胰腺癌外泌体(exosome)诱导的RFXAP基因沉默在胰腺癌早期转移发生中的作用及机制

Pancreatic cancer is one of the most malignant tumors with high ability of invasion and metastasis which caused low radical resection rate and poor prognosis. Regulatory factor X-associated protein (RFXAP) is a transcription factor of MHC II gene, its deficiency can lead to a rare severe immunodeficiency disorder termed bare lymphocyte syndrome (BLS). Its correlation with tumor metastasis was never reported. Our previous study has founded RFXAP deficiency in pancreatic cancer which was induced by pancreatic cancer derived exosome and correlated with tumor metastasis and immune escape. The aim of the project is to demostrate the mechanism that how pancreatic derived exosome promoting cancer invasion and metastasis and the roles of RFXAP deficiency induced by pancreatic derived exosome, explore new diagnostic model for earlier pancreatic cancer metastasis detection. We will study dendritic cell differentiation and function in exosome stimulated and RFXAP gene transfected DC. MHC II expression and metastasis suppressor expression will also be studied by gene transfection, knock down, profile analysis and cell biological experiments in pancreatic cell. The clinical roles of RFXAP and anti-oncogenes will be studied by RT-PCR. The results will be great valuable for pancreatic cancer detection, improving radical resection rate, developing new strategies to block early invasion and metastasis of pancreatic cancer, which would provide better prognosis for pancreatic cancer patients.

胰腺癌是一种临床常见的高度恶性肿瘤，其早期浸润和转移能力强，是造成目前手术根治率低、预后差的主要原因。RFXAP是调控MHC II类分子表达的关键转录因子，其表达缺失将导致细胞免疫缺陷，但它与肿瘤转移的相关性尚未见报道。我们研究发现胰腺癌exosome可诱导RFXAP基因表达沉默，促进胰腺癌免疫逃逸和转移发生。本课题研究目标是阐明RFXAP基因沉默在胰腺癌早期转移发生中的作用和机制，并建立胰腺癌转移的早期诊断模型。我们拟分别建立RFXAP高表达和低表达的胰腺癌细胞株和树突状细胞模型，通过转录组测序等手段研究RFXAP调控的抑癌基因；通过分子生物学实验和动物实验研究RFXAP沉默对胰腺癌增殖转移能力和树突状细胞免疫功能的影响；通过检测胰腺癌标本中RFXAP及相关抑癌基因的表达水平，提出胰腺癌转移的诊断模型。本项目将为胰腺癌靶向治疗提供新的研究方向，对提高胰腺癌手术根治率具有重要的指导意义。

胰腺癌是一种临床常见的高度恶性肿瘤，其早期浸润和转移能力强，是造成目前手术根治率低、预后差的主要原因。RFXAP是调控MHC II类分子表达的关键转录因子，其表达缺失将导致细胞免疫缺陷，但它与肿瘤转移的相关性尚未见报道。我们研究发现胰腺癌RFXAP表达水平低于癌旁组织，且与胰腺癌患者分期和预后相关。胰腺癌细胞通过RFXAP调控KDM4A转录从而参与DNA损伤修复。其次，胰腺癌exosome可以通过抑制DC细胞和T细胞杀伤活性，促进胰腺癌免疫逃逸和转移发生。此外我们发现胰腺癌患者外周血血浆外泌体miR-21表达水平较高，具有胰腺癌早期诊断功能，且与患者预后相关。本项目研究结果将为胰腺癌靶向治疗提供新的研究方向，对提高胰腺癌手术预后具有重要的意义。