Specific patterns of PIWI-interacting small noncoding RNA expression in dysplastic liver nodules and hepatocellular carcinoma.
Specific patterns of PIWI-interacting small noncoding RNA expression in dysplastic liver nodules and hepatocellular carcinoma.
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DOI：
10.18632/oncotarget.10567
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发表时间：
2016-08-23
期刊：
影响因子：
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通讯作者：
Weisz A
中科院分区：
文献类型：
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作者：
Rizzo F;Rinaldi A;Marchese G;Coviello E;Sellitto A;Cordella A;Giurato G;Nassa G;Ravo M;Tarallo R;Milanesi L;Destro A;Torzilli G;Roncalli M;Di Tommaso L;Weisz A
肝细胞癌 (HCC) 是一个逐步过程的结果，通常始于肝硬化肝脏内癌前病变的发展，其形态学特征为低级别 (LGDN) 和高级别 (HGDN) 发育不良结节。 PIWI 相互作用 RNA (piRNA) 是小型非编码 RNA (sncRNA)，长度为 23-35 个核苷酸，对基因表达发挥表观遗传和转录后调节作用。最近，PIWI-piRNA 通路在生殖系细胞中得到了最好的表征，也在体细胞组织中得到了鉴定，包括干细胞和癌细胞，它影响着关键的细胞过程。应用小RNA测序来寻找肝脏piRNA，并分析其在肝硬化结节（CN）、LGDN、HGDN、早期HCC和进展性HCC（pHCC）中的表达模式，分析了17名患者的55个样本（14个CN、9个LGDN、6个HGDN、6个eHCC和20个pHCC），旨在确定这些sncRNA与肝癌发生之间的可能关系。我们从匹配的 CN 中鉴定出表征 HCC 的 125 个 piRNA 表达特征，也与 HCC 中的微血管侵袭相关。对失调的 piRNA 的预测 RNA 靶点的功能分析表明，这些靶点可以靶向参与肝癌发生和 HCC 进展的关键信号通路，从而影响其活性。有趣的是，24 个 piRNA 在肝硬化肝脏和/或 pHCC 的发育不良结节中显示出特定的表达模式。结果表明，PIWI-piRNA 通路在人类肝脏中很活跃，它代表了从早期阶段到 pHCC 的肝癌发生特征的分子事件中的新参与者。此外，他们认为 piRNA 可能是新的疾病生物标志物，可用于鉴别诊断发育不良和肿瘤性肝脏病变。
Hepatocellular carcinoma (HCC) is the result of a stepwise process, often beginning with development within a cirrhotic liver of premalignant lesions, morphologically characterized by low- (LGDN) and high-grade (HGDN) dysplastic nodules. PIWI-interacting RNAs (piRNAs) are small noncoding RNAs (sncRNAs), 23–35 nucleotide-long, exerting epigenetic and post-transcriptional regulation of gene expression. Recently the PIWI-piRNA pathway, best characterized in germline cells, has been identified also in somatic tissues, including stem and cancer cells, where it influences key cellular processes. Small RNA sequencing was applied to search for liver piRNAs and to profile their expression patterns in cirrhotic nodules (CNs), LGDN, HGDN, early HCC and progressed HCC (pHCC), analyzing 55 samples (14 CN, 9 LGDN, 6 HGDN, 6 eHCC and 20 pHCC) from 17 patients, aiming at identifying possible relationships between these sncRNAs and liver carcinogenesis. We identified a 125 piRNA expression signature that characterize HCC from matched CNs, correlating also to microvascular invasion in HCC. Functional analysis of the predicted RNA targets of deregulated piRNAs indicates that these can target key signaling pathways involved in hepatocarcinogenesis and HCC progression, thereby affecting their activity. Interestingly, 24 piRNAs showed specific expression patterns in dysplastic nodules, respect to cirrhotic liver and/or pHCC. The results demonstrate that the PIWI-piRNA pathway is active in human liver, where it represents a new player in the molecular events that characterize hepatocarcinogenesis, from early stages to pHCC. Furthermore, they suggest that piRNAs might be new disease biomarkers, useful for differential diagnosis of dysplastic and neoplastic liver lesions.