title: An illegitimate microRNA target site within the 3' UTR of MDM4 affects ovarian cancer progression and chemosensitivity.
abstract: Overexpression of MDM4 (also known as MDMX or HDMX) is thought to promote tumorigenesis by decreasing p53 tumor suppressor function. Even modest decrease in Mdm4 levels affects tumorigenesis in mice, suggesting that genetic variants of MDM4 might have similar effects in humans. We sequenced the MDM4 gene in a series of ovarian cancer cell lines and carcinomas to identify mutations and/or single nucleotide polymorphisms (SNPs). We identified an SNP (SNP34091) in the 3'-UTR of MDM4 that creates a putative target site for hsa-miR-191, a microRNA that is highly expressed in normal and tumor tissues. Biochemical evidence supports specific miR-191-dependent regulation of the MDM4-C, but not MDM4-A, variant. Consistently, the A-allele was associated with statistically significant increased expression of MDM4 mRNA and protein levels in ovarian carcinomas. Importantly, the wild-type genotype (A/A) is more frequent (57.8% vs. 42.2% for A/C and C/C, respectively) in patients with high-grade carcinomas than in patients with low-grade carcinomas (47.2% vs. 52.5% for A/A and A/C + C/C, respectively). Moreover, A/A patients who do not express the estrogen receptor had a 4.2-fold [95% confidence interval (CI) = 1.2-13.5; P = 0.02] increased risk of recurrence and 5.5-fold (95% CI = 1.5-20.5; P = 0.01) increased risk of tumor-related death. Unexpectedly, the frequency of p53 mutations was not significantly lower in A/A patients. We conclude that acquisition of an illegitimate miR-191 target site causes downregulation of MDM4 expression, thereby significantly delaying ovarian carcinoma progression and tumor-related death. Importantly, these effects appear to be, at least partly, independent of p53.
authors.affiliation: Laboratory for Molecular Cancer Biology, Department of Biomedical Molecular Biology, VIB-UGent, Technologiepark, Ghent, Belgium.
authors.forename: Jessika
authors.initials: J
authors.lastname: Wynendaele
authors.forename: Anja
authors.initials: A
authors.lastname: Böhnke
authors.forename: Eleonora
authors.initials: E
authors.lastname: Leucci
authors.forename: Søren Jensby
authors.initials: SJ
authors.lastname: Nielsen
authors.forename: Irina
authors.initials: I
authors.lastname: Lambertz
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hammer
authors.forename: Nadja
authors.initials: N
authors.lastname: Sbrzesny
authors.forename: Dana
authors.initials: D
authors.lastname: Kubitza
authors.forename: Anja
authors.initials: A
authors.lastname: Wolf
authors.forename: Elise
authors.initials: E
authors.lastname: Gradhand
authors.forename: Katharina
authors.initials: K
authors.lastname: Balschun
authors.forename: Ioana
authors.initials: I
authors.lastname: Braicu
authors.forename: Jalid
authors.initials: J
authors.lastname: Sehouli
authors.forename: Silvia
authors.initials: S
authors.lastname: Darb-Esfahani
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
authors.forename: Christoph
authors.initials: C
authors.lastname: Thomssen
authors.forename: Steffen
authors.initials: S
authors.lastname: Hauptmann
authors.forename: Anders
authors.initials: A
authors.lastname: Lund
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Marine
authors.forename: Frank
authors.initials: F
authors.lastname: Bartel
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000368:Aged; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; C546177:MIRN191 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53