肿瘤细胞来源外泌体miRNA调控巨噬细胞极化参与胰腺癌化疗敏感性研究

Pancreatic cancer is chemoresistant. It is of great value to study the mechanism underlied and to identify the therapeutic target. In previous study we have confirmed that pancreatic cancer cell induced macrophage M2 polarization which contributed to chemoresistance. Our further mechanism study suggested that tumor-derived exosomal miR-19b could induced macrophage M2 polarization which over-produced inflammatory cytokine IL-8. The IL-8 could activate CXCR1-STAT3 signaling and then increased autophagy level and stemness of pancreatic cancer cells. Therefore, in this study we will try to confirm the involvement of tumor-derived exosomal miR-19 in the macrophage M2 polarization and chemoresistance, which may help understand the mechanism underlying chemoesistance of pancreatic cancer cells, and identify new therapeutic targets for pancreatic cancer treatment.

胰腺癌对化疗不敏感，探索胰腺癌化疗抵抗分子机制，寻找防治化疗抵抗新靶点已成为当务之急。申请人前期研究发现人胰腺癌细胞可诱导微环境巨噬细胞发生M2极化，而后者可进一步诱导胰腺癌细胞化疗抵抗。初步的机制研究提示，胰腺癌细胞来源外泌体miR-19b可能通过远端调控微环境巨噬细胞发生M2极化，使巨噬细胞过表达/分泌炎性因子IL-8，进而通过CXCR1-STAT3通路诱导胰腺癌细胞自噬和干细胞“干性”维持来参与化疗抵抗。因此，本研究旨在通过体外、体内研究和人体标本检测明确胰腺癌细胞来源外泌体miR-19b在诱导巨噬细胞M2极化、进而促进胰腺癌细胞化疗抵抗中的作用及可能机制，同时，通过对该通路各环节的干预研究，为后续寻找逆转胰腺癌化疗抵抗新靶点提供依据。

胰腺癌预后差，对治疗抵抗。探索胰腺癌新的发病机制、寻找新的治疗靶点将具有重要临床价值。本研究中，我们证实，胰腺癌细胞来源外泌体miR-19b可诱导巨噬细胞发生M2极化，而KLF13为miR-19b调控性靶基因。同时我们发现，胰腺癌细胞来源IL-8参与化疗抵抗，IL-8炎症通路与胰腺癌患者预后差及治疗抵抗相关。机制研究发现IL-8参与调控胰腺癌巨噬细胞M2极化，而其表达又受到Jagged1信号调控。动物模型证实抑制IL-8炎症通路可在体内抑制胰腺癌转移。相关研究发表通讯（含共同）作者SCI论文10篇。因此，我们的研究揭示了胰腺癌细胞来源外泌体在参与胰腺癌治疗抵抗及预后中的价值及其可能机制，为后续胰腺癌治疗提供有益的干预靶点。