Upregulation of the microRNA cluster at the Dlk1-Dio3 locus in lung adenocarcinoma.
Upregulation of the microRNA cluster at the Dlk1-Dio3 locus in lung adenocarcinoma.
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作者：
其中肺上皮细胞可以被诱导以表达致癌KrasG 12 D的小鼠以类似于人类的方式发展肺腺癌。肺腺癌伴随着无数的遗传变化，其中许多还知之甚少。为了全面了解伴随肺腺癌的转录和转录后变化，我们采用组学方法在诱导的肺腺癌小鼠模型中分析编码基因和非编码小RNA。来自F1杂交小鼠的KrasG 12 D肿瘤的RNAseq转录组分析揭示了肿瘤样品的特异性特征。这包括抑制肿瘤样本中的GTP酶相关基因（Prkg 1，Gnao 1和Rgs 9）网络，以及富集Apobec 1介导的胞嘧啶到尿苷RNA编辑。此外，对已知SNPs的分析不仅揭示了Cd 22表达的变化，而且其表达在肿瘤中变得具有等位基因特异性。然而，最突出的发现来自肿瘤样本的小RNA测序，其揭示了小鼠染色体12 qF 1上Dlk 1-Dio 3位点的约53个microRNA和mRNA的簇在肿瘤中显著且一致地增加。该基因座的激活特异性地发生在分选的肿瘤源性癌细胞中。有趣的是，12 qF 1 RNA在培养的KrasG 12 D肿瘤细胞中被抑制，但在体内移植时被重新激活。这些microRNA与干细胞多能性有关，这些microRNA靶向的蛋白质参与癌症和胚胎发生的关键途径。总之，我们的结果强烈暗示这些microRNA代表了解开肺癌发生机制的关键靶点。
Mice in which lung epithelial cells can be induced to express an oncogenic KrasG12D develop lung adenocarcinomas in a manner analogous to humans. A myriad of genetic changes accompany lung adenocarcinomas, many of which are poorly understood. To get a comprehensive understanding of both the transcriptional and post-transcriptional changes that accompany lung adenocarcinomas, we took an omics approach in profiling both the coding genes and the non-coding small RNAs in an induced mouse model of lung adenocarcinoma. RNAseq transcriptome analysis of KrasG12D tumors from F1 hybrid mice revealed features specific to tumor samples. This includes the repression of a network of GTPase related genes (Prkg1, Gnao1 and Rgs9) in tumor samples and an enrichment of Apobec1-mediated cytosine to uridine RNA editing. Furthermore, analysis of known SNPs revealed not only a change in expression of Cd22 but also that its expression became allele-specific in tumors. The most salient finding however, came from small RNA sequencing of the tumor samples, which revealed that a cluster of ~53 microRNAs and mRNAs at the Dlk1-Dio3 locus on mouse chromosome 12qF1 was dramatically and consistently increased in tumors. Activation of this locus occurred specifically in sorted tumor-originating cancer cells. Interestingly, the 12qF1 RNAs were repressed in cultured KrasG12D tumor cells but reactivated when transplanted in vivo. These microRNAs have been implicated in stem cell pleuripotency and proteins targeted by these microRNAs are involved in key pathways in cancer as well as embryogenesis. Taken together our results strongly imply that these microRNAs represent key targets in unraveling the mechanism of lung oncogenesis.
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影响因子：
30.8
作者：
Burns, Michael B.;Temiz, Nuri A.;Harris, Reuben S.
通讯作者：
Harris, Reuben S.
影响因子：
8
作者：
Garcia-Marcos, M.;Ghosh, P.;Farquhar, M. G.
通讯作者：
Farquhar, M. G.
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
14.9
作者：
Betel D;Wilson M;Gabow A;Marks DS;Sander C
通讯作者：
Sander C
影响因子：
12.3
作者：
Danecek P;Nellåker C;McIntyre RE;Buendia-Buendia JE;Bumpstead S;Ponting CP;Flint J;Durbin R;Keane TM;Adams DJ
通讯作者：
Adams DJ