转录辅激活因子SRC-3在胰腺癌发生发展中的作用及其机理研究

Recent studies indicated that metabolic reprogramming and intracellular redox state played important roles in pancreatic ductal adenocarcinoma (PDAC). Steroid receptor coactivator-3 (SRC-3), as an oncogene, promotes carcinoma progress through multi-pathway. However, the role of SRC-3 involved in regulating metabolic reprogramming and intracellular redox state is still unclear. Our previous study indicated that SRC-3 enhanced the activity of transcriptional factor Nrf2, which played important roles in causing metabolic reprogramming and suppressing oxidative stress. Therefore, our hypothesis is that SRC-3 may have effect on the progress of PDAC through regulating metabolic reprogramming and intracellular redox state. In the project, we will investigate whether SRC-3 has effect on glucose and glutamine metabolism, and on intracellular redox state. Meanwhile, we will explore the molecular mechanisms responsible for these functions of SRC-3. Furthermore, we will investigate whether SRC-3 promotes the progress of PDAC through regulating metabolic reprogramming and intracellular redox state. Finally, we will measure the expression and localization of SRC-3 and Nrf2 in PDAC clinical samples, and study whether SRC-3 has relationship with severity and survival rate of PDAC patients. The project will illuminate potential targets that can be exploited for therapeutic benefit in PDAC.

细胞代谢的重编程及胞内氧化还原平衡在胰腺癌发展进程中起着重要作用。转录辅激活因子SRC-3作为癌基因通过多种途径促进肿瘤的发生发展，然而SRC-3在肿瘤细胞代谢及氧化还原水平调节中的作用仍不清楚。我们的研究表明SRC-3可促进转录因子Nrf2的活性，而Nrf2在氧化应激及代谢的重编程中具有重要作用。因此，我们假设SRC-3可能在胰腺癌代谢的重编程及氧化还原水平调节中发挥作用并影响其发生发展。本课题拟以KrasG12D MEF及人胰腺癌细胞为研究对象，研究SRC-3对葡萄糖及谷氨酰胺代谢的影响并探讨分子机制，同时研究SRC-3对氧化还原水平调节的影响及相关机制；进而探讨SRC-3是否通过这两条途径影响胰腺癌发展进程；最后我们将利用胰腺癌样本探讨SRC-3的临床意义。本课题以期通过SRC-3将代谢的重编程及胞内氧化还原水平调节两条途径有机的联系起来，为寻找安全有效的治疗胰腺癌的靶点提供新思路。

类固醇激素受体辅激活子-3（Steroid receptor coactivator-3，SRC-3）是类固醇受体辅激活因子家族（Steroid receptor family）成员之一，与多种类固醇激素核受体以及其他转录因子相互作用而增强它们的转录活性，从而表现出多种生物学功能。本项目研究发现SRC-3在胰腺癌组织呈现过表达，并与预后呈负相关；进而，我们利用体内体外实验证明了SRC-3在胰腺癌细胞的增殖、成瘤、迁移及耐药性方面具有重要作用，并且我们发现SRC-3在胰腺癌细胞糖酵解方面也具有调控作用；然后，我们利用RNA-Seq技术探讨了SRC-3对胰腺癌发生发展影响的分子机制，发现SRC-3可以通过调控SMO、Intergrinβ3等基因的表达而影响Hedgehog及ECM等信号通路的活性，从而影响胰腺癌的发生发展。此外，我们利用LC-MS技术分析了SRC-3对胰腺癌细胞中代谢组分的影响，发现SRC-3可通过调控超长链脂肪酸延伸酶来影响细胞中长链脂肪酸的含量，为揭示SRC-3在代谢方面中新的生物学功能奠定了基础。总之，本课题按照计划书执行并基本完成了预期目标，揭示了SRC-3在胰腺癌发生发展中的作用及相关分子机制，为寻找胰腺癌的治疗靶点提供了新的思路。