IFN-γ/MACC1/MMP1信号轴促进胰腺癌侵袭转移的作用及分子机制研究

结肠癌转移相关基因1(MACC1) 在多种肿瘤中促侵袭转移，但在胰腺癌中作用机制及其自身调控机理不清。预实验发现胰腺癌组织中MACC1高表达且不赖于经典c-Met通路促侵袭转移。qPCR芯片及基因沉默发现，MACC1通过上调MMP1促侵袭转移。报告基因及Co-IP提示，MACC1可能通过与ETS1互作上调MMP1。炎症因子芯片发现，胰腺癌组织中IFN-γ高表达且可通过上调MACC1促侵袭转移。机制研究发现，IFN-γ通过STAT1上调MACC1启动子活性，生信预测提示MACC1启动子区存在STAT1潜在结合位点。据此提出IFN-γ通过STAT1促进MACC1表达，后者结合ETS1进而上调MMP1促胰腺癌侵袭转移的假说。本项目拟采用ESMA，ChIP，Co-IP等技术解析STAT1调控MACC1及MACC1与ETS1互作的机制，为靶向IFN-γ/MACC1/MMP1信号轴抗胰腺癌侵袭转移提供新依据。

Colon cancer metastasis-associated gene 1 (MACC1), a key regulator of the hepatocyte growth factor and its receptor(HGF-MET) pathway, is involved in promoting invasion and metastasis in a variety of tumors, but the role and self-regulation mechanism of which in pancreatic cancer are still unclear.Here we show that MACC1 is highly expressed in pancreatic cancer tissues, and more remarkably, which is not dependent on the classical c-Met pathway to promote invasion and metastasis. The qPCR chip and gene silencing found that MACC1 is capable of up-regulating matrix metallopeptidase 1 (MMP1) to promote invasion and metastasis. Reporter gene and Co-IP further suggest that the up-regulation of MMP1 is probably attributed to the interaction between ETS proto-oncogene 1, transcription factor (ETS1) and MMP1. In addition, by means of the inflammatory factor chip, interferon gamma (IFN-γ) is also found to be highly expressed in pancreatic cancer tissues, which exerts its tumor-promoting effect through increasing the expression of MACC1. Meanwhile, luciferase reporter assay shows that the IFN-γ downstream effector STAT1(signal transducer and activator of transcription 1) is able to up-regulate the MACC1 promoter activity and bioinformatics also predicts that there is a potential binding site for STAT1 in the promoter region of MACC1. Based on the above evidence, it is reasonable to put forward the hypothesis that IFN-γ is capable of increasing MACC1 expression through its downstream effector STAT1, and the binding of ETS1 by MACC1 subsequently up-regulates the expression of MMP1, thus promoting invasion and metastasis of pancreatic cancer. This project intends to use ESMA, ChIP, Co-IP and other technologies to analyze the mechanism by which STAT1 regulates MACC1 as well as the interaction between MACC1 and ETS1, providing a new evidence for targeting IFN-γ/MACC1/MMP1 signaling axis in anti-pancreatic cancer treatment.