A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells
Ulrike Burk,Joerg Schubert,Ulrich F. Wellner,Otto Schmalhofer,Elizabeth Vincan,Simone Spaderna,Thomas Brabletz +6 more
Reads0
Chats0
TLDR
Results indicate that ZEB1 triggers an microRNA‐mediated feedforward loop that stabilizes EMT and promotes invasion of cancer cells, and thus explain the strong intratumorous heterogeneity observed in many human cancers.Abstract:
The embryonic programme 'epithelial-mesenchymal transition' (EMT) is thought to promote malignant tumour progression. The transcriptional repressor zinc-finger E-box binding homeobox 1 (ZEB1) is a crucial inducer of EMT in various human tumours, and was recently shown to promote invasion and metastasis of tumour cells. Here, we report that ZEB1 directly suppresses transcription of microRNA-200 family members miR-141 and miR-200c, which strongly activate epithelial differentiation in pancreatic, colorectal and breast cancer cells. Notably, the EMT activators transforming growth factor beta2 and ZEB1 are the predominant targets downregulated by these microRNAs. These results indicate that ZEB1 triggers an microRNA-mediated feedforward loop that stabilizes EMT and promotes invasion of cancer cells. Alternatively, depending on the environmental trigger, this loop might switch and induce epithelial differentiation, and thus explain the strong intratumorous heterogeneity observed in many human cancers.read more
Citations
More filters
Journal ArticleDOI
Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression
Limo Chen,Don L. Gibbons,Sangeeta Goswami,Maria Angelica Cortez,Young Ho Ahn,Lauren Averett Byers,Xuejun Zhang,Xiaohui Yi,David Dwyer,Wei Lin,Lixia Diao,Jing Wang,Jonathon D. Roybal,Mayuri Patel,Christin Ungewiss,David H. Peng,Scott J. Antonia,Melanie Mediavilla-Varela,Gordon Robertson,Steve Jones,Milind Suraokar,James W. Welsh,Baruch Erez,Ignacio I. Wistuba,Lieping Chen,Di Peng,Shanshan Wang,Stephen E. Ullrich,John V. Heymach,Jonathan M. Kurie,F. Xiao Feng Qin,F. Xiao Feng Qin +31 more
TL;DR: A molecular link between epithelial-to-mesenchymal transition (EMT) and CD8+ TIL immunosuppression and cancer progression is demonstrated and ZEB1 promotes metastasis through a heretofore unappreciated cell non-autonomous mechanism, and subgroups of patients in whom malignant progression is driven by EMT activators may respond to treatment with PD-L1 antagonists.
Journal ArticleDOI
MicroRNA-155 Is Regulated by the Transforming Growth Factor β/Smad Pathway and Contributes to Epithelial Cell Plasticity by Targeting RhoA
TL;DR: The data suggest that miR-155 may play an important role in TGF-β-induced EMT and cell migration and invasion by targeting RhoA and indicate that it is a potential therapeutic target for breast cancer intervention.
Journal ArticleDOI
The Increasing Complexity of the Cancer Stem Cell Paradigm
Jeffrey M. Rosen,Craig T. Jordan +1 more
TL;DR: The nature of the debate, the parameters by which CSCs can or cannot be defined, and the identification of new potential therapeutic targets elucidated by considering cancer as a problem in stem cell biology are discussed.
Journal ArticleDOI
A MicroRNA targeting dicer for metastasis control.
Graziano Martello,Antonio Rosato,Francesco Ferrari,Andrea Manfrin,Michelangelo Cordenonsi,Sirio Dupont,Elena Enzo,Vincenza Guzzardo,Maria Rondina,Thomas Spruce,Anna Parenti,Maria Grazia Daidone,Silvio Bicciato,Stefano Piccolo +13 more
TL;DR: These findings suggest a new pathway by which Dicer inhibition drifts epithelial cancer toward a less-differentiated, mesenchymal fate to foster metastasis, and attenuates miRNA biosynthesis by targeting Dicer, a key component of the miRNA processing machinery.
Journal ArticleDOI
p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs
Chun Ju Chang,Chi-Hong Chao,Weiya Xia,Jer Yen Yang,Jer Yen Yang,Yan Xiong,Chia Wei Li,Wen Hsuan Yu,Sumaiyah K. Rehman,Jennifer L. Hsu,Heng Huan Lee,Mo Liu,Chun Te Chen,Dihua Yu,Mien Chie Hung +14 more
TL;DR: This study elucidates a role for p53 in regulating EMT–MET (mesenchymal–epithelial transition) and stemness or differentiation plasticity, and reveals a potential therapeutic implication to suppress EMT-associated cancer stem cells through activation of the p53–miR-200c pathway.
References
More filters
Journal ArticleDOI
MicroRNAs: Genomics, Biogenesis, Mechanism, and Function
TL;DR: Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.
Journal Article
Oncomirs : microRNAs with a role in cancer
TL;DR: I MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that function as negative gene regulators as discussed by the authors, and have been shown to repress the expression of important cancer-related genes and might prove useful in the diagnosis and treatment of cancer.
Journal ArticleDOI
Prediction of Mammalian MicroRNA Targets
TL;DR: The predicted regulatory targets of mammalian miRNAs were enriched for genes involved in transcriptional regulation but also encompassed an unexpectedly broad range of other functions.
Journal ArticleDOI
Complex networks orchestrate epithelial–mesenchymal transitions
TL;DR: Understanding how mesenchymal cells arise from an epithelial default status will also have a strong impact in unravelling the mechanisms that control fibrosis and cancer progression.
Journal ArticleDOI
Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis
Jing Yang,Sendurai A. Mani,Joana Liu Donaher,Sridhar Ramaswamy,Sridhar Ramaswamy,Raphael Itzykson,Christophe Côme,Pierre Savagner,Inna Gitelman,Andrea L. Richardson,Robert A. Weinberg +10 more
TL;DR: A mechanistic link between Twist, EMT, and tumor metastasis is established, suggesting that Twist contributes to metastasis by promoting an epithelial-mesenchymal transition (EMT).