TWIST1-induced miR-424 reversibly drives mesenchymal programming while inhibiting tumor initiation

David J. Drasin, Anna L. Guarnieri, Deepika Neelakantan, Jihye Kim, Joshua H. Cabrera, Chu An Wang, Vadym Zaberezhnyy, Pierluigi Gasparini, Luciano Cascione, Kay Huebner, Aik Choon Tan, Heide L. Ford

研究成果: Article同行評審

46 引文 斯高帕斯(Scopus)

摘要

Epithelial-to-mesenchymal transition (EMT) is a dynamic process that relies on cellular plasticity. Recently, the process of an oncogenic EMT, followed by a reverse mesenchymal-to-epithelial transition (MET), has been implicated as critical in the metastatic colonization of carcinomas. Unlike governance of epithelial programming, regulation of mesenchymal programming is not well understood in EMT. Here, we describe and characterize the first microRNA that enhances exclusively mesenchymal programming. We demonstrate that miR-424 is upregulated early during a TWIST1 or SNAI1-induced EMT, and that it causes cells to express mesenchymal genes without affecting epithelial genes, resulting in a mixed/intermediate EMT. Furthermore, miR-424 increases motility, decreases adhesion, and induces a growth arrest, changes associated with a complete EMT that can be reversed when miR-424 expression is lowered, concomitant with an MET-like process. Breast cancer patient miR-424 levels positively associate with TWIST1/2 and EMT-like gene signatures, and miR-424 is increased in primary tumors versus matched normal breast. However, miR-424 is downregulated in patient metastases versus matched primary tumors. Correspondingly, miR-424 decreases tumor initiation and is posttranscriptionally downregulated in macrometastases in mice, suggesting the need for biphasic expression of miR-424 to transit the EMT-MET axis. Next-generation RNA sequencing revealed miR-424 regulates numerous EMT and cancer stemness-associated genes, including TGFBR3, whose downregulation promotes mesenchymal phenotypes, but not tumor-initiating phenotypes. Instead, we demonstrate that increased MAPK-ERK signaling is critical for miR-424-mediated decreases in tumor-initiating phenotypes. These findings suggest miR-424 plays distinct roles in tumor progression, potentially facilitating earlier, but repressing later, stages of metastasis by regulating an EMT-MET axis.

原文English
頁(從 - 到)1908-1921
頁數14
期刊Cancer Research
75
發行號9
DOIs
出版狀態Published - 2015 五月 1

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

指紋 深入研究「TWIST1-induced miR-424 reversibly drives mesenchymal programming while inhibiting tumor initiation」主題。共同形成了獨特的指紋。

引用此