Network modeling identifies molecular functions targeted by miR-204 to suppress head and neck tumor metastasis.
Network modeling identifies molecular functions targeted by miR-204 to suppress head and neck tumor metastasis.
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DOI：
10.1371/journal.pcbi.1000730
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发表时间：
2010-04-01
影响因子：
4.3
通讯作者：
Lussier YA
中科院分区：
文献类型：
--
作者：
Lee Y;Yang X;Huang Y;Fan H;Zhang Q;Wu Y;Li J;Hasina R;Cheng C;Lingen MW;Gerstein MB;Weichselbaum RR;Xing HR;Lussier YA
由于序列比对数据库预测了大量假定的 microRNA 基因靶标，并且这种预测的准确性相对较低，而这种预测是独立于生物背景而设计的，因此每个功能性 microRNA 靶标的系统实验鉴定和验证目前具有挑战性。因此，生物学研究尚未在基因组规模上确定癌症背景下 microRNA 功能改变所扰乱的关键调控网络。在这份报告中，我们首次证明了如何将遗传性癌症特征和危险因素基因座的表型知识与基因表达分析结合起来，以有效地优先考虑解除管制的 microRNA 进行生物学表征。使用这种方法，我们将 miR-204 描述为肿瘤抑制 microRNA，并揭示了 microRNA 调控、网络拓扑和表达动态之间以前未知的联系。具体来说，我们验证了 miR-204 的 18 个基因靶标，这些靶标显示 mRNA 表达升高，并且富含与头颈鳞状细胞癌 (HNSCC) 肿瘤进展相关的生物过程。我们进一步证明了 miR-204 基因靶标中瓶颈性（关键分子网络拓扑）的富集。 HNSCC 细胞系中 miR-204 功能的恢复会抑制其功能相关基因靶标的表达，导致体外粘附、迁移和侵袭减少，并减弱体内实验性肺转移。同样重要的是，我们的研究还提供了实验证据，将位于癌症相关基因组区域 (CAGR) 的 microRNA 的功能与观察到的人类癌症易感性联系起来。具体来说，我们表明 miR-204 可能在 9q21.1-22.3 CAGR 位点上充当抑癌基因，这是头颈癌中一个已确定的危险因素位点，但尚未确定其抑癌基因。与现有技术相比，这种整合了表达谱、遗传学和新型计算生物学方法的新策略提高了癌症中 microRNA 功能的表征和建模效率，并且适用于其他生物过程和疾病中 microRNA 功能的研究。 MicroRNA 调节细胞中基因的表达，对癌症的发生和进展很重要。设计新的基于 microRNA 的治疗方法需要了解其作用机制。之前的生物学研究缺乏深度，因为只有少数基因被确认为 microRNA 靶标。此外，在癌症背景下受 microRNA 功能改变扰动的关键生物系统仍有待确定。在这里，我们首次展示了如何将有关癌症遗传的遗传知识与有关癌症样本中基因表达的数据结合起来，在多个生物学尺度上模拟失调的 microRNA 及其功能。我们的方法进一步揭示了 microRNA、其调控基因及其动态之间以前未知的联系。使用头颈癌作为模型，我们预测了尚未确定候选基因的癌症相关染色体区域中新肿瘤抑制 microRNA 的存在、功能和基因靶标。然后，我们通过广泛而彻底的生物学表征证实了它们的有效性，并显示小鼠肺转移的减弱。由 microRNA 调节的分子网络的发现可用于设计新的治疗方法，作为单基因靶标范式的替代方案。
Due to the large number of putative microRNA gene targets predicted by sequence-alignment databases and the relative low accuracy of such predictions which are conducted independently of biological context by design, systematic experimental identification and validation of every functional microRNA target is currently challenging. Consequently, biological studies have yet to identify, on a genome scale, key regulatory networks perturbed by altered microRNA functions in the context of cancer. In this report, we demonstrate for the first time how phenotypic knowledge of inheritable cancer traits and of risk factor loci can be utilized jointly with gene expression analysis to efficiently prioritize deregulated microRNAs for biological characterization. Using this approach we characterize miR-204 as a tumor suppressor microRNA and uncover previously unknown connections between microRNA regulation, network topology, and expression dynamics. Specifically, we validate 18 gene targets of miR-204 that show elevated mRNA expression and are enriched in biological processes associated with tumor progression in squamous cell carcinoma of the head and neck (HNSCC). We further demonstrate the enrichment of bottleneckness, a key molecular network topology, among miR-204 gene targets. Restoration of miR-204 function in HNSCC cell lines inhibits the expression of its functionally related gene targets, leads to the reduced adhesion, migration and invasion in vitro and attenuates experimental lung metastasis in vivo. As importantly, our investigation also provides experimental evidence linking the function of microRNAs that are located in the cancer-associated genomic regions (CAGRs) to the observed predisposition to human cancers. Specifically, we show miR-204 may serve as a tumor suppressor gene at the 9q21.1–22.3 CAGR locus, a well established risk factor locus in head and neck cancers for which tumor suppressor genes have not been identified. This new strategy that integrates expression profiling, genetics and novel computational biology approaches provides for improved efficiency in characterization and modeling of microRNA functions in cancer as compared to the state of art and is applicable to the investigation of microRNA functions in other biological processes and diseases. MicroRNAs regulate the expression of genes in cells and are important in cancer development and progression. Designing new microRNA-based treatments requires the understanding of their mechanisms of action. Previous biological studies lack in depth since only a few genes are confirmed as microRNA targets. Additionally, key biological systems perturbed by altered microRNA functions in the context of cancer remain to be identified. Here, we demonstrate for the first time how genetic knowledge about the inheritance of cancer can be utilized jointly with data about the expression of genes in cancer samples to model deregulated microRNAs and their functions at multiple scales of biology. Our approach further uncovers previously unknown connections between microRNAs, their regulated genes, and their dynamics. Using head and neck cancer as a model, we predict the presence, functions, and gene targets of a new tumor suppressor microRNA in a cancer-associated chromosomal region where a candidate gene has not been identified. We then confirm their validity with extensive and thorough biological characterization and show attenuation of lung metastasis in mice. The discovery of molecular networks regulated by microRNAs could be exploited for the design of new treatments as an alternative to the single-gene target paradigm.
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影响因子：
6.4
作者：
Chang, Steven S.;Jiang, Wei Wen;Smith, Ian;Poeta, Luana M.;Begum, Shahnaz;Glazer, Chad;Shan, Shannon;Westra, William;Sidransky, David;Califano, Joseph A.
通讯作者：
Califano, Joseph A.
DOI：
10.1158/1078-0432.ccr-08-3131
发表时间：
2009-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Avissar M;Christensen BC;Kelsey KT;Marsit CJ
通讯作者：
Marsit CJ
影响因子：
56.9
作者：
Farh, KKH;Grimson, A;Bartel, DP
通讯作者：
Bartel, DP
影响因子：
--
作者：
Arora A;Guduric-Fuchs J;Harwood L;Dellett M;Cogliati T;Simpson DA
通讯作者：
Simpson DA
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y