title: p53/mdm2 feedback loop sustains miR-221 expression and dictates the response to anticancer treatments in hepatocellular carcinoma.
abstract: The overexpression of microRNA-221 (miR-221) is reported in several human cancers including hepatocellular carcinoma, and its targeting by tailored treatments has been proposed. The evidence supporting the role of miR-221 in cancer is growing and has been mainly focused on the discovery of miR-221 targets as well as on its possible therapeutic exploitations. However, the mechanism sustaining miR-221 aberrant expression remains to be elucidated. In this study, MDM2 (E3 ubiquitin-protein ligase homolog), a known p53 (TP53) modulator, is identified as a direct target of miR-221, and a feed-forward loop is described that sustains miR-221 aberrant expression. Interestingly, miR-221 can activate the p53/mdm2 axis by inhibiting MDM2 and, in turn, p53 activation contributes to miR-221 enhanced expression. Moreover, by modulating the p53 axis, miR-221 impacts cell-cycle progression and apoptotic response to doxorubicin in hepatocellular carcinoma-derived cell lines. Finally, CpG island methylation status was assessed as a causative event associated with miR-221 upregulation in hepatocellular carcinoma cells and primary tumor specimens. In hepatocellular carcinoma-derived cell lines, pharmacologically induced DNA hypomethylation potentiated a significant increase in miR-221 expression. These data were confirmed in clinical specimens of hepatocellular carcinoma in which elevated miR-221 expression was associated with the simultaneous presence of wild-type p53 and DNA hypomethylation.
  
  
  CONCLUSIONS
  These findings reveal a novel miR-221-sustained regulatory loop that determines a p53-context-specific response to doxorubicin treatment in hepatocellular carcinoma.
authors: St. Orsola-Malpighi University Hospital, via Albertoni, 15, 40138 Bologna, Italy. laura.gramantieri@aosp.bo.it.
authors: Francesca
authors: F
authors: Fornari
authors: Maddalena
authors: M
authors: Milazzo
authors: Marzia
authors: M
authors: Galassi
authors: Elisa
authors: E
authors: Callegari
authors: Angelo
authors: A
authors: Veronese
authors: Hisamitsu
authors: H
authors: Miyaaki
authors: Silvia
authors: S
authors: Sabbioni
authors: Vilma
authors: V
authors: Mantovani
authors: Elena
authors: E
authors: Marasco
authors: Pasquale
authors: P
authors: Chieco
authors: Massimo
authors: M
authors: Negrini
authors: Luigi
authors: L
authors: Bolondi
authors: Laura
authors: L
authors: Gramantieri
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D010766:Phosphorylation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D035683:MicroRNAs; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53; C525709:MIR221, human; C495901:TP53 protein, human; C497206:MDM2 protein, human