ERK2-ZEB1-miR-101-1 axis contributes to epithelial–mesenchymal transition and cell migration in cancer

• Published in: Cancer letters Vol. 391; pp. 59 - 73
• Main Authors: Chandra Mangalhara, Kailash, Manvati, Siddharth, Saini, Sunil Kumar, Ponnusamy, Kalaiarasan, Agarwal, Gaurav, Abraham, Suresh K, Bamezai, Rameshwar N.K
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 10-04-2017; Elsevier Limited
• Subjects: Bioinformatics; Breast cancer; Cell adhesion & migration; Cell Line, Tumor; Cell Movement; Cytoskeleton; EMT-TFs; Epidermal growth factor (EGF); Epithelial-Mesenchymal Transition; Experiments; Genes; Hematology, Oncology and Palliative Medicine; Humans; Lymphatic system; Metastasis; microRNA; MicroRNAs - metabolism; miR-101; Mitogen-Activated Protein Kinase 1 - metabolism; Protocol; Stem cells; Transcription factors; Transfection; Tumors; EMT-TFs; microRNA; Cytoskeleton; Breast cancer; Epidermal growth factor; miR-101; Epidermal growth factor (EGF)
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2017.01.016

Abstract Regulation of metastasis continues to remain enigmatic despite our improved understanding of cancer. Identification of microRNAs associated with metastasis in the recent past has provided a new hope. Here, we show how microRNA-101 (miR-101) regulates two independent processes of cellular metastasis by targeting pro-metastatic upstream regulatory transcription factors, ZEB1 and ZEB2, and downstream effector-actin modulators, RHOA and RAC1, providing a single target for therapeutic intervention. Further, we depict how down-regulation of miR-101 by extracellular signal-regulated kinase-2 (ERK2) is vital for MAP kinase pathway induced cellular migration and mesenchymal transition. Importantly, EKR2 induced expression of ZEB1 seems essential for down-regulation of miR-101-1 and induction of EMT. Given the role of EMT in metastasis, we also observe a significant correlation between miR-101 expression and lymph node metastasis; and identify the ERK2-ZEB1 - miR-101-1 pathway active in breast cancer tissues, with an apparent clinicopathological implication.