title: Gain-of-function mutant p53 downregulates miR-223 contributing to chemoresistance of cultured tumor cells.
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.
authors.affiliation: Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Masciarelli
authors.affiliation: Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Fontemaggi
authors.affiliation: Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Di Agostino
authors.affiliation: Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Donzelli
authors.affiliation: Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Carcarino
authors.affiliation: Chemoprevention Unit, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Strano
authors.affiliation: Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Blandino
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D050777:Stathmin / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; D050777:Stathmin; D016159:Tumor Suppressor Protein p53; C525067:MIR223, human; C493995:STMN1 protein, human