Exosomes derived from pancreatic cancer cells induce activation and profibrogenic activities in pancreatic stellate cells
Exosomes derived from pancreatic cancer cells induce activation and profibrogenic activities in pancreatic stellate cells
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DOI：
10.1016/j.bbrc.2017.10.141
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发表时间：
2018-01-01
影响因子：
3.1
通讯作者：
Shimosegawa, Tooru
中科院分区：
文献类型：
--
作者：
Masamune, Atsushi;Yoshida, Naoki;Shimosegawa, Tooru
胰腺癌细胞 (PCC) 与胰腺星状细胞 (PSC) 相互作用，在胰腺纤维形成中发挥关键作用，从而形成癌症条件性肿瘤微环境。外泌体是膜封闭的纳米囊泡，越来越多地被认为是细胞间通讯的重要介质。本研究的目的是阐明 PCC 衍生的外泌体对 PSC 细胞功能的影响。从 Panc-1 和 SUIT-2 PCC 的条件培养基中分离出外泌体。用 PCC 衍生的外泌体处理人原代 PSC。 PCC 来源的外泌体刺激 PSC 中 ERK 和 Akt 的增殖、迁移、激活、α-平滑肌肌动蛋白 (ACTA2) 和纤维化相关基因的 mRNA 表达，以及 I 型前胶原 C 肽的产生。对微阵列数据的独创性途径分析确定转化生长因子β1和肿瘤坏死因子是顶级上游调节因子。 PCC 增加了 PSC 中 PCC 衍生的外泌体中丰富的 miR-1246 和 miR-1290 的表达。 miR-1290 的过表达诱导 PSC 中 ACTA2 和纤维化相关基因的表达。总之，PCC 衍生的外泌体刺激 PSC 的激活和促纤维化活性。外泌体介导的 PSC 和 PCC 之间的相互作用可能在肿瘤微环境的发展中发挥作用。 (C) 2017 Elsevier Inc. 保留所有权利。
Pancreatic cancer cells (PCCs) interact with pancreatic stellate cells (PSCs), which play a pivotal role in pancreatic fibrogenesis, to develop the cancer-conditioned tumor microenvironment. Exosomes are membrane-enclosed nanovesicles, and have been increasingly recognized as important mediators of cell to-cell communications. The aim of this study was to clarify the effects of PCC-derived exosomes on cell functions in PSCs. Exosomes were isolated from the conditioned medium of Panc-1 and SUIT-2 PCCs. Human primary PSCs were treated with PCC-derived exosomes. PCC-derived exosomes stimulated the proliferation, migration, activation of ERK and Akt, the mRNA expression of a-smooth muscle actin (ACTA2) and fibrosis-related genes, and procollagen type I C-peptide production in PSCs. Ingenuity pathway analysis of the microarray data identified transforming growth factor beta 1 and tumor necrosis factor as top upstream regulators. PCCs increased the expression of miR-1246 and miR-1290, abundantly contained in PCC-derived exosomes, in PSCs. Overexpression of miR-1290 induced the expression of ACTA2 and fibrosis-related genes in PSCs. In conclusion, PCC-derived exosomes stimulate activation and profibrogenic activities in PSCs. Exosome-mediated interactions between PSCs and PCCs might play a role in the development of the tumor microenvironment. (C) 2017 Elsevier Inc. All rights reserved.