Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism*
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Carcinoma, Hepatocellular / pathology
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Epithelial-Mesenchymal Transition*
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Female
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic*
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Hep G2 Cells
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Homeodomain Proteins / biosynthesis*
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Homeodomain Proteins / genetics
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Humans
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism*
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Liver Neoplasms / pathology
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Male
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Neoplasm Metastasis
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RNA, Neoplasm / genetics
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RNA, Neoplasm / metabolism*
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Repressor Proteins / biosynthesis*
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Repressor Proteins / genetics
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Transcription Factors / biosynthesis*
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Transcription Factors / genetics
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Transcriptional Activation / genetics
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Zinc Finger E-box Binding Homeobox 2
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Zinc Finger E-box-Binding Homeobox 1
Substances
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Homeodomain Proteins
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MicroRNAs
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RNA, Neoplasm
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Repressor Proteins
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TP53 protein, human
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Transcription Factors
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Tumor Suppressor Protein p53
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ZEB1 protein, human
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ZEB2 protein, human
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Zinc Finger E-box Binding Homeobox 2
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Zinc Finger E-box-Binding Homeobox 1