Exosome-derived FGD5-AS1 promotes tumor-associated macrophage M2 polarization-mediated pancreatic cancer cell proliferation and metastasis
Exosome-derived FGD5-AS1 promotes tumor-associated macrophage M2 polarization-mediated pancreatic cancer cell proliferation and metastasis
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外泌体来源的FGD5-AS1促进肿瘤相关巨噬细胞M2极化介导的胰腺癌细胞增殖和转移
DOI：
10.1016/j.canlet.2022.215751
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发表时间：
2022-09-01
期刊：
影响因子：
9.7
通讯作者：
Sun, Chengyi
中科院分区：
文献类型：
--
作者：
He, Zhiwei;Wang, Jie;Sun, Chengyi
炎症分子和外泌体对于肿瘤相关巨噬细胞和肿瘤细胞之间的信号转导至关重要。IL-6是M2巨噬细胞极化后分泌的关键炎症分子，可介导胰腺癌（PC）的恶性进展。然而，IL-6和肿瘤源性外泌体在肿瘤相关巨噬细胞和PC中的功能和机制尚不清楚。转录组芯片和定量反转录PCR实验表明，FGD5-AS1诱导IL-6， FGD5-AS1高表达与PC患者预后不良相关。采用RNA下拉法、质谱法和双荧光素酶报告基因检测来鉴定外泌体FGD5-AS1促进PC进展和M2巨噬细胞极化的机制。FGD5-AS1与M2巨噬细胞共培养时发挥促癌作用。pc源性外泌体FGD5-AS1通过激活STAT3/ NF-Kappa B通路刺激M2巨噬细胞极化。FGD5-AS1与p300相互作用，导致STAT3乙酰化，从而促进STAT3/NF-Kappa b的核定位和转录活性。这些数据表明PC细胞产生富含FGD5-AS1的外泌体，使M2巨噬细胞极化，促进PC细胞的恶性行为。靶向外泌体FGD5-AS1可能为PC提供潜在的诊断和治疗策略。
Inflammatory molecules and exosomes are crucial for signal transduction between tumor-associated macro-phages and tumor cells. IL-6, a key inflammatory molecule secreted by M2 macrophages after polarization, can mediate malignant progression of pancreatic cancer (PC). However, the functions and mechanisms of IL-6 and tumor-derived exosomes in tumor-associated macrophages and PC remain unclear. Transcriptome chip and quantitative reverse transcription PCR experiments indicated that FGD5-AS1 induced IL-6 and high FGD5-AS1 expression correlated with the poor prognosis in PC patients. RNA pulldown, mass spectrometry, and dual luciferase reporter assays were used to identify the mechanism of exosomal FGD5-AS1 in promoting PC pro-gression and M2 macrophage polarization. FGD5-AS1 exerted cancer-promoting functions when co-cultured with M2 macrophages. PC-derived exosomal FGD5-AS1 stimulated M2 macrophage polarization by activating STAT3/ NF-Kappa B pathway. FGD5-AS1 interacts with p300, resulting in STAT3 acetylation, thus promoting nuclear locali-zation and transcriptional activity of STAT3/NF-Kappa B. These data indicated that PC cells generate FGD5-AS1-rich exosomes, which cause M2 macrophage polarization to promote the malignant behaviors of PC cells. Targeting exosomal FGD5-AS1 may provide a potential diagnosis and treatment strategy for PC.