An illegitimate microRNA target site within the 3' UTR of MDM4 affects ovarian cancer progression and chemosensitivity

Jessika Wynendaele; Anja Böhnke; Eleonora Leucci; Søren Jensby Nielsen; Irina Lambertz; Stefanie Hammer; Nadja Sbrzesny; Dana Kubitza; Anja Wolf; Elise Gradhand; Katharina Balschun; Ioana Braicu; Jalid Sehouli; Silvia Darb-Esfahani; Carsten Denkert; Christoph Thomssen; Steffen Hauptmann; Anders Lund; Jean-Christophe Marine; Frank Bartel

doi:10.1158/0008-5472.CAN-10-0527

An illegitimate microRNA target site within the 3' UTR of MDM4 affects ovarian cancer progression and chemosensitivity

Jessika Wynendaele, Anja Böhnke, Eleonora Leucci, Søren Jensby Nielsen, Irina Lambertz, Stefanie Hammer, Nadja Sbrzesny, Dana Kubitza, Anja Wolf, Elise Gradhand, Katharina Balschun, Ioana Braicu, Jalid Sehouli, Silvia Darb-Esfahani, Carsten Denkert, Christoph Thomssen, Steffen Hauptmann, Anders Lund, Jean-Christophe Marine, Frank Bartel

126 Citations (Scopus)

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.

Original language	English
Journal	Cancer Research
Volume	70
Issue number	23
Pages (from-to)	9641-9
Number of pages	9
ISSN	1538-7445
DOIs	https://doi.org/10.1158/0008-5472.CAN-10-0527
Publication status	Published - 1 Dec 2010

Keywords

3' Untranslated Regions
Aged
Binding Sites
Blotting, Western
Cell Line, Tumor
Disease Progression
Female
Gene Expression Regulation, Neoplastic
Gene Frequency
Genotype
Hela Cells
Humans
MicroRNAs
Middle Aged
Mutation
Nuclear Proteins
Ovarian Neoplasms
Polymorphism, Single Nucleotide
Proto-Oncogene Proteins
RNA, Messenger
Receptors, Estrogen
Reverse Transcriptase Polymerase Chain Reaction
Tumor Suppressor Protein p53

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/0008-5472.CAN-10-0527

Cite this

Wynendaele, J., Böhnke, A., Leucci, E., Nielsen, S. J., Lambertz, I., Hammer, S., Sbrzesny, N., Kubitza, D., Wolf, A., Gradhand, E., Balschun, K., Braicu, I., Sehouli, J., Darb-Esfahani, S., Denkert, C., Thomssen, C., Hauptmann, S., Lund, A., Marine, J-C., & Bartel, F. (2010). An illegitimate microRNA target site within the 3' UTR of MDM4 affects ovarian cancer progression and chemosensitivity. Cancer Research, 70(23), 9641-9. https://doi.org/10.1158/0008-5472.CAN-10-0527

Wynendaele, J, Böhnke, A, Leucci, E, Nielsen, SJ, Lambertz, I, Hammer, S, Sbrzesny, N, Kubitza, D, Wolf, A, Gradhand, E, Balschun, K, Braicu, I, Sehouli, J, Darb-Esfahani, S, Denkert, C, Thomssen, C, Hauptmann, S, Lund, A, Marine, J-C & Bartel, F 2010, 'An illegitimate microRNA target site within the 3' UTR of MDM4 affects ovarian cancer progression and chemosensitivity', Cancer Research, vol. 70, no. 23, pp. 9641-9. https://doi.org/10.1158/0008-5472.CAN-10-0527

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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.",

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TY - JOUR

T1 - An illegitimate microRNA target site within the 3' UTR of MDM4 affects ovarian cancer progression and chemosensitivity

AU - Wynendaele, Jessika

AU - Böhnke, Anja

AU - Leucci, Eleonora

AU - Nielsen, Søren Jensby

AU - Lambertz, Irina

AU - Hammer, Stefanie

AU - Sbrzesny, Nadja

AU - Kubitza, Dana

AU - Wolf, Anja

AU - Gradhand, Elise

AU - Balschun, Katharina

AU - Braicu, Ioana

AU - Sehouli, Jalid

AU - Darb-Esfahani, Silvia

AU - Denkert, Carsten

AU - Thomssen, Christoph

AU - Hauptmann, Steffen

AU - Lund, Anders

AU - Marine, Jean-Christophe

AU - Bartel, Frank

PY - 2010/12/1

Y1 - 2010/12/1

N2 - 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.

AB - 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.

KW - 3' Untranslated Regions

KW - Aged

KW - Binding Sites

KW - Blotting, Western

KW - Cell Line, Tumor

KW - Disease Progression

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Gene Frequency

KW - Genotype

KW - Hela Cells

KW - Humans

KW - MicroRNAs

KW - Middle Aged

KW - Mutation

KW - Nuclear Proteins

KW - Ovarian Neoplasms

KW - Polymorphism, Single Nucleotide

KW - Proto-Oncogene Proteins

KW - RNA, Messenger

KW - Receptors, Estrogen

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Tumor Suppressor Protein p53

U2 - 10.1158/0008-5472.CAN-10-0527

DO - 10.1158/0008-5472.CAN-10-0527

M3 - Journal article

C2 - 21084273

SN - 0008-5472

VL - 70

SP - 9641

EP - 9649

JO - Cancer Research

JF - Cancer Research

IS - 23

ER -

An illegitimate microRNA target site within the 3' UTR of MDM4 affects ovarian cancer progression and chemosensitivity

Abstract

Keywords

UN SDGs

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