Hepatocellular carcinoma-derived exosomes promote motility of immortalized hepatocyte through transfer of oncogenic proteins and RNAs
Hepatocellular carcinoma-derived exosomes promote motility of immortalized hepatocyte through transfer of oncogenic proteins and RNAs
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DOI：
10.1093/carcin/bgv081
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发表时间：
2015-09-01
期刊：
影响因子：
4.7
通讯作者：
Wong, Nathalie
中科院分区：
文献类型：
--
作者：
He, Mian;Qin, Hao;Wong, Nathalie
外泌体被认为是癌症进展中细胞间通讯的介质，通过将 RNA 和蛋白质水平转移到邻近细胞。我们在这项研究中表明，源自 HCC 的外泌体可以诱导肝细胞的迁移和侵袭。通过将 RNA 和蛋白质水平转移到邻近或远处的细胞，外泌体越来越被认为是癌症进展中细胞间通讯的重要介质。肝细胞癌（HCC）是一种高度恶性的癌症，其转移很大程度上受肿瘤微环境的影响。然而，外泌体在 HCC 肿瘤细胞与其周围肝环境之间相互作用中的可能作用在很大程度上尚不清楚。在本研究中，我们分别使用 Ion Torrent 测序和质谱全面表征了来自三种 HCC 细胞系（HKCI-C3、HKCI-8 和 MHCC97L）和永生化肝细胞系 (MIHA) 的外泌体 RNA 和蛋白质组含量。 RNA深度测序和蛋白质组分析显示，源自转移性HCC细胞系的外泌体携带大量促肿瘤RNA和蛋白质，例如MET原癌基因、S100家族成员和小窝蛋白。有趣的是，我们发现来自运动性 HCC 细胞系的外泌体可以显着增强非运动性 MIHA 细胞的迁移和侵袭能力。我们进一步证明，摄取这些穿梭分子可以触发 MIHA 中的 PI3K/AKT 和 MAPK 信号通路，并增加活性 MMP-2 和 MMP-9 的分泌。我们的研究首次表明，肝癌来源的外泌体可以动员正常肝细胞，这可能有助于促进肝癌细胞在转移过程中通过肝实质突出活动。
Exosomes are recognized as mediators of cell-cell communication in cancer progression through the horizontal transfer of RNAs and proteins to neighboring cells. We show in this study exosomes derived from HCC could induce migration and invasion of hepatocytes.Exosomes are increasingly recognized as important mediators of cell-cell communication in cancer progression through the horizontal transfer of RNAs and proteins to neighboring or distant cells. Hepatocellular carcinoma (HCC) is a highly malignant cancer, whose metastasis is largely influenced by the tumor microenvironment. The possible role of exosomes in the interactions between HCC tumor cell and its surrounding hepatic milieu are however largely unknown. In this study, we comprehensively characterized the exosomal RNA and proteome contents derived from three HCC cell lines (HKCI-C3, HKCI-8 and MHCC97L) and an immortalized hepatocyte line (MIHA) using Ion Torrent sequencing and mass spectrometry, respectively. RNA deep sequencing and proteomic analysis revealed exosomes derived from metastatic HCC cell lines carried a large number of protumorigenic RNAs and proteins, such as MET protooncogene, S100 family members and the caveolins. Of interest, we found that exosomes from motile HCC cell lines could significantly enhance the migratory and invasive abilities of non-motile MIHA cell. We further demonstrated that uptake of these shuttled molecules could trigger PI3K/AKT and MAPK signaling pathways in MIHA with increased secretion of active MMP-2 and MMP-9. Our study showed for the first time that HCC-derived exosomes could mobilize normal hepatocyte, which may have implication in facilitating the protrusive activity of HCC cells through liver parenchyma during the process of metastasis.