MicroRNAs-143 and -145 induce epithelial to mesenchymal transition and modulate the expression of junction proteins

作者: Lidia Avalle , Danny Incarnato , Aurora Savino , Marta Gai , Francesca Marino

DOI: 10.1038/CDD.2017.103

关键词: STAT3Cell biologyRegulation of gene expressionCell migrationBiologyTranscription factorTransforming growth factorSMADEpithelial–mesenchymal transitionTumor progression

摘要: Transforming growth factor (TGF)-β is one of the major inducers epithelial to mesenchymal transition (EMT), a crucial program that has critical role in promoting carcinoma’s metastasis formation. MicroRNAs-143 and -145, which are both TGF-β direct transcriptional targets, essential for differentiation vascular smooth muscle cells (VSMC) during embryogenesis, TGF-β-dependent process reminiscent EMT. Their adult tissues however less well defined even ambiguous, as their expression was correlated positively negatively with tumor progression. Here we show high miRs-143 -145 mouse mammary expressing constitutively active STAT3 (S3C) involved mediating disrupted cell–cell junctions. Additionally, miR-143 appears have unique tumorigenesis by enhancing cell migration vitro extravasation vivo while impairing anchorage-independent growth, may explain contradictory reports about its tumors. Accordingly, demonstrate overexpression either miRNA non-transformed NMuMG leads upregulation EMT markers several endogenous downmodulation number junction proteins increased motility, correlating enhanced basal TGF-β-induced SMAD-mediated transcription. Moreover, pervasive transcriptome perturbation consistent described phenotype observed. In particular, transcription factors mitogenic responses, MAPK family members and, importantly, tight SMAD co-repressor TGIF significantly reduced. Our results provide important mechanistic insight into non-redundant EMT-related processes transformed cells, suggest must be finely coordinated warrant optimal migration/invasion not interfering growth.

参考文章(52)
Pak-Yin Lui, Dong-Yan Jin, Nigel J. Stevenson, MicroRNA: master controllers of intracellular signaling pathways Cellular and Molecular Life Sciences. ,vol. 72, pp. 3531- 3542 ,(2015) , 10.1007/S00018-015-1940-0
Yin-Yuan Mo, Mohit Sachdeva, miR-145-mediated suppression of cell growth, invasion and metastasis. American Journal of Translational Research. ,vol. 2, pp. 170- 180 ,(2010)
Aurora Esquela-Kerscher, Frank J. Slack, Oncomirs — microRNAs with a role in cancer Nature Reviews Cancer. ,vol. 6, pp. 259- 269 ,(2006) , 10.1038/NRC1840
Joan Massagué, TGFβ signalling in context. Nature Reviews Molecular Cell Biology. ,vol. 13, pp. 616- 630 ,(2012) , 10.1038/NRM3434
Maria J Blanco, Gema Moreno-Bueno, David Sarrio, Annamaria Locascio, Amparo Cano, José Palacios, M Angela Nieto, None, Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene. ,vol. 21, pp. 3241- 3246 ,(2002) , 10.1038/SJ.ONC.1205416
Leigh Zawel, Jia Le Dai, Phillip Buckhaults, Shibin Zhou, Kenneth W Kinzler, Bert Vogelstein, Scott E Kern, Human smad3 and smad4 are sequence-specific transcription activators Molecular Cell. ,vol. 1, pp. 611- 617 ,(1999) , 10.1016/S1097-2765(00)80061-1
J Zhang, Q Sun, Z Zhang, S Ge, ZG Han, WT22330136 Chen, None, Loss of microRNA-143/145 disturbs cellular growth and apoptosis of human epithelial cancers by impairing the MDM2-p53 feedback loop Oncogene. ,vol. 32, pp. 61- 69 ,(2013) , 10.1038/ONC.2012.28
Oliver A. Kent, Matthew N. McCall, Toby C. Cornish, Marc K. Halushka, Lessons from miR-143/145: the importance of cell-type localization of miRNAs Nucleic Acids Research. ,vol. 42, pp. 7528- 7538 ,(2014) , 10.1093/NAR/GKU461
Kimberly R. Cordes, Neil T. Sheehy, Mark P. White, Emily C. Berry, Sarah U. Morton, Alecia N. Muth, Ting-Hein Lee, Joseph M. Miano, Kathryn N. Ivey, Deepak Srivastava, miR-145 and miR-143 regulate smooth muscle cell fate and plasticity Nature. ,vol. 460, pp. 705- 710 ,(2009) , 10.1038/NATURE08195