miR-31 is a broad regulator of β1-integrin expression and function in cancer cells.
miR-31 is a broad regulator of β1-integrin expression and function in cancer cells.
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DOI：
10.1158/1541-7786.mcr-11-0311
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Sossey-Alaoui K
中科院分区：
文献类型：
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作者：
Augoff K;Das M;Bialkowska K;McCue B;Plow EF;Sossey-Alaoui K
整合素是参与双向信号传导的粘附受体，其对于正常稳态和病理状况（例如癌症进展和转移）期间的各种细胞应答至关重要。非编码microRNA的异常表达与整联蛋白表达和活性的失调有关，导致癌症肿瘤的发展和进展，包括其转移表型的获得。miR-31是参与癌症侵袭-转移级联反应的几个关键基因的关键调节因子。使用基于不同细胞的遗传、生物化学、流式细胞术和功能分析，我们报告了miR-31是整合素的主要调节剂，因为它靶向β1整合素和β3整合素的多个α亚基伴侣（α2、α5和αV）。我们发现癌细胞中miR-31的表达导致这些整合素亚基在mRNA和蛋白水平上的显著抑制。α2、α5、αV和β3的表达缺失是miR-31靶向这些整联蛋白亚基的3 'UTR中的保守种子序列导致其转录后抑制的直接结果，这反映在其在活细胞中的表面表达减少。这些整合素细胞表面减少的生物学后果是以配体依赖性方式显着抑制细胞扩散。虽然不同的报告表明，一个单一的整合素可以由几个microRNA调节，在这里，我们表明，一个单一的microRNA，miR-31，能够特异性靶向几个整合素亚基，调节癌细胞侵袭和转移的关键方面。
Integrins are adhesion receptors involved in bidirectional signaling that are crucial for various cellular responses during normal homeostasis and pathological conditions such as cancer progression and metastasis. Aberrant expression of noncoding microRNAs has been implicated in the deregulation of integrin expression and activity, leading to the development and progression of cancer tumors, including their acquisition of the metastatic phenotype. miR-31 is a key regulator of several critical genes involved in the invasion-metastasis cascade in cancer. Using diverse cell based, genetic, biochemical, flow cytometry and functional analyses, we report that miR-31 is a master regulator of integrins as it targets multiple α subunit partners (α2, α5 and αV) of β1 integrins and also β3 integrins. We found that expression of miR-31 in cancer cells resulted in a significant repression of these integrin subunits both at the mRNA and protein levels. Loss of expression of α2, α5, αV and β3 was a direct consequence of miR-31 targeting conserved seed sequences in the 3’UTR of these integrin subunits leading to their posttranscriptional repression, which was reflected in their diminished surface expression in live cells. The biological consequence of decreased the cell surface of these integrins was a significant inhibition of cell spreading in a ligand-dependent manner. While different reports have shown that a single integrin can be regulated by several microRNAs, here we show that a single microRNA, miR-31, is able to specifically target several integrin subunits to regulate key aspects of cancer cell invasion and metastasis.