miR-34 miRNAs Regulate Cellular Senescence in Type II Alveolar Epithelial Cells of Patients with Idiopathic Pulmonary Fibrosis.
miR-34 miRNAs Regulate Cellular Senescence in Type II Alveolar Epithelial Cells of Patients with Idiopathic Pulmonary Fibrosis.
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DOI：
10.1371/journal.pone.0158367
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Wolters PJ
中科院分区：
文献类型：
--
作者：
Disayabutr S;Kim EK;Cha SI;Green G;Naikawadi RP;Jones KD;Golden JA;Schroeder A;Matthay MA;Kukreja J;Erle DJ;Collard HR;Wolters PJ
特发性肺纤维化(IPF)的病理特征包括遗传易感性、未折叠蛋白反应激活、端粒磨损和细胞衰老。导致肺泡上皮细胞(AEC)衰老的机制尚不清楚。MicroRNAs(MiRNAs)被认为是细胞衰老的调节因子。检测来自IPF肺和未使用的供体肺的II型AEC的衰老标志物p16、p21、p53和衰老相关β-半乳糖苷酶(SA-βGAL)活性。利用基因表达阵列和定量RT-PCR对II型AECs中的miRNAs进行定量。IPF II型AECs衰老的分子标志物(p16、p21和p53)水平升高。从IPF患者分离的II型AEC中SA-βGal活性的比例(23.1%)高于其他间质性肺疾病患者(1.2%)和正常对照组(0.8%)。在IPF患者的II型AEC中，与衰老相关的miR-34a、miR-34b和miR-34c的相对水平显著升高，而不是miR-20a、miR-29c和miR-let-7f的相对水平显著升高。肺上皮细胞过表达miR-34a、miR-34b和miR-34c后，SA-βGal活性(分别为27.8%、35.1%和38.2%)高于对照组(8.8%)。在IPF II型AEC中，miR-34miRNAs的靶点较低，包括E2F1、c-Myc和细胞周期蛋白E2。这些结果表明，IPF II型AECs中的衰老标志物独特地升高，提示miR-34家族的miRNAs调控IPF II型AECs的衰老。
Pathologic features of idiopathic pulmonary fibrosis (IPF) include genetic predisposition, activation of the unfolded protein response, telomere attrition, and cellular senescence. The mechanisms leading to alveolar epithelial cell (AEC) senescence are poorly understood. MicroRNAs (miRNAs) have been reported as regulators of cellular senescence. Senescence markers including p16, p21, p53, and senescence-associated β-galactosidase (SA-βgal) activity were measured in type II AECs from IPF lungs and unused donor lungs. miRNAs were quantified in type II AECs using gene expression arrays and quantitative RT-PCR. Molecular markers of senescence (p16, p21, and p53) were elevated in IPF type II AECs. SA-βgal activity was detected in a greater percentage in type II AECs isolated from IPF patients (23.1%) compared to patients with other interstitial lung diseases (1.2%) or normal controls (0.8%). The relative levels of senescence-associated miRNAs miR-34a, miR-34b, and miR-34c, but not miR-20a, miR-29c, or miR-let-7f were significantly higher in type II AECs from IPF patients. Overexpression of miR-34a, miR-34b, or miR-34c in lung epithelial cells was associated with higher SA-βgal activity (27.8%, 35.1%, and 38.2%, respectively) relative to control treated cells (8.8%). Targets of miR-34 miRNAs, including E2F1, c-Myc, and cyclin E2, were lower in IPF type II AECs. These results show that markers of senescence are uniquely elevated in IPF type II AECs and suggest that the miR-34 family of miRNAs regulate senescence in IPF type II AECs.