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Gain-of-function mutant p53 downregulates miR-223 contributing to chemoresistance of cultured tumor cells

Oncogene volume 33, pages 1601–1608 (2014)Cite this article

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Abstract

Mutant p53 proteins are expressed at high frequency in human tumors and are associated with poor clinical prognosis and resistance to chemotherapeutic treatments. Here we show that mutant p53 proteins downregulate micro-RNA (miR)-223 expression in breast and colon cancer cell lines. Mutant p53 binds the miR-223 promoter and reduces its transcriptional activity. This requires the transcriptional repressor ZEB-1. We found that miR-223 exogenous expression sensitizes breast and colon cancer cell lines expressing mutant p53 to treatment with DNA-damaging drugs. Among the putative miR-223 targets, we focused on stathmin-1 (STMN-1), an oncoprotein known to confer resistance to chemotherapeutic drugs associated with poor clinical prognosis. Mutant p53 silencing or miR-223 exogenous expression lowers the levels of STMN-1 and knockdown of STMN-1 by small interfering RNA increases cell death of mutant p53-expressing cell lines. On the basis of these findings, we propose that one of the pathways affected by mutant p53 to increase cellular resistance to chemotherapeutic agents involves miR-223 downregulation and the consequent upregulation of STMN-1.

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Acknowledgements

We are grateful for the support given by AIRC (Grant Number: 10454) to GB. We thank Francesca Fausti for providing the SW480-sh53 cell line and Dr Taro Fukao for kindly providing the ppri-hmiR-223−669-Luc luciferase reporter.

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Authors and Affiliations

  1. Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy

    S Masciarelli, G Fontemaggi, S Di Agostino, S Donzelli, E Carcarino & G Blandino

  2. Chemoprevention Unit, Regina Elena National Cancer Institute, Rome, Italy

    S Strano

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  1. S Masciarelli
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  2. G Fontemaggi
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  3. S Di Agostino
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Correspondence to G Blandino.

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Masciarelli, S., Fontemaggi, G., Di Agostino, S. et al. Gain-of-function mutant p53 downregulates miR-223 contributing to chemoresistance of cultured tumor cells. Oncogene 33, 1601–1608 (2014). https://doi.org/10.1038/onc.2013.106

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