Germline genetic variants disturbing the Let-7/LIN28 double-negative feedback loop alter breast cancer susceptibility.
Germline genetic variants disturbing the Let-7/LIN28 double-negative feedback loop alter breast cancer susceptibility.
复制标题
DOI：
10.1371/journal.pgen.1002259
复制
发表时间：
2011-09
期刊：
影响因子：
4.5
通讯作者：
Shao ZM
中科院分区：
文献类型：
--
作者：
Chen AX;Yu KD;Fan L;Li JY;Yang C;Huang AJ;Shao ZM
此前的研究表明，let-7可以抑制LIN28的转录后翻译，而LIN28反过来又可以阻止let-7的成熟，形成双负反馈循环。在这项研究中，我们研究了种系遗传变异对 let-7/LIN28 环稳态调节和乳腺癌风险的影响。我们最初证明，rs3811463（位于 LIN28 中 let-7 结合位点附近的单核苷酸多态性（SNP））的 T/C 变体可能导致 let-7 对 LIN28 的差异调节。具体来说，rs3811463 的 C 等位基因削弱了 let-7 诱导的 LIN28 mRNA 抑制，导致 LIN28 蛋白产量增加，进而下调成熟 let-7 的水平。然后在组织水平上验证了这种效应，因为与具有 rs3811463-TT 基因型的个体相比，具有 rs3811463-TC 基因型的个体的正常乳腺组织表达显着较低水平的 let-7 和较高水平的 LIN28 蛋白。由于之前的体外和离体实验一致表明LIN28可以促进细胞转化，因此我们逐步系统地评估了rs3811463以及其他常见的LIN28 SNP与乳腺癌风险之间的关系。第一项以医院为基础的关联研究（n = 2,300）证明，两个 SNP 与乳腺癌风险显着相关，其中一个是 rs3811463，另一个是 rs6697410。 rs3811463 SNP 的 C 等位基因与乳腺癌风险增加相对应，比值比 (OR) 为 1.25 (P = 0.0091)，这一结果在第二项以社区为基础的对照独立研究 (n = 1,156) 中得到了成功复制。两项研究的综合 P 值为 8.0×10−5。综上所述，我们的研究表明宿主遗传变异可能会扰乱 let-7/LIN28 双负反馈环的调节并改变乳腺癌风险。遗传变异是个体间对癌症等常见疾病易感性差异的遗传基础。单核苷酸多态性（SNP）是人类遗传变异的主要类型，之前的研究已将许多SNP与人类罹患恶性肿瘤的风险联系起来。在这项研究中，我们重点关注 microRNA (miRNA) 相关的 SNP 及其与乳腺癌风险的关系。 miRNA是一类微小的内源性RNA，具有重要的调控作用。 Let-7是一种已被证明能够抑制肿瘤发生的miRNA。 LIN28 是一种促进癌症的基因，是 let-7 的已知调节因子，有趣的是，LIN28 本身会受到 let-7 的抑制。我们发现LIN28中let-7靶位点附近的一个SNP扰乱了let-7对LIN28的调节。这种干扰最终导致 LIN28 水平升高和 let-7 水平降低。我们还首次证实该 SNP 与中国汉族女性乳腺癌风险增加相关。我们的结果表明，遗传变异可能会在乳腺组织中的let-7/LIN28环上建立从生理状态到异常甚至病理状态的桥梁，从而促进癌变。
Previous studies have shown that let-7 can repress the post-transcriptional translation of LIN28, and LIN28 in turn could block the maturation of let-7, forming a double-negative feedback loop. In this study, we investigated the effect of germline genetic variants on regulation of the homeostasis of the let-7/LIN28 loop and breast cancer risk. We initially demonstrated that the T/C variants of rs3811463, a single nucleotide polymorphism (SNP) located near the let-7 binding site in LIN28, could lead to differential regulation of LIN28 by let-7. Specifically, the C allele of rs3811463 weakened let-7–induced repression of LIN28 mRNA, resulting in increased production of LIN28 protein, which could in turn down-regulate the level of mature let-7. This effect was then validated at the tissue level in that the normal breast tissue of individuals with the rs3811463-TC genotype expressed significantly lower levels of let-7 and higher levels of LIN28 protein than those individuals with the rs3811463-TT genotype. Because previous in vitro and ex vivo experiments have consistently suggested that LIN28 could promote cellular transformation, we then systematically evaluated the relationship between rs3811463 as well as other common LIN28 SNPs and the risk of breast cancer in a stepwise manner. The first hospital-based association study (n = 2,300) demonstrated that two SNPs were significantly associated with breast cancer risk, one of which was rs3811463, while the other was rs6697410. The C allele of the rs3811463 SNP corresponded to an increased risk of breast cancer with an odds ratio (OR) of 1.25 (P = 0.0091), which was successfully replicated in a second independent study (n = 1,156) with community-based controls. The combined P-value of the two studies was 8.0×10−5. Taken together, our study demonstrates that host genetic variants could disturb the regulation of the let-7/LIN28 double-negative feedback loop and alter breast cancer risk. Genetic variants are the genetic basis of inter-individual differences in susceptibility to common diseases like cancer. Single nucleotide polymorphisms (SNPs) are the major type of genetic variation in human beings, and previous studies have linked many SNPs with the risk of suffering human malignancies. In this study, we focused on microRNA (miRNA)–related SNPs and their relationship with the risk of breast cancer. MiRNAs are a kind of tiny endogenous RNAs that play important regulatory roles. Let-7 is a miRNA that has been proven to be capable of inhibiting the tumor occurrence. LIN28, a gene that promotes cancer, is a known regulator of let-7 and, interestingly, LIN28 itself is subject to repression by let-7. We have discovered that an SNP located near the target site of let-7 in LIN28 disturbs let-7's regulation of LIN28. This disturbance eventually leads to an increased level of LIN28 and a decreased level of let-7. We also, for the first time, confirmed that this SNP is associated with an increased risk of breast cancer in Han Chinese women. Our results suggest that genetic variants may potentially build a bridge from a physiological status to an aberrant, even pathological, status with the let-7/LIN28 loop in breast tissue, thus, facilitating carcinogenesis.
登录
查看更多内容
影响因子：
2.7
作者：
Morrogh, Mary;Olvera, Narciso;King, Tari A.
通讯作者：
King, Tari A.
影响因子：
11.2
作者：
Saetrom P;Biesinger J;Li SM;Smith D;Thomas LF;Majzoub K;Rivas GE;Alluin J;Rossi JJ;Krontiris TG;Weitzel J;Daly MB;Benson AB;Kirkwood JM;O'Dwyer PJ;Sutphen R;Stewart JA;Johnson D;Larson GP
通讯作者：
Larson GP
影响因子：
30.8
作者：
Stratton, Michael R.;Rahman, Nazneen
通讯作者：
Rahman, Nazneen
影响因子：
11.2
作者：
Sampson, Valerie B.;Rong, Nancy H.;Krueger, Leslie J.
通讯作者：
Krueger, Leslie J.
影响因子：
64.8
作者：
Gibbs, RA;Belmont, JW;Tanaka, T
通讯作者：
Tanaka, T