Ras Post-transcriptionally Enhances a Pre-malignantly Primed EMT to Promote Invasion.
Ras Post-transcriptionally Enhances a Pre-malignantly Primed EMT to Promote Invasion.
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DOI：
10.1016/j.isci.2018.05.011
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发表时间：
2018-06-29
期刊：
影响因子：
5.8
通讯作者：
Keene JD
中科院分区：
文献类型：
--
作者：
Bisogno LS;Friedersdorf MB;Keene JD
上皮-间充质转化（EMT）是癌症进展的组成部分，有相当多的证据表明EMT有多个中间阶段。了解这种逐步激活的机制是非常有趣的。我们重建了一个遗传定义的模型，其中原代细胞永生化，导致迁移能力，随后H-Ras转化，导致恶性肿瘤和侵袭。为了确定协调逐步恶性肿瘤的机制，我们量化了信使RNA（mRNA）和蛋白质丰度的变化。在永生化过程中，我们发现mRNA发生了巨大的变化，与EMT一致，这与蛋白质丰度相关。这些相同的蛋白质中的许多在Ras转化后也发生了变化，这表明癌前细胞被引发恶性转化。出乎意料的是，蛋白质丰度的变化与转化后mRNA的变化无关。重要的是，参与细胞粘附和细胞骨架结构的蛋白质在永生化过程中减少，并在Ras转化后进一步减少，而它们的编码mRNA仅在永生化步骤中发生变化。因此，Ras诱导EMT相关的入侵通过转录后机制在引发的癌前细胞。两阶段进行性细胞培养模型证明部分EMT状态癌前永生化改变RNA丰度以诱导细胞迁移Ras转化改变蛋白质丰度，但不改变RNA，以诱导细胞侵袭两个阶段共同调节粘附分子和RBP的蛋白质表达分子网络;癌症系统生物学;转录组学
Epithelial-to-mesenchymal transition (EMT) is integral to cancer progression, with considerable evidence that EMT has multiple intermediary stages. Understanding the mechanisms of this stepwise activation is of great interest. We recreated a genetically defined model in which primary cells were immortalized, resulting in migratory capacity, and subsequently H-Ras-transformed, causing malignancy and invasion. To determine the mechanisms coordinating stepwise malignancy, we quantified the changes in messenger RNA (mRNA) and protein abundance. During immortalization, we found dramatic changes in mRNA, consistent with EMT, which correlated with protein abundance. Many of these same proteins also changed following Ras transformation, suggesting that pre-malignant cells were primed for malignant conversion. Unexpectedly, changes in protein abundance did not correlate with changes in mRNA following transformation. Importantly, proteins involved in cellular adhesion and cytoskeletal structure decreased during immortalization and decreased further following Ras transformation, whereas their encoding mRNAs only changed during the immortalization step. Thus, Ras induced EMT-associated invasion via post-transcriptional mechanisms in primed pre-malignant cells. Two-stage progressive cell culture model demonstrates partial EMT states Pre-malignant immortalization alters RNA abundance to induce cell migration Ras transformation alters protein abundance, but not RNA, to induce cell invasion Both stages cooperate to regulate protein expression of adhesion molecules and RBPs Molecular Network; Cancer Systems Biology; Transcriptomics
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