基于IL-6/STAT3/PIN1功能轴探讨间质影响胰腺癌糖代谢重塑及恶性生物学行为的实验研究

Glucose metabolic reprogramming provides energy support for malignant behaviors in pancreatic cancer. However, the mechanism underlying the effect of crosstalk between abundant stroma and tumor cells on induction of glucose metabolic reprogramming has always been the hotspot and difficulty in the research field of metabolism on pancreatic cancer. This project focuses on the effect and mechanism of cancer-associated fibroblast (CAF) on metabolic reprogramming of pancreatic cancer cells. We previously demonstrated that PIN1 was involved in mitochondrial oxidative phosphorylation to induce glucose metabolic reprogramming by regulation of FBW7/c-Myc axis in pancreatic cancer cells. Further studies indicated that PIN1 was potentially regulated by stroma in pancreatic cancer. Based on our previous study about the co-culture system, we speculated that stromal CAF-derived IL-6 induced the upregulation of PIN1 expression in pancreatic cancer cells by activating the STAT3 signaling pathway. Thus, we suggest that there is a new molecular mechanism as an axis of IL-6/STAT3/PIN1 to take effect. We are going to carry out some researches to disturb this functional axis by in vitro and in vivo assays and validation of clinical specimens to repress the glucose metabolic reprogramming and the malignant behaviors, which could help effectively improving the unfavorable prognosis and providing a potential target for anti-stroma therapy in pancreatic cancer.

糖代谢重塑为胰腺癌多种恶性生物学行为的进行提供能量保障。而胰腺癌中丰富的间质成分与肿瘤细胞之间的交互对话，诱导其发生糖代谢重塑的分子机制一直是胰腺肿瘤代谢研究的热点及难点。本项目针对于间质中肿瘤相关成纤维细胞（CAF），探索其对胰腺癌细胞糖代谢重塑的作用及机制。我们前期证明，PIN1通过对FBW7/c-Myc功能轴的调控影响线粒体氧化磷酸化功能，进而诱导胰腺癌细胞发生糖代谢重塑；深入研究发现，胰腺癌细胞内PIN1的表达受到间质的潜在调控；基于共培养体系及前期研究分析，我们又推测间质CAF来源的IL-6通过激活胰腺癌细胞内的STAT3，介导PIN1的表达上调，由此提出“IL-6/STAT3/PIN1”这一新功能轴。针对这一功能轴，我们拟进一步开展体内外和临床样本验证及干预研究，进而改变胰腺癌的糖代谢重塑，逆转其恶性生物学行为，为临床上改善胰腺癌的不良预后及抗间质治疗提供潜在的靶点。

胰腺癌是一种具有高度恶性的消化系统肿瘤，确诊胰腺癌的患者5年生存率往往不到8%，其病情特征复杂、异质性高是胰腺癌长期以来疗效不佳的重要原因。有效地完善胰腺癌的分子分型，是当前医学界攻克胰腺癌、改善患者预后的重要方向。代谢重塑是包括胰腺癌在内的多种恶性肿瘤的重要生物学特征，参与影响了胰腺癌增殖凋亡，侵袭转移及化疗抵抗等多种生物学行为。因此，本项目基于前期研究，进一步探讨了PIN1在胰腺癌细胞中异常表达的间质调控因素，同时，我们证明了SMAD4在胰腺癌细胞中的代谢调控作用，进一步通过代谢组学和PCR芯片方法，筛选出PGK1可能是其靶基因。进一步通过染色质免疫共沉淀、荧光素酶报告基因实验及相关代谢检测手段，证实了SMAD4可以有效抑制PGK1的转录，从而实现其对胰腺癌细胞代谢重塑的重要调节作用。此外，在SMAD4阴性胰腺癌中发现，PGK1入核后作为转录辅助因子，参与调控CDH1的转录，诱导胰腺癌细胞的侵袭转移能力，而胞浆内的PGK1则作为重要的代谢酶，促进细胞内糖酵解的顺利进行，进而支持肿瘤细胞的增殖。此外，我们确定了糖酵解及脂肪合成是胰腺癌具有不同预后意义的两个重要代谢亚型，并且间质来源的TGF-β1在胰腺癌代谢转化过程中的重要作用。因此，本项目研究从肿瘤分子生物学的角度，阐述了代谢重塑在胰腺癌恶性生物学行为中的重要支持作用。本研究结果有助于我们更好地理解胰腺癌的分子特点，及其与生物学特征的联系。可以预测胰腺癌的发展模式及代谢特征，从而有利于我们针对不同亚群胰腺癌患者，实施有效的干预措施，对今后胰腺癌患者的治疗策略的研究提供了新思路。