炎症微环境诱导胰腺癌细胞自噬参与其化放疗抵抗的研究

Pancreatic cancer has poor prognosis, partly because it is chemo- and redioresistant. It is of great value to study the mechanism underlied and identify the therapeutic target. In previous study we have confirmed that the high level of autophagy contributed to chemo- and radioresistance of pancreatic cancer cells. In addition, we found that tumor-associated macrophage (TAM) derived IL-8 induced pancreatic cancer cell autophagy and chemo- and radioresistance. The potential mechanism seems to be that IL-8/CXCL8 inflammatory signaling downregulated miR-27b, a autophagy regulating microRNA,in pancreatic cancer cells,which resulted in cell resistant to chemo- and radiation therapy. Therefore, in this study we will try to confirm the involvement of IL-8-miR-27b signaling in autophagy regulating and its effects on chemo- and radioresistance, which may help understand the mechanism underlying chemo- and radioresistance of pancreatic cancer cells, and identify new therapeutic targets for pancreatic cancer treatment.

胰腺癌对放、化疗均不敏感，预后差。探索胰腺癌治疗抵抗分子机制，寻找新的干预靶点将具有重要临床价值。申请人前期研究发现胰腺癌化放疗抵抗与其高水平自噬有关，并且我们发现，微环境肿瘤相关巨噬细胞（TAM）来源的炎性因子IL-8可诱导胰腺癌细胞自噬及化、放疗抵抗，其机制可能是IL-8/CXCR1炎性信号负调控了胰腺癌细胞miR-27b的表达，后者作为自噬调控性microRNA参与了胰腺癌细胞的自噬过程，进而诱导胰腺癌细胞治疗抵抗。因此，本研究旨在通过体外、体内研究和人体标本检测明确炎性通路IL-8-miR-27b在TAM诱导胰腺癌细胞自噬中可能发挥的调控作用及其对胰腺癌治疗敏感性的影响，从而探寻胰腺癌化放疗抵抗新机制，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治疗抵抗新靶点提供依据。

胰腺癌预后差，对化放疗抵抗。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，肿瘤相关巨噬细胞（TAM）可通过激活胰腺癌细胞自噬诱导其化疗抵抗，而自噬抑制剂可增加胰腺癌细胞对化疗的敏感性。进一步研究发现，巨噬细胞来源IL-8体外可诱导胰腺癌细胞自噬水平升高，而IL-8受体CXCR1单抗可阻断该作用。进一步机制研究发现，IL-8可诱导miR-27b表达下调，而miR-27b调控胰腺癌细胞自噬通过STMN1和RAB5A两个自噬相关基因来实现。最后，基于M2型巨噬细胞相关因子建立炎性因子指数SIRI，该指数可用于预测患者化疗后无进展生存期和总生存期。相关研究发表通讯作者SCI论文6篇。因此，我们的研究揭示了胰腺癌细胞与肿瘤相关巨噬细胞相互作用在胰腺癌侵袭转移中的重要作用，为后续胰腺癌治疗提供有益的干预靶点。