miR-203 regulates cell proliferation through its influence on Hakai expression.
miR-203 regulates cell proliferation through its influence on Hakai expression.
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DOI：
10.1371/journal.pone.0052568
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Figueroa A
中科院分区：
文献类型：
--
作者：
Abella V;Valladares M;Rodriguez T;Haz M;Blanco M;Tarrío N;Iglesias P;Aparicio LA;Figueroa A
基因表达通过microRNA（miRNAs）的作用而有效地调节。在这里，我们提出了一个miRNA调节Hakai蛋白的证据。Hakai被发现是一种E3泛素连接酶，介导E-钙粘蛋白的翻译后下调，E-钙粘蛋白是上皮细胞粘附连接的主要成分，也是一种有效的肿瘤抑制剂。最近的数据提供的证据表明，Hakai影响细胞增殖的E-钙粘蛋白独立的方式，从而揭示了Hakai在肿瘤进展的早期阶段的作用。此外，与正常组织相比，Hakai在人结肠腺癌中高度上调。然而，调节哈卡伊丰度的分子机制尚不清楚。我们在Hakai mRNA的3′-非翻译区（UTR）鉴定了两个miR-203相互作用的推定位点。在测试的几种人癌细胞系中，miR-203前体（Pre-miR-203）的过表达降低了Hakai丰度，而通过使用反义RNA（Anti-miR-203）抑制miR-203提高了Hakai水平。miR-203对Hakai 3′-UTR的抑制作用使用异源报告构建体证实。与Hakai的增殖影响一致，Anti-miR-203显著增加了细胞数量和BrdU掺入，而Pre-miR-203降低了这些参数。重要的是，抗miR-203的生长促进作用需要Hakai的存在，因为siRNA下调Hakai抑制了其增殖作用。最后，原位杂交显示，与正常结肠组织相比，miR-203在结肠肿瘤组织中的表达减弱，这表明miR-203可能是结肠癌中潜在的新预后标志物和治疗靶点。总之，我们的研究结果首次揭示了Hakai表达的转录后调节因子。此外，通过降低Hakai丰度，miR-203还减少了Hakai调节的细胞分裂。
Gene expression is potently regulated through the action of microRNAs (miRNAs). Here, we present evidence of a miRNA regulating Hakai protein. Hakai was discovered as an E3 ubiquitin-ligase that mediates the posttranslational downregulation of E-cadherin, a major component of adherens junctions in epithelial cells and a potent tumour suppressor. Recent data have provided evidence that Hakai affects cell proliferation in an E-cadherin-independent manner, thus revealing a role for Hakai in the early stages of tumour progression. Furthermore, Hakai is highly up-regulated in human colon adenocarcinomas compared to normal tissues. However, the molecular mechanisms that regulate Hakai abundance are unknown. We identified two putative sites of miR-203 interaction on the Hakai mRNA, in its 3′-untranslated region (UTR). In several human carcinoma cell lines tested, overexpression of a miR-203 precursor (Pre-miR-203) reduced Hakai abundance, while inhibiting miR-203 by using an antisense RNA (Anti-miR-203) elevated Hakai levels. The repressive influence of miR-203 on the Hakai 3′-UTR was confirmed using heterologous reporter constructs. In keeping with Hakai's proliferative influence, Anti-miR-203 significantly increased cell number and BrdU incorporation, while Pre-miR-203 reduced these parameters. Importantly, the growth-promoting effects of anti-miR-203 required the presence of Hakai, because downregulation of Hakai by siRNA suppressed its proliferative action. Finally, in situ hybridization showed that miR-203 expression is attenuated in colon tumour tissues compared to normal colon tissues, suggesting that miR-203 could be a potential new prognostic marker and therapeutic target to explore in colon cancer. In conclusion, our findings reveal, for the first time, a post-transcriptional regulator of Hakai expression. Furthermore, by lowering Hakai abundance, miR-203 also reduces Hakai-regulated-cell division.
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影响因子：
3.3
作者：
Figueroa, Angelica;Kotani, Hirokazu;Fujita, Yasuyuki
通讯作者：
Fujita, Yasuyuki
影响因子：
7
作者：
Gennarino, Vincenzo Alessandro;Sardiello, Marco;Banfi, Sandro
通讯作者：
Banfi, Sandro
影响因子：
8
作者：
Fan, SJ;Ma, YX;Rosen, EM
通讯作者：
Rosen, EM
影响因子：
64.5
作者：
Eulalio, Ana;Huntzinger, Eric;Izaurralde, Elisa
通讯作者：
Izaurralde, Elisa
影响因子：
3.7
作者：
Hartsock A;Nelson WJ
通讯作者：
Nelson WJ