What is it about?
In this study, we discovered a novel mechanism, showing that p53 gain-of-function (GOF) mutations are sufficient for inducing EMT, through the direct binding to and transrepression of miR-130b, an inhibitor of ZEB1, which leads to activation of the ZEB1-dependent signaling pathway. Moreover, our data suggest that blocking mutant p53-dependent EMT programming by using miR-130b or other miRNAs with tumor suppressive functions may have broad clinical implications for the treatment of not only endometrial cancer, but also other human tumors that harbor p53 mutations. Consequently, our fundamental work will be attractive for researchers with an interest in the development of metastasis-targeted diagnostics and therapeutics.
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Why is it important?
Our findings open a significant new area for mutant p53-related research, since we have shown that mutant p53 GOF plays a critical in the regulation of EMT and cancer metastasis though multiple molecular mechanisms involving miR-130b and miR-194. Importantly, these miRNAs are capable of targeting diverse EMT regulator genes such as ZEB1 and BMI-1, respectively. Therefore, our results are of interest to a broad audience of professional scientists who are focused on understanding cellular and molecular mechanisms of cancer metastasis.
Perspectives
Our results open a possibility that multiple molecular mechanisms with different miRNAs are involved in p53 GOF mutant-dependent EMT programming. Further research is clearly needed to understand the mechanisms of p53 mutant-mediated EMT induction and the functional crosstalk between p53 signal pathways and miRNA-modulated gene expression profiles.
Dr Peixin Dong
hokkaido university
Read the Original
This page is a summary of: Mutant p53 gain-of-function induces epithelial–mesenchymal transition through modulation of the miR-130b–ZEB1 axis, Oncogene, July 2012, Springer Science + Business Media,
DOI: 10.1038/onc.2012.334.
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Supplemental Figure and tables
SUPPLEMENTARY METHODS Figure S1 shows that upregulation of mutant p53s induce expressions of metastatic markers. Figure S2 shows that transient overexpression mutant p53 R248Q induces EMT phenotype. Figure S3 shows that ZEB1 is a key downstream mediator in mutant p53 GOF-induced EMT. Figure S4 shows that the p53 GOF mutants contribute to global repression of miRNA expression. Figure S5 shows the suppressive effects of mutant p53s on miR-200c expression in HEC-50 cells Figure S6 shows that p63 inhibition is not likely responsible for mutant p53 GOF-induced suppression of miR-130b. Figure S7 shows that miR-130b interacts with ZEB1 mRNA. Table S1 shows primers used for site-directed mutagenesis.
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