Intercellular nanovesicle-mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth.
Intercellular nanovesicle-mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth.
复制标题
细胞间纳米层介导的microRNA转移：肝癌细胞生长的环境调节机制。
DOI：
10.1002/hep.24504
复制
发表时间：
2011-10
期刊：
影响因子：
13.5
通讯作者：
Patel, Tushar
中科院分区：
文献类型：
--
作者：
Kogure, Takayuki;Lin, Wen-Lang;Yan, Irene K.;Braconi, Chiara;Patel, Tushar
肝细胞癌（HCC）的特点是多灶性、局部扩散生长和多种信号通路失调。这些特征可以由肿瘤微环境决定。肿瘤细胞通过分泌蛋白调节HCC生长和行为的潜力已被广泛研究。与此相反，对遗传调节的潜力了解甚少。我们研究了能够改变基因表达的肿瘤源性纳米囊泡的作用和参与，并表征了它们在其他细胞中调节细胞信号传导和生物学效应的能力。我们表明，肝癌细胞可以产生纳米囊泡（外泌体），其RNA和蛋白质含量与其来源细胞不同。这些可以被其他细胞吸收和内化，并可以传递功能性转基因。检查了这些外来体的microRNA含量，并鉴定了在外来体内高度富集的子集。一种鉴定潜在靶点的组合方法将转化生长因子β激活激酶-1（TAK 1）鉴定为最可能被这些miRNA调节的候选途径。TAK 1的缺失与肝癌发生有关，并且是细胞间调节的生物学合理靶点。我们发现，HCC细胞来源的外泌体可以调节TAK 1表达和相关信号传导，并增强受体细胞中转化细胞的生长。结论：外泌体介导的miRNA转移是HCC细胞间通讯的重要机制。这些观察结果确定了一种独特的细胞间机制，可能有助于HCC的局部扩散、肝内转移或多灶性生长。
Hepatocellular carcinoma (HCC) is characterized by a propensity for multifocality, growth by local spread, and dysregulation of multiple signaling pathways. These features may be determined by the tumoral microenvironment. The potential of tumor cells to modulate HCC growth and behavior by secreted proteins has been extensively studied. In contrast the potential for genetic modulation is poorly understood. We investigated the role and involvement of tumor derived nanovesicles capable of altering gene expression, and characterized their ability to modulate cell signaling and biological effects in other cells. We show that HCC cells can produce nanovesicles, exosomes, that differ in both RNA and protein content from their cells of origin. These can be taken up and internalized by other cells, and can transmit a functional transgene. The microRNA content of these exosomes was examined, and a subset that is highly enriched within exosomes was identified. A combinatorial approach to identify potential targets identified transforming growth factor β activated kinase-1 (TAK1) as the most likely candidate pathway that could be modulated by these miRNA. Loss of TAK1 has been implicated in hepatocarcinogenesis and is a biologically plausible target for inter-cellular modulation. We showed that HCC cell derived exosomes can modulate TAK1 expression and associated signaling and enhance transformed cell growth in recipient cells. Conclusion: Exosome mediated miRNA transfer is an important mechanism of inter-cellular communication in HCC cells. These observations identify a unique inter-cellular mechanism that could potentially contribute to local spread, intrahepatic metastases or multifocal growth in HCC.
登录
查看更多内容
影响因子：
14.9
作者：
Jensen LJ;Kuhn M;Stark M;Chaffron S;Creevey C;Muller J;Doerks T;Julien P;Roth A;Simonovic M;Bork P;von Mering C
通讯作者：
von Mering C
影响因子：
3.8
作者：
Li J;Sherman-Baust CA;Tsai-Turton M;Bristow RE;Roden RB;Morin PJ
通讯作者：
Morin PJ
影响因子：
82.9
作者：
Zitvogel, L;Regnault, A;Amigorena, S
通讯作者：
Amigorena, S
影响因子：
4.4
作者：
Utsugi-Kobukai, S;Fujimaki, H;Minami, M
通讯作者：
Minami, M
影响因子：
21.3
作者：
Skog, Johan;Wuerdinger, Tom;van Rijn, Sjoerd;Meijer, Dimphna H.;Gainche, Laura;Sena-Esteves, Miguel;Curry, William T., Jr.;Carter, Bob S.;Krichevsky, Anna M.;Breakefield, Xandra O.
通讯作者：
Breakefield, Xandra O.