MicroRNA‐10a controls airway smooth muscle cell proliferation via direct targeting of the PI3 kinase pathway

作者：Ruoxi Hu, Wen‐Chi Pan, Alexey V. Fedulov, William F. Jester, Matthew R. Jones, Scott T. Weiss, Reynold A. Panettieri, Kelan G. Tantisira, Quan Lu · 发表于：The FASEB Journal · 年份：2014 · DOI：10.1096/fj.13-247247 · 被引用次数：70 · 研究领域：MicroRNA in disease regulation、Cancer-related molecular mechanisms research、Genomics, phytochemicals, and oxidative stress

Airway smooth muscle (ASM) cells play important physiological roles in the lung, and abnormal proliferation of ASM directly contributes to the airway remodeling during development of lung diseases such as asthma. MicroRNAs are small yet versatile gene tuners that regulate a variety of cellular processes, including cell growth and proliferation; however, little is known about the precise role of microRNAs in the proliferation of the ASM. Here we report that a specific microRNA (miR-10a) controls ASM proliferation through directly inhibiting the phosphoinositide 3-kinase (PI3K) pathway. Next-generation sequencing identified miR-10a as the most abundant microRNA expressed in primary human airway smooth muscle (HASM) cells, accounting for > 20% of all small RNA reads. Overexpression of miR-10a reduced mitogen-induced HASM proliferation by ∼50%, whereas inhibition of miR-10a increased HASM proliferation by ∼40%. Microarray profiling of HASM cells expressing miR-10a mimics identified 52 significantly down-regulated genes as potential targets of miR-10a, including the catalytic subunit α of PI3K (PIK3CA), the central component of the PI3K pathway. MiR-10a directly suppresses PIK3CA expression by targeting the 3'-untranslated region (3'-UTR) of the gene. Inhibition of PIK3CA by miR-10a reduced V-akt murine thymoma viral oncogene homolog 1 (AKT) phosphorylation and blunted the expression of cyclins and cyclin-dependent kinases that are required for HASM proliferation. Together, our st...