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

Mutant p53 proteins are expressed at high frequency in human tumors and are associated with poor clinical prognosis andresistance to chemotherapeutic treatments. Here we show that mutant p53 proteins downregulate micro-RNA (miR)-223 expressionin breast and colon cancer cell lines. Mutant p53 binds the miR-223 promoter and reduces its transcriptional activity. This requiresthe transcriptional repressor ZEB-1. We found that miR-223 exogenous expression sensitizes breast and colon cancer cell linesexpressing 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. Mutantp53 silencing or miR-223 exogenous expression lowers the levels of STMN-1 and knockdown of STMN-1 by small interfering RNAincreases cell death of mutant p53-expressing cell lines. On the basis of these findings, we propose that one of the pathwaysaffected by mutant p53 to increase cellular resistance to chemotherapeutic agents involves miR-223 downregulation and theconsequent upregulation of STMN-1