Myc target gene, long intergenic noncoding RNA, Linc00176 in hepatocellular carcinoma regulates cell cycle and cell survival by titrating tumor suppressor microRNAs
Myc target gene, long intergenic noncoding RNA, Linc00176 in hepatocellular carcinoma regulates cell cycle and cell survival by titrating tumor suppressor microRNAs
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DOI：
10.1038/onc.2017.312
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发表时间：
2018-01-04
期刊：
影响因子：
8
通讯作者：
Tamura, T.
中科院分区：
文献类型：
--
作者：
Tran, D. D. H.;Kessler, C.;Tamura, T.
肝细胞癌（HCC）是一种常见的癌症，预后不良，医疗干预的可能性有限。最近的证据表明，长链非编码RNA（lncRNA）是包括癌症在内的疾病过程的重要调节因子。癌细胞中的染色质重塑可能导致lncRNA的异常表达，事实上，已经显示超过7000种未注释的lncRNA在HCC中表达。我们发现了一种新的长基因间非编码RNA，Linc 00176，它在HCC的增殖和存活中起作用。Linc 00176通过海绵功能调节200多个基因的表达，用于肿瘤抑制miRNAs，miR-9和miR-185。Linc 00176仅在HCC中以高水平表达，并且由Myc、Max和AP-4转录调节因子激活。Myc还上调miR-9和miR-185。在Linc 00176缺失的HCC中，这些miRNAs从Linc 00176释放并下调其靶mRNA。因此，Linc 00176的消耗破坏了细胞周期，并通过释放肿瘤抑制miRNA诱导HCC中的坏死性凋亡。这些数据表明，肿瘤表达的lncRNA可能是癌症治疗的有用靶标。
Hepatocellular carcinoma (HCC) is a frequent form of cancer with a poor prognosis and with limited possibilities for medical intervention. Recent evidence has accumulated that long noncoding RNAs (lncRNAs) are important regulators of disease processes including cancer. Chromatin remodeling in cancer cells may result in an unusual expression of lncRNAs and indeed it has been shown that more than 7000 unannotated lncRNAs are expressed in HCCs. We identified a novel long intergenic noncoding RNA, Linc00176, that plays a role in proliferation and survival of HCC. Linc00176 regulates expression of more than 200 genes by the sponge function for tumor suppressor miRNAs, miR-9 and miR-185. Linc00176 is expressed at a high level only in HCC, and is activated by Myc, Max and AP-4 transcription regulators. Myc also upregulates miR-9 and miR-185. In Linc00176-depleted HCC, these miRNAs were released from Linc00176 and downregulated their target mRNAs. Thus, depletion of Linc00176 disrupted the cell cycle and induced necroptosis in HCC via released tumor suppressor miRNAs. These data indicate that atypically expressed lncRNAs may be useful targets for cancer therapy.