Laboratory for Molecular Cancer Biology, Department of Biomedical Molecular Biology, VIB-UGent, Technologiepark, Ghent, Belgium.
Cancer Res. 2010 Dec 1;70(23):9641-9. doi: 10.1158/0008-5472.CAN-10-0527. Epub 2010 Nov 16.
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.
MDM4（也称为 MDMX 或 HDMX）的过表达被认为通过降低 p53 肿瘤抑制功能来促进肿瘤发生。即使 Mdm4 水平略有降低也会影响小鼠的肿瘤发生，这表明 MDM4 的遗传变异可能在人类中具有类似的影响。我们对一系列卵巢癌细胞系和癌组织进行了 MDM4 基因测序，以鉴定突变和/或单核苷酸多态性（SNP）。我们在 MDM4 的 3'-UTR 中发现了一个 SNP（SNP34091），该 SNP 创建了一个假定的 hsa-miR-191 靶位点，miR-191 是一种在正常和肿瘤组织中高度表达的 microRNA。生化证据支持特定的 miR-191 依赖性调节 MDM4-C，但不调节 MDM4-A 变体。一致地，A-等位基因与卵巢癌中 MDM4 mRNA 和蛋白水平的统计学显著增加相关。重要的是，野生型基因型（A/A）在高级别癌患者中更为常见（分别为 57.8%对 A/C 和 C/C，42.2%），而在低级别癌患者中则不常见（分别为 47.2%对 A/A 和 A/C + C/C，52.5%）。此外，不表达雌激素受体的 A/A 患者的复发风险增加了 4.2 倍（95%CI=1.2-13.5；P=0.02），肿瘤相关死亡的风险增加了 5.5 倍（95%CI=1.5-20.5；P=0.01）。出乎意料的是，A/A 患者的 p53 突变频率并没有明显降低。我们得出结论，获得一个非法的 miR-191 靶位点导致 MDM4 表达下调，从而显著延迟卵巢癌的进展和肿瘤相关死亡。重要的是，这些影响至少部分独立于 p53。
