Abstract
p53 mutations have profound effects on non-small-cell lung cancer (NSCLC) resistance to chemotherapeutic treatments. Mutant p53 proteins are usually expressed at high levels in tumors, where they exert oncogenic functions. Here we show that p53R175H, a hotspot p53 mutant, induces microRNA (miRNA)-128-2 expression. Mutant p53 binds to the putative promoter of miR128-2 host gene, ARPP21, determining a concomitant induction of ARPP21 mRNA and miR-128-2. miR-128-2 expression in lung cancer cells inhibits apoptosis and confers increased resistance to cisplatin, doxorubicin and 5-fluorouracyl treatments. At the molecular level, miR-128-2 post-transcriptionally targets E2F5 and leads to the abrogation of its repressive activity on p21(waf1) transcription. p21(waf1) protein localizes to the cytoplasmic compartment, where it exerts an anti-apoptotic effect by preventing pro-caspase-3 cleavage. This study emphasizes miRNA-128-2 role as a master regulator in NSCLC chemoresistance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Cisplatin / pharmacology
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Doxorubicin / pharmacology
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Drug Resistance, Neoplasm / drug effects
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E2F5 Transcription Factor / metabolism*
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Fluorouracil / pharmacology
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Humans
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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MicroRNAs / metabolism*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Promoter Regions, Genetic
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RNA, Messenger / metabolism
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Transcription, Genetic
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Cyclin-Dependent Kinase Inhibitor p21
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E2F5 Transcription Factor
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MIRN128 microRNA, human
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MicroRNAs
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Phosphoproteins
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RNA, Messenger
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Tumor Suppressor Protein p53
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cyclic AMP-regulated phosphoprotein ARPP-21
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Doxorubicin
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Cisplatin
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Fluorouracil