Hypoxic Tumor-Derived Exosomal miR-301a Mediates M2 Macrophage Polarization via PTEN/PI3Kγ to Promote Pancreatic Cancer Metastasis
Hypoxic Tumor-Derived Exosomal miR-301a Mediates M2 Macrophage Polarization via PTEN/PI3Kγ to Promote Pancreatic Cancer Metastasis
复制标题
缺氧肿瘤源性外泌体 miR-301a 通过 PTEN/PI3K γ 介导 M2 巨噬细胞极化促进胰腺癌转移
DOI：
10.1158/0008-5472.can-17-3841
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发表时间：
2018-08-15
期刊：
影响因子：
11.2
通讯作者：
Qiu, Zhengjun
中科院分区：
文献类型：
--
作者：
Wang, Xiaofeng;Luo, Guangtao;Qiu, Zhengjun
外泌体正在成为肿瘤细胞与微环境之间相互作用的重要介质。然而，外泌体在胰腺癌中在缺氧条件下调节肿瘤发展的机制在很大程度上仍然未知。在这里，我们发现来自胰腺癌细胞的缺氧外泌体以HIF 1a或HIF 2a依赖性方式激活巨噬细胞为M2表型，然后促进胰腺癌细胞的迁移，侵袭和上皮-间质转化。鉴于外泌体已被证明可以转运miRNA以改变细胞功能，我们发现miR-301 a-3 p在缺氧胰腺癌细胞中高度表达，并在缺氧胰腺癌细胞来源的外泌体中富集。循环外泌体miR-301 a-3 p水平与胰腺癌的浸润深度、淋巴结转移、晚期TNM分期和不良预后正相关。低表达的外泌体miR-301 a-3 p通过激活PTEN/PI 3 K γ信号通路诱导巨噬细胞的M2极化。胰腺癌细胞与其中miR-301 a-3 p上调或用低氧外泌体处理的巨噬细胞的共培养增强了它们的转移能力。总的来说，这些数据表明胰腺癌细胞在缺氧微环境中产生富含miR-301 a-3 p的外泌体，其然后刺激巨噬细胞以促进胰腺癌细胞的恶性行为。针对exosomal miR-301 a-3 p的研究可能为胰腺癌的诊断和治疗提供一个潜在的策略。意义：这些发现确定了一个对微环境串扰至关重要的exosomal miRNA，可能被证明是胰腺癌诊断和治疗的潜在靶点。[图形]。(C)2018年AACR。
Exosomes are emerging as important mediators of the cross-talk between tumor cells and the micro-environment. However, the mechanisms by which exosomes modulate tumor development under hypoxia in pancreatic cancer remain largely unknown. Here, we found that hypoxic exosomes derived from pancreatic cancer cells activate macrophages to the M2 phenotype in a HIF1a or HIF2a-dependent manner, which then facilitates the migration, invasion, and epithelial-mesenchymal transition of pancreatic cancer cells. Given that exosomes have been shown to transport miRNAs to alter cellular functions, we discovered that miR-301a-3p was highly expressed in hypoxic pancreatic cancer cells and enriched in hypoxic pancreatic cancer cell-derived exosomes. Circulating exosomal miR-301a-3p levels positively associated with depth of invasion, lymph node metastasis, late TNM stage, and poor prognosis of pancreatic cancer. Hypoxic exosomal miR-301a-3p induced the M2 polarization of macrophages via activation of the PTEN/PI3K gamma signaling pathway. Coculturing of pancreatic cancer cells with macrophages in which miR-301a-3p was upregulated or treated with hypoxic exosomes enhanced their metastatic capacity. Collectively, these data indicate that pancreatic cancer cells generate miR-301a-3p-rich exosomes in a hypoxic microenvironment, which then polarize macrophages to promote malignant behaviors of pancreatic cancer cells. Targeting exosomal miR-301a-3p may provide a potential diagnosis and treatment strategy for pancreatic cancer.Significance: These findings identify an exosomal miRNA critical for microenvironmental cross-talk that may prove to be a potential target for diagnosis and treatment of pancreatic cancer.[GRAPHICS]. (C) 2018 AACR.