Systemically circulating viral and tumor-derived microRNAs in KSHV-associated malignancies.
Systemically circulating viral and tumor-derived microRNAs in KSHV-associated malignancies.
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DOI：
10.1371/journal.ppat.1003484
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Dittmer DP
中科院分区：
文献类型：
--
作者：
Chugh PE;Sin SH;Ozgur S;Henry DH;Menezes P;Griffith J;Eron JJ;Damania B;Dittmer DP
microRNA（miRNAs）是一类稳定的小分子非编码RNA，可调控下游靶基因的表达。最近，在各种体液和外来体中检测到循环miRNA，促使其作为疾病，特别是癌症的候选生物标志物进行评估。卡波西肉瘤（KS）是最常见的艾滋病相关癌症，尽管进行了高效抗逆转录病毒治疗（HAART），但仍然很普遍。KS是由KS相关疱疹病毒（KSHV）引起的，KSHV是一种γ疱疹病毒，也与原发性渗出性淋巴瘤（PEL）有关。我们试图确定来自KSHV相关恶性肿瘤KS和PEL患者以及来自两种KS小鼠模型的血浆、胸腔液或血清中的宿主和病毒循环miRNA。KSHV编码的miRNA和宿主miRNA，包括miR-17-92簇的成员，在来自KSHV小鼠模型的患者外泌体和循环miRNA谱中均可检测到。进一步的表征揭示了似乎优先掺入外泌体的miRNA的子集。对标志性外泌体miRNA靶标的基因本体分析揭示了已知在KSHV发病机制中重要的几种信号传导途径。对暴露于患者来源的外泌体的内皮细胞的功能分析证明了增强的细胞迁移和IL-6分泌。这表明来源于KSHV相关恶性肿瘤的外泌体是功能性的，并且含有不同的miRNA子集。这些可能代表疾病的候选生物标志物，并可能有助于作为KS特征的旁分泌表型。循环microRNA（miRNAs），如在外来体中发现的那些，已成为诊断工具，并有望成为微创，稳定的生物标志物。肿瘤来源的外泌体miRNA向周围细胞的转移可能是细胞通信的重要形式。卡波西肉瘤相关疱疹病毒（KSHV）是卡波西肉瘤（KS）的病原体，KS是世界上最常见的艾滋病定义癌症。在这里，我们调查了全身循环的miRNA，并揭示了KS和原发性渗出性淋巴瘤（PEL）的潜在生物标志物。这扩展了以前的组织培养研究，通过分析临床样本和使用两个新的小鼠模型KSHV肿瘤发生。对循环miRNA的分析显示，致癌和病毒miRNA存在于来自KS患者血浆、胸腔积液和KS小鼠模型的外来体中。对人类致癌miRNAs的分析，包括众所周知的miR-17-92簇，揭示了在我们的KS小鼠模型中，几种miRNAs优先掺入外泌体中。上调的miRNAs的基因本体分析表明，大多数受影响的途径是KSHV信号通路的已知靶点。将这些致癌外泌体转移至永生化hTERT-HUVEC细胞增强了细胞迁移和IL-6分泌。因此，这些循环miRNA和KS衍生的外泌体可能是介导KSHV发病机制的旁分泌信号机制的一部分。
MicroRNAs (miRNAs) are stable, small non-coding RNAs that modulate many downstream target genes. Recently, circulating miRNAs have been detected in various body fluids and within exosomes, prompting their evaluation as candidate biomarkers of diseases, especially cancer. Kaposi's sarcoma (KS) is the most common AIDS-associated cancer and remains prevalent despite Highly Active Anti-Retroviral Therapy (HAART). KS is caused by KS-associated herpesvirus (KSHV), a gamma herpesvirus also associated with Primary Effusion Lymphoma (PEL). We sought to determine the host and viral circulating miRNAs in plasma, pleural fluid or serum from patients with the KSHV-associated malignancies KS and PEL and from two mouse models of KS. Both KSHV-encoded miRNAs and host miRNAs, including members of the miR-17–92 cluster, were detectable within patient exosomes and circulating miRNA profiles from KSHV mouse models. Further characterization revealed a subset of miRNAs that seemed to be preferentially incorporated into exosomes. Gene ontology analysis of signature exosomal miRNA targets revealed several signaling pathways that are known to be important in KSHV pathogenesis. Functional analysis of endothelial cells exposed to patient-derived exosomes demonstrated enhanced cell migration and IL-6 secretion. This suggests that exosomes derived from KSHV-associated malignancies are functional and contain a distinct subset of miRNAs. These could represent candidate biomarkers of disease and may contribute to the paracrine phenotypes that are a characteristic of KS. Circulating microRNAs (miRNAs), such as those found in exosomes, have emerged as diagnostic tools and hold promise as minimally invasive, stable biomarkers. Transfer of tumor-derived exosomal miRNAs to surrounding cells may be an important form of cellular communication. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), the most common AIDS-defining cancer worldwide. Here, we survey systemically circulating miRNAs and reveal potential biomarkers for KS and Primary Effusion Lymphoma (PEL). This expands previous tissue culture studies by profiling clinical samples and by using two new mouse models of KSHV tumorigenesis. Profiling of circulating miRNAs revealed that oncogenic and viral miRNAs were present in exosomes from KS patient plasma, pleural effusions and mouse models of KS. Analysis of human oncogenic miRNAs, including the well-known miR-17-92 cluster, revealed that several miRNAs were preferentially incorporated into exosomes in our KS mouse model. Gene ontology analysis of upregulated miRNAs showed that the majority of pathways affected were known targets of KSHV signaling pathways. Transfer of these oncogenic exosomes to immortalized hTERT-HUVEC cells enhanced cell migration and IL-6 secretion. These circulating miRNAs and KS derived exosomes may therefore be part of the paracrine signaling mechanism that mediates KSHV pathogenesis.
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DOI：
10.1038/mt.2008.1
发表时间：
2008-04
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
Dai S;Wei D;Wu Z;Zhou X;Wei X;Huang H;Li G
通讯作者：
Li G
影响因子：
6.7
作者：
Chen W;Sin SH;Wen KW;Damania B;Dittmer DP
通讯作者：
Dittmer DP
影响因子：
7.3
作者：
Chugh, Pauline;Dittmer, Dirk P.
通讯作者：
Dittmer, Dirk P.
DOI：
10.1073/pnas.1209414109
发表时间：
2012-07-31
影响因子：
11.1
作者：
Fabbri, Muller;Paone, Alessio;Croce, Carlo M.
通讯作者：
Croce, Carlo M.
一种定量PCR方法，可检测转基因小鼠中与肿瘤发生相关的血液microRNA。
影响因子：
37.3
作者：
Fan, Alice C.;Goldrick, Marianna M.;Ho, Jennifer;Liang, Yu;Bachireddy, Pavan;Felsher, Dean W.
通讯作者：
Felsher, Dean W.