SNHG15 is a bifunctional MYC-regulated noncoding locus encoding a lncRNA that promotes cell proliferation, invasion and drug resistance in colorectal cancer by interacting with AIF
SNHG15 is a bifunctional MYC-regulated noncoding locus encoding a lncRNA that promotes cell proliferation, invasion and drug resistance in colorectal cancer by interacting with AIF
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DOI：
10.1186/s13046-019-1169-0
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发表时间：
2019-04-24
影响因子：
11.3
通讯作者：
Huarte, Maite
中科院分区：
文献类型：
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作者：
Saeinasab, Morvarid;Bahrami, Ahmad Reza;Huarte, Maite
背景成千上万的长链非编码RNA（lncRNA）在各种类型的癌症中异常表达，然而我们对它们在疾病中的作用的理解仍然非常有限。我们遵循这些研究与基因调控分析以及实验解剖的作用，确定lncRNA通过多种体外和体内methods.ResultsWe分析RNA-seq数据从肿瘤的456 CRC患者相比，正常的样品，并确定SNHG 15作为一个潜在的致癌lncRNA编码的snoRNA在其内含子之一。经过加工的SNHG 15在CRC肿瘤中过表达，其表达与患者的生存率低高度相关。有趣的是，SNHG 15在具有高水平MYC表达的肿瘤中更高地表达，而MYC蛋白结合SNHG 15序列上的两个E-box基序，表明SNHG 15转录直接受致癌基因MYC调节。通过siRNA或CRISPR-Cas9消耗SNHG 15抑制细胞增殖和侵袭，降低集落形成以及CRC细胞的致瘤能力。而其过度表达导致相反的效果。在SNHG 15抑制后进行的基因表达分析显示了与癌症进展有关的多个相关基因的变化，包括MYC、NRAS、BAG 3或ERBB 3。其中几个基因在功能上与AIF相关，AIF是一种我们发现与SNHG 15特异性相互作用的蛋白质，这表明SNHG 15至少部分地通过调节AIF的活性来发挥作用。有趣的是，由AIF直接调节的ROS水平在SNHG 15耗尽的细胞中显示出显著降低。此外，敲除SNHG 15增加了细胞对5-FU的敏感性，而其过表达使它们对化疗药物更具抗性。ConclusionAltogether，这些结果描述了SNHG 15在促进结肠癌和介导耐药性中的重要作用，表明其作为预后标志物和靶点的潜力。
BackgroundThousands of long noncoding RNAs (lncRNAs) are aberrantly expressed in various types of cancers, however our understanding of their role in the disease is still very limited.MethodsWe applied RNAseq analysis from patient-derived data with validation in independent cohort of patients. We followed these studies with gene regulation analysis as well as experimental dissection of the role of the identified lncRNA by multiple in vitro and in vivo methods.ResultsWe analyzed RNA-seq data from tumors of 456 CRC patients compared to normal samples, and identified SNHG15 as a potentially oncogenic lncRNA that encodes a snoRNA in one of its introns. The processed SNHG15 is overexpressed in CRC tumors and its expression is highly correlated with poor survival of patients. Interestingly, SNHG15 is more highly expressed in tumors with high levels of MYC expression, while MYC protein binds to two E-box motifs on SNHG15 sequence, indicating that SNHG15 transcription is directly regulated by the oncogene MYC.The depletion of SNHG15 by siRNA or CRISPR-Cas9 inhibits cell proliferation and invasion, decreases colony formation as well as the tumorigenic capacity of CRC cells, whereas its overexpression leads to opposite effects. Gene expression analysis performed upon SNHG15 inhibition showed changes in multiple relevant genes implicated in cancer progression, including MYC, NRAS, BAG3 or ERBB3. Several of these genes are functionally related to AIF, a protein that we found to specifically interact with SNHG15, suggesting that the SNHG15 acts, at least in part, by regulating the activity of AIF. Interestingly, ROS levels, which are directly regulated by AIF, show a significant reduction in SNHG15-depleted cells. Moreover, knockdown of SNHG15 increases the sensitiveness of the cells to 5-FU, while its overexpression renders them more resistant to the chemotherapeutic drug.ConclusionAltogether, these results describe an important role of SNHG15 in promoting colon cancer and mediating drug resistance, suggesting its potential as prognostic marker and target for RNA-based therapies.