Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
EMBO Mol Med. 2012 Mar;4(3):206-17. doi: 10.1002/emmm.201100200. Epub 2012 Feb 3.
Endometriosis is found in 5-15% of women of reproductive age and is more frequent in relatives of women with the disease. Activation of KRAS results in de novo endometriosis in mice, however, activating KRAS mutations have not been identified in women. We screened 150 women with endometriosis for a polymorphism in a let-7 microRNA (miRNA) binding site in the 3'-UTR of KRAS and detected a KRAS variant allele in 31% of women with endometriosis as opposed to 5% of a large diverse control population. KRAS mRNA and protein expression were increased in cultured endometrial stromal cells of women with the KRAS variant. Increased KRAS protein was due to altered miRNA binding as demonstrated in reporter assays. Endometrial stromal cells from women with the KRAS variant showed increased proliferation and invasion. In a murine model, endometrial xenografts containing the KRAS variant demonstrated increased proliferation and decreased progesterone receptor levels. These findings suggest that an inherited polymorphism of a let-7 miRNA binding site in KRAS leads to abnormal endometrial growth and endometriosis. The LCS6 polymorphism is the first described genetic marker of endometriosis risk.
子宫内膜异位症在生育年龄的妇女中发病率为 5-15%，且在患有该病的女性亲属中更为常见。KRAS 的激活会导致小鼠出现新发性子宫内膜异位症，然而，在女性中并未发现激活的 KRAS 突变。我们对 150 名患有子宫内膜异位症的女性进行了 KRAS 3'-UTR 中 let-7 微小 RNA（miRNA）结合位点的多态性筛查，发现患有子宫内膜异位症的女性中有 31%存在 KRAS 变体等位基因，而在大型多样化对照组中只有 5%存在。在患有 KRAS 变体的女性的培养子宫内膜基质细胞中，KRAS mRNA 和蛋白表达增加。通过报告基因实验证明，KRAS 蛋白的增加是由于 miRNA 结合的改变所致。携带 KRAS 变体的女性的子宫内膜基质细胞表现出增殖和侵袭增加。在小鼠模型中，含有 KRAS 变体的子宫内膜异种移植物表现出增殖增加和孕激素受体水平降低。这些发现表明，KRAS 中 let-7 miRNA 结合位点的遗传多态性导致异常的子宫内膜生长和子宫内膜异位症。LCS6 多态性是第一个描述的子宫内膜异位症风险的遗传标记。
