Mahlab-Aviv Shelly, Linial Nathan, Linial Michal
The Rachel and Selim Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.
Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
Front Mol Biosci. 2021 Dec 21;8:772852. doi: 10.3389/fmolb.2021.772852. eCollection 2021.
A hallmark of cancer evolution is that the tumor may change its cell identity and improve its survival and fitness. Drastic change in microRNA (miRNA) composition and quantities accompany such dynamic processes. Cancer samples are composed of cells' mixtures of varying stages of cancerous progress. Therefore, cell-specific molecular profiling represents cellular averaging. In this study, we consider the degree to which altering miRNAs composition shifts cell behavior. We used COMICS, an iterative framework that simulates the stochastic events of miRNA-mRNA pairing, using a probabilistic approach. COMICS simulates the likelihood that cells change their transcriptome following many iterations (100 k). Results of COMICS from the human cell line (HeLa) confirmed that most genes are resistant to miRNA regulation. However, COMICS results suggest that the composition of the abundant miRNAs dictates the nature of the cells (across three cell lines) regardless of its actual mRNA steady-state. perturbations of cell lines (i.e., by overexpressing miRNAs) allowed to classify genes according to their sensitivity and resilience to any combination of miRNA perturbations. Our results expose an overlooked quantitative dimension for a set of genes and miRNA regulation in living cells. The immediate implication is that even relatively modest overexpression of specific miRNAs may shift cell identity and impact cancer evolution.
癌症演变的一个标志是肿瘤可能会改变其细胞特性，提高其生存能力和适应性。在这种动态过程中，微小RNA（miRNA）的组成和数量会发生剧烈变化。癌症样本由处于癌变进展不同阶段的细胞混合物组成。因此，细胞特异性分子谱代表了细胞的平均情况。在本研究中，我们考虑了改变miRNA组成对细胞行为的影响程度。我们使用了COMICS，这是一个迭代框架，采用概率方法模拟miRNA与mRNA配对的随机事件。COMICS通过多次迭代（100k次）模拟细胞改变其转录组的可能性。来自人类细胞系（HeLa）的COMICS结果证实，大多数基因对miRNA调控具有抗性。然而，COMICS结果表明，丰富miRNA的组成决定了细胞的性质（在三种细胞系中），而不管其实际的mRNA稳态如何。对细胞系的扰动（即通过过表达miRNA）能够根据基因对任何miRNA扰动组合的敏感性和恢复力对基因进行分类。我们的结果揭示了活细胞中一组基因和miRNA调控中一个被忽视的定量维度。直接的影响是，即使特定miRNA的相对适度过表达也可能改变细胞特性并影响癌症演变。
