Exosomal HIF1α supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes.
Exosomal HIF1α supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes.
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最近发现外泌体是参与肿瘤发生的促肿瘤因子的潜在载体。然而，致癌转录因子是否由外来体转导尚不清楚。缺氧诱导因子-1 α（HIF 1 α）通过促进更具侵袭性的肿瘤表型（其特征为增殖和侵袭性增加以及新血管生成）在转录上调节肿瘤发生和进展的许多关键方面。已经显示，EB病毒（EBV）的主要癌蛋白，潜伏膜蛋白1（LMP 1），驱动高度侵袭性EBV恶性肿瘤，鼻咽癌（NPC）的致癌过程和肿瘤进展。我们现在证明了内源性HIF 1 α在外泌体中是可检测的，并且LMP 1显著增加了外泌体中HIF 1 α的水平。从外泌体回收的HIF 1保留DNA结合活性，并且在外泌体摄取后在受体细胞中具有转录活性。我们还表明，用LMP 1-外泌体处理EBV阴性细胞在功能测定中增加了NP细胞系的迁移和侵袭力，这与上皮-间充质转化（EMT）相关的表型相关。此外，我们提供证据表明，HIF 1 α本身参与了受体细胞中外泌体介导的促转移作用，因为外泌体介导的活性和非活性形式的HIF 1 α的递送导致与EMT相关的E-和N-钙粘蛋白表达的相互变化。此外，NPC肿瘤组织的免疫组织化学分析揭示了LMP 1和内体/外泌体标记物四跨膜蛋白（tetraspanin）CD 63的蛋白水平之间的直接相关性，这表明在这种EBV阳性恶性肿瘤中外泌体形成增加。我们假设外泌体介导的LMP 1阳性NPC细胞向周围肿瘤细胞转移功能性促转移因子促进癌症进展。
It has emerged recently that exosomes are potential carriers of pro-tumorigenic factors that participate in oncogenesis. However, whether oncogenic transcription factors are transduced by exosomes is unknown. Hypoxia-inducible factor-1α (HIF1α) transcriptionally regulates numerous key aspects of tumor development and progression by promoting a more aggressive tumor phenotype, characterized by increased proliferation and invasiveness coupled with neoangiogenesis. It has been shown that the principal oncoprotein of Epstein–Barr virus (EBV), latent membrane protein 1 (LMP1), drives oncogenic processes and tumor progression of the highly invasive EBV malignancy, nasopharyngeal carcinoma (NPC). We now demonstrate that endogenous HIF1α is detectable in exosomes and that LMP1 significantly increases levels of HIF1α in exosomes. HIF1 recovered from exosomes retains DNA-binding activity and is transcriptionally active in recipient cells after exosome uptake. We also show that treatment of EBV-negative cells with LMP1-exosomes increases migration and invasiveness of NP cell lines in functional assays, which correlates with the phenotype associated with epithelial–mesenchymal transition (EMT). In addition, we provide evidence that HIF1α itself participates in exosome-mediated pro-metastatic effects in recipient cells, as exosome-mediated delivery of active and inactive forms of HIF1α results in reciprocal changes in the expression of E- and N-cadherins associated with EMT. Further, immunohistochemical analysis of NPC tumor tissues revealed direct correlation between protein levels of LMP1 and of the endosome/exosome marker tetraspanin, CD63, which suggests an increase in exosome formation in this EBV-positive malignancy. We hypothesize that exosome-mediated transfer of functional pro-metastatic factors by LMP1-positive NPC cells to surrounding tumor cells promotes cancer progression.
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影响因子：
5.8
作者：
Pant S;Hilton H;Burczynski ME
通讯作者：
Burczynski ME
影响因子：
3.9
作者：
Rana, Sanyukta;Zoeller, Margot
通讯作者：
Zoeller, Margot
影响因子：
2.2
作者：
Lamparski, HG;Metha-Damani, A;Le Pecq, JB
通讯作者：
Le Pecq, JB
影响因子：
11.2
作者：
Kondo, Satoru;Seo, So Young;Pagano, Joseph S.
通讯作者：
Pagano, Joseph S.
DOI：
10.1073/pnas.0914843107
发表时间：
2010-04-06
影响因子：
11.1
作者：
Pegtel, D. Michiel;Cosmopoulos, Katherine;Middeldorp, Jaap M.
通讯作者：
Middeldorp, Jaap M.