An Illegitimate microRNA Target Site within the 3′ UTR of MDM4 Affects Ovarian Cancer Progression and Chemosensitivity
An Illegitimate microRNA Target Site within the 3′ UTR of MDM4 Affects Ovarian Cancer Progression and Chemosensitivity
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DOI：
10.1158/0008-5472.can-10-0527
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发表时间：
2010-12-01
期刊：
影响因子：
11.2
通讯作者：
Bartel, Frank
中科院分区：
文献类型：
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作者：
Wynendaele, Jessika;Boehnke, Anja;Bartel, Frank
MDM4(也称为MDMX或HDMX)的过表达被认为通过降低p53的肿瘤抑制功能而促进肿瘤的发生。即使mdm4水平的轻微下降也会影响小鼠的肿瘤发生，这表明mdm4的基因变异可能对人类有类似的影响。我们对一系列卵巢癌细胞系和癌症中的MDM4基因进行了测序，以确定突变和/或单核苷酸多态(SNPs)。我们在MDM4的3‘-UTR中发现了一个SNP(SNP34091)，它为hsa-miR-191创造了一个可能的靶点，hsa-miR-191是一种在正常组织和肿瘤组织中高表达的微小RNA。生化证据支持依赖miR-191的MDM4-C变体的特定调控，但不支持MDM4-A变体。一致地，A等位基因与卵巢癌中MDM4mRNA和蛋白水平的表达显著增加有关。重要的是，高度恶性癌患者中野生型(A/A)的频率(A/C和C/C分别为57.8%和42.2%)高于低度癌患者(A/A和A/C+C/C分别为47.2%和52.5%)。此外，不表达雌激素受体的A/A患者复发风险增加4.2倍[95%可信区间(CI)1.2-13.5；P=0.02]，肿瘤相关死亡风险增加5.5倍(95%CI 1.5-20.5；P=0.01)。出乎意料的是，在A/A患者中，P53突变的频率并没有显著降低。我们的结论是，获取不合法的miR-191靶点会导致MDM4表达下调，从而显著延迟卵巢癌的进展和肿瘤相关的死亡。重要的是，这些效应似乎至少部分地不依赖于p53。癌症资源；70(23)；9641-9。(C)2010年AACR。
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); 9641-9. (C) 2010 AACR.