Time-course analysis of microRNA-induced mesenchymal-to-epithelial transition underscores the complexity of the underlying molecular processes
Time-course analysis of microRNA-induced mesenchymal-to-epithelial transition underscores the complexity of the underlying molecular processes
复制标题
DOI：
10.1016/j.canlet.2018.05.001
复制
发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
McDonald, John F.
中科院分区：
文献类型：
--
作者：
Lili, Loukia N.;Huang, Andrew D.;McDonald, John F.
miR-200家族的miRNA的表达水平在上皮-间充质转化（EMT）和随后的卵巢癌和其他癌症的转移期间显著降低。一致地，miR-200家族miRNA在间充质样细胞中的异位过表达通过将处理的细胞转化为上皮表型来逆转该过程，从而降低侵袭性并增加对化疗药物的敏感性。为了更好地理解miRNA诱导的间充质-间充质转化（MET）的动力学和分子过程，进行了一项时程研究，其中在144 h内监测了与MET相关的miRNA诱导的形态学和分子变化。从细长间充质样表型到立方上皮样表型的形态转变在48小时达到最大化，到144小时细胞恢复到细长表型。> 3000个基因的表达变化，包括许多先前与上皮-间充质转化（EMT）相关的基因，在48 h时最明显，并且在144 h时接近起始表达水平。这些基因中的大多数不是miR-429的直接靶点。先前涉及作为EMT/MET驱动因子的关键miR-429调节基因的靶向（siRNA）抑制不能概括miR-429诱导的MET，表明潜在的分子过程是复杂的。
Expression levels of the miR-200 family of miRNAs are significantly reduced during the epithelial-to-mesenchymal transition (EMT) and consequent metastasis of ovarian and other cancers. Consistently, ectopic over expression of miR-200 family miRNAs in mesenchymal-like cells reverses the process by converting treated cells to an epithelial phenotype, thereby reducing invasiveness and increasing sensitivity to chemotherapeutic drugs. To better understand the dynamics and molecular processes underlying miRNA-induced mesenchymal-to mesenchymal transition (MET), a time-course study was conducted where miRNA-induced morphological and molecular changes associated with MET were monitored over a period of 144 h. Morphological transition from an elongated mesenchymal-like to a cuboidal epithelial-like phenotype is maximized at 48 h with cells returning to the elongated phenotype by 144 h. Changes in the expression of > 3000 genes, including many previously associated with epithelial-to-mesenchymal transition (EMT), are most pronounced at 48 h, and approach starting levels of expression by 144 h. The majority of these genes are not direct targets of miR-429. Targeted (siRNA) inhibition of key miR-429 regulated genes previously implicated as drivers of EMT/MET, do not recapitulate miR-429 induced MET indicating that the underlying molecular processes are complex.