Loss of miR-10a activates lpo and collaborates with activated Wnt signaling in inducing intestinal neoplasia in female mice.
Loss of miR-10a activates lpo and collaborates with activated Wnt signaling in inducing intestinal neoplasia in female mice.
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DOI：
10.1371/journal.pgen.1003913
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发表时间：
2013-10
期刊：
影响因子：
4.5
通讯作者：
Lund AH
中科院分区：
文献类型：
--
作者：
Stadthagen G;Tehler D;Høyland-Kroghsbo NM;Wen J;Krogh A;Jensen KT;Santoni-Rugiu E;Engelholm LH;Lund AH
miRNA是小的调节RNA，由于其靶向广泛的mRNA的相当大的潜力，其涉及基本上所有的生物过程，包括癌症。考虑到其在发育调节因子的Hox簇中的保守位置，miR-10a特别有趣。这种microRNA在发育调节以及各种癌症中的作用已经被描述。然而，先前的miR-10a研究仅基于该miRNA的瞬时敲除，并且为了广泛研究miR-10a损失，我们产生了miR-10a敲除小鼠。在此，我们发现，在Apcmin小鼠肠肿瘤模型中，雌性miR-10a缺陷小鼠比miR-10+/+和雄性对照小鼠发生更多的腺瘤。我们进一步发现，Lpo在缺乏miR-10a的小鼠的肠上皮中广泛上调。使用体外试验，我们证明了主要的miR-10a靶点KLF 4可以上调LPO的转录，而KLF 4的siRNA敲低降低了HCT-116细胞中的LPO水平。此外，Klf 4在miR-10a敲除小鼠的肠道中上调。以前已经证明脂蛋白有能力氧化雌激素成为有效的脱嘌呤诱变剂，创造一个不稳定的基因组环境，可以导致癌症的发生。因此，我们推测miR-10a缺陷小鼠肠上皮中的Lpo上调以及雌性动物中雌激素的主要丰度主要解释了我们观察到的性别相关癌症表型。这表明，miR-10a可用作发现结直肠癌高风险女性群体的有效诊断标志物，结直肠癌是当今癌症相关死亡的主要原因之一。microRNA分子的转录后调节构成了基因调节的重要机制，并且许多研究已经证明了失调的microRNA水平与疾病（例如癌症）之间的相关性。然而，将个体microRNA与癌症病因联系起来的遗传学研究仍然很少。在这里，我们提供了因果关系的证据，保守的microRNA miR-10a参与肠腺瘤的发展，在面对激活的Wnt信号。有趣的是，我们发现miR-10a的丢失仅介导雌性小鼠肠腺瘤的增加，并描绘了涉及miR-10a靶Klf 4的异常上调和随后编码抗菌蛋白Lactoperoxidase的Lpo基因的转录激活的途径。反过来，以前已经证明Lpo可以将雌激素氧化成DNA损伤诱变剂。
miRNAs are small regulatory RNAs that, due to their considerable potential to target a wide range of mRNAs, are implicated in essentially all biological process, including cancer. miR-10a is particularly interesting considering its conserved location in the Hox cluster of developmental regulators. A role for this microRNA has been described in developmental regulation as well as for various cancers. However, previous miR-10a studies are exclusively based on transient knockdowns of this miRNA and to extensively study miR-10a loss we have generated a miR-10a knock out mouse. Here we show that, in the Apcmin mouse model of intestinal neoplasia, female miR-10a deficient mice develop significantly more adenomas than miR-10+/+ and male controls. We further found that Lpo is extensively upregulated in the intestinal epithelium of mice deprived of miR-10a. Using in vitro assays, we demonstrate that the primary miR-10a target KLF4 can upregulate transcription of Lpo, whereas siRNA knockdown of KLF4 reduces LPO levels in HCT-116 cells. Furthermore, Klf4 is upregulated in the intestines of miR-10a knockout mice. Lpo has previously been shown to have the capacity to oxidize estrogens into potent depurinating mutagens, creating an instable genomic environment that can cause initiation of cancer. Therefore, we postulate that Lpo upregulation in the intestinal epithelium of miR-10a deficient mice together with the predominant abundance of estrogens in female animals mainly accounts for the sex-related cancer phenotype we observed. This suggests that miR-10a could be used as a potent diagnostic marker for discovering groups of women that are at high risk of developing colorectal carcinoma, which today is one of the leading causes of cancer-related deaths. Posttranscriptional regulation by microRNA molecules constitutes an important mechanism for gene regulation and numerous studies have demonstrated a correlation between deregulated microRNA levels and diseases, such as cancer. However, genetics studies linking individual microRNAs to the etiology of cancer remain scarce. Here, we provide causal evidence for the involvement of the conserved microRNA miR-10a in the development of intestinal adenomas in the face of activated Wnt signaling. Interestingly, we find that loss of miR-10a mediates an increase in intestinal adenomas in female mice only and delineate the pathway to involve aberrant upregulation of the miR-10a target Klf4 and subsequent transcriptional activation of the Lpo gene encoding the antibacterial protein Lactoperoxidase. Lpo, in turn, has previously been demonstrated to oxidize estrogens into DNA-damaging mutagens.
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影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
影响因子：
5.7
作者：
Chai, Guolin;Liu, Ning;Yu, Xijie
通讯作者：
Yu, Xijie
影响因子：
37.3
作者：
Bryant A;Palma CA;Jayaswal V;Yang YW;Lutherborrow M;Ma DD
通讯作者：
Ma DD
影响因子：
64.5
作者：
Hafner M;Landthaler M;Burger L;Khorshid M;Hausser J;Berninger P;Rothballer A;Ascano M Jr;Jungkamp AC;Munschauer M;Ulrich A;Wardle GS;Dewell S;Zavolan M;Tuschl T
通讯作者：
Tuschl T
影响因子：
4.8
作者：
Frankel, Lisa B.;Christoffersen, Nanna R.;Lund, Anders H.
通讯作者：
Lund, Anders H.