Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Mol Cancer Res. 2011 Nov;9(11):1500-8. doi: 10.1158/1541-7786.MCR-11-0311. Epub 2011 Aug 29.
Integrins are adhesion receptors involved in bidirectional signaling that are crucial for various cellular responses during normal homeostasis and pathologic conditions such as cancer progression and metastasis. Aberrant expression of noncoding microRNAs (miRNA) 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' untranslated region 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. Although different reports have shown that a single integrin can be regulated by several miRNAs, here we show that a single miRNA, miR-31, is able to specifically target several integrin subunits to regulate key aspects of cancer cell invasion and metastasis.
整合素是参与双向信号传递的黏附受体，对于正常生理状态和病理条件下（如癌症进展和转移）的各种细胞反应至关重要。非编码 microRNA（miRNA）的异常表达与整合素表达和活性的失调有关，导致癌症肿瘤的发生和发展，包括获得转移表型。miR-31 是参与癌症侵袭-转移级联反应的几个关键基因的重要调节剂。通过多种基于细胞的、遗传的、生化的、流式细胞术和功能分析，我们报告 miR-31 是整合素的主要调节剂，因为它靶向β1 整合素的多个α亚基伴侣（α2、α5 和αV）以及β3 整合素。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 靶向这些整合素亚基 3'UTR 中保守种子序列的直接结果，导致它们的转录后抑制，这反映在活细胞中它们表面表达的减少。这些整合素细胞表面减少的生物学后果是细胞在配体依赖性方式下的显著铺展抑制。尽管有不同的报道表明单个整合素可以被几个 miRNA 调节，但我们在这里表明，单个 miRNA，miR-31，能够特异性地靶向几个整合素亚基来调节癌细胞侵袭和转移的关键方面。
