究阐明了胰腺癌FOG2/MIST1/YBX1-MAPK/AKT/GSK3B信号通路在胰腺癌细胞生物学行为中的作用机制，为胰腺癌的精准治疗提供了干预靶点。

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