1. p53 regulates epithelial–mesenchymal transition through microRNAs targeting ZEB1 and ZEB2
- Author
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Young-Jun Jeon, Flavia Pichiorri, Angelo Veronese, Pascal Pineau, Anne Dejean, Tae Jin Lee, Hansjuerg Alder, Agnès Marchio, Stefano Volinia, Taewan Kim, Jeff Palatini, Chang Gong Liu, Sung Suk Suh, Carlo M. Croce, Comprehensive Cancer Center [Colombus], Ohio State University [Columbus] (OSU), Molecular, Cellular, and Developmental Biology Program [Columbus] (MCDB), Organisation Nucléaire et Oncogenèse, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was funded by National Cancer Institute grant RC2 CA148302., We thank Dr. B. Vogelstein for p53+/+ and p53−/− RKO cells, Dr. Gustavo Leone for p53+/+ and p53−/− MEFs, Dr. Gregory J. Goodall for pCIneo-hRL-ZEB1/2 constructs, and Dr. Anders H. Lund for pcDNA3-Zeb2-HA constructs. We also thank Dr. Kay Huebner (The Ohio State University), Dr. Thomas D. Schmittgen (The Ohio State University), and Susan Lutz for careful editing of this paper, and Sharon Palko and Dorothee Wernicke-Jameson for the administrative support., Pineau, Pascal, and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Male ,MESH: Zinc Finger E-box-Binding Homeobox 1 ,genetics/metabolism ,biosynthesis/genetics ,Metastasis ,genetics/metabolism/pathology ,0302 clinical medicine ,MESH: Liver Neoplasms ,Immunology and Allergy ,genetics ,RNA, Neoplasm ,Neoplasm Metastasis ,MESH: Carcinoma, Hepatocellular ,MESH: Tumor Suppressor Protein p53 ,0303 health sciences ,digestive, oral, and skin physiology ,Liver Neoplasms ,Hep G2 Cells ,MESH: Gene Expression Regulation, Neoplastic ,MESH: Transcription Factors ,Gene Expression Regulation, Neoplastic ,MESH: Repressor Proteins ,030220 oncology & carcinogenesis ,embryonic structures ,Female ,Transcriptional Activation ,Carcinoma, Hepatocellular ,Epithelial-Mesenchymal Transition ,Immunology ,Repressor ,MESH: Hep G2 Cells ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,03 medical and health sciences ,MESH: Gene Expression Profiling ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,microRNA ,MESH: Homeodomain Proteins ,medicine ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Epithelial–mesenchymal transition ,Transcription factor ,Zinc Finger E-box Binding Homeobox 2 ,030304 developmental biology ,MESH: Zinc Finger E-box Binding Homeobox 2 ,Homeodomain Proteins ,Neoplastic ,MESH: Humans ,Gene Expression Profiling ,Carcinoma ,Brief Definitive Report ,Zinc Finger E-box-Binding Homeobox 1 ,Hepatocellular ,Cell Biology ,HCCS ,medicine.disease ,MESH: RNA, Neoplasm ,MESH: Neoplasm Metastasis ,MESH: Male ,Repressor Proteins ,Gene expression profiling ,MicroRNAs ,MESH: Epithelial-Mesenchymal Transition ,Gene Expression Regulation ,Tumor progression ,Cancer research ,RNA ,Neoplasm ,MESH: Transcriptional Activation ,genetics/metabolism/pathology, Epithelial-Mesenchymal Transition, Female, Gene Expression Profiling, Gene Expression Regulation ,Neoplastic, Hep G2 Cells, Homeodomain Proteins ,biosynthesis/genetics, Humans, Liver Neoplasms ,genetics/metabolism/pathology, Male, MicroRNAs ,genetics/metabolism, Neoplasm Metastasis, RNA ,genetics/metabolism, Repressor Proteins ,biosynthesis/genetics, Transcription Factors ,biosynthesis/genetics, Transcriptional Activation ,genetics, Tumor Suppressor Protein p53 ,Tumor Suppressor Protein p53 ,MESH: Female ,MESH: MicroRNAs ,030215 immunology ,Transcription Factors - Abstract
By transactivating expression of miRNAs that repress expression of the ZEB1 and ZEB2 transcription factors, p53 inhibits the epithelial–mesenchymal transition., p53 suppresses tumor progression and metastasis. Epithelial–mesenchymal transition (EMT) is a key process in tumor progression and metastasis. The transcription factors ZEB1 and ZEB2 promote EMT. Here, we show that p53 suppresses EMT by repressing expression of ZEB1 and ZEB2. By profiling 92 primary hepatocellular carcinomas (HCCs) and 9 HCC cell lines, we found that p53 up-regulates microRNAs (miRNAs), including miR-200 and miR-192 family members. The miR-200 family members transactivated by p53 then repress ZEB1/2 expression. p53-regulated miR-192 family members also repress ZEB2 expression. Inhibition or overexpression of the miRNAs affects p53-regulated EMT by altering ZEB1 and ZEB2 expression. Our findings indicate that p53 can regulate EMT, and that p53-regulated miRNAs are critical mediators of p53-regulated EMT.
- Published
- 2011