Title: An Illegitimate microRNA Target Site within the 3' UTR of MDM4 Affects Ovarian Cancer Progression and Chemosensitivity
Authors: Wynendaele, Jessika ×
Böhnke, Anja
Leucci, Eleonora
Nielsen, Søren Jensby
Lambertz, Irina
Hammer, Stefanie
Sbrzesny, Nadja
Kubitza, Dana
Wolf, Anja
Gradhand, Elise
Balschun, Katharina
Braicu, Ioana
Sehouli, Jalid
Darb-Esfahani, Silvia
Denkert, Carsten
Thomssen, Christoph
Hauptmann, Steffen
Lund, Anders
Marine, Chris
Bartel, Frank #
Issue Date: 16-Nov-2010
Publisher: Waverly Press
Series Title: Cancer Research vol:70 issue:23 pages:9641-9649
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. Cancer Res; 70(23); 1-9. ©2010 AACR.
ISSN: 0008-5472
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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