Lung adenocarcinoma subtypes definable by lung development-related miRNA expression profiles in association with clinicopathologic features
Lung adenocarcinoma subtypes definable by lung development-related miRNA expression profiles in association with clinicopathologic features
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DOI：
10.1093/carcin/bgu127
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发表时间：
2014-10-01
期刊：
影响因子：
4.7
通讯作者：
Takahashi, Takashi
中科院分区：
文献类型：
--
作者：
Arima, Chinatsu;Kajino, Taisuke;Takahashi, Takashi
遗传和表观遗传变化的积累改变了包括microRNAs(MiRNAs)在内的一系列相互关联的基因的调控，这些基因赋予了标志性的能力和特有的癌症特征。在这项研究中，我们分析了126例非小细胞肺癌标本的miRNA和Messenger RNA的表达谱，特别是肺腺癌的多样性。其中，76例腺癌根据其独特的miRNA表达谱分别类似于发育中的肺或成人肺，被分为两个主要亚型，发展中的肺样和成人的肺样。使用贝叶斯网络和非参数回归的基于系统生物学的方法被用来估计患者肿瘤中基因调控电路的功能，以便识别富含两个主要亚型之间差异表达的基因的子网络。MiR-30d和miR-195是这些亚网络中的中枢基因，在发育中的肺样亚型中表达水平较低，而将miR-30d或miR-195导入肺癌细胞系后，信使RNA的表达谱向成年肺样亚型转移。相反，在我们对患者数据集的分析中，miR-30d和miR-195在发育中的肺样亚型和成人肺样亚型之间的影响显著不同。此外，以miR-30d为中心的亚网络的一个子基因RRM2被发现是miR-30d的直接靶点。总之，我们的发现揭示了两种miRNA表达谱定义的肺腺癌亚型的存在，它们具有不同的临床病理特征，也表明基于系统生物学的方法对于深入了解参与癌症发展的改变的调节电路是有用的。
Accumulation of genetic and epigenetic changes alters regulation of a web of interconnected genes including microRNAs (miRNAs), which confer hallmark capabilities and characteristic cancer features. In this study, the miRNA and messenger RNA expression profiles of 126 non-small cell lung cancer specimens were analyzed, with special attention given to the diversity of lung adenocarcinomas. Of those, 76 adenocarcinomas were classified into two major subtypes, developing lung-like and adult lung-like, based on their distinctive miRNA expression profiles resembling those of either developing or adult lungs, respectively. A systems biology-based approach using a Bayesian network and non-parametric regression was employed to estimate the gene regulatory circuitry functioning in patient tumors in order to identify subnetworks enriched for genes with differential expression between the two major subtypes. miR-30d and miR-195, identified as hub genes in such subnetworks, had lower levels of expression in the developing lung-like subtype, whereas introduction of miR-30d or miR-195 into the lung cancer cell lines evoked shifts of messenger RNA expression profiles toward the adult lung-like subtype. Conversely, the influence of miR-30d and miR-195 was significantly different between the developing lung-like and adult lung-like subtypes in our analysis of the patient data set. In addition, RRM2, a child gene of the miR-30d-centered subnetwork, was found to be a direct target of miR-30d. Together, our findings reveal the existence of two miRNA expression profile-defined lung adenocarcinoma subtypes with distinctive clinicopathologic features and also suggest the usefulness of a systems biology-based approach to gain insight into the altered regulatory circuitry involved in cancer development.