Department of Respiratory and Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 611731, P.R. China.
Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 611731, P.R. China.
Aging (Albany NY). 2020 May 12;12(9):8339-8351. doi: 10.18632/aging.103142.
Interstitial pulmonary fibrosis (IPF) is a progressive disease of diverse etiology manifesting with proliferation of lung fibroblasts and accumulation of extracellular matrix deposition in pulmonary interstitium. Recent studies show aberrant expression of mRNAs and microRNAs (miRNAs) in human embryonic pulmonary fibroblasts (HEPFs). In this study, we investigated effects of the YY1/HSF1/miR-214/THY1 axis on the functions of HEPFs and IPF. Loss- and gain-of-function tests were conducted to identify roles of YY1, HSF1, miR-214, and THY1 in IPF. As determined by RT-qPCR or western blot assay, silencing YY1 down-regulated HSF1 expression and attenuated the expression of pro-proliferative and fibrosis markers in HEPFs. Meanwhile, viability of HEPFs was impeded by YY1 knockdown. The binding relationship between miR-214 and THY1 was verified using dual-luciferase reporter assay. In HEPFs, down-regulation of HSF1 reduced miR-214 expression to repress proliferation and fibrogenic transformation of HEPFs, while inhibition of miR-214 expression could restrain the fibrogenic transformation property of HEPFs by up-regulating THY1. Subsequently, IPF model in mice was induced by bleomycin treatment. These animal experiments validated the protective effects of YY1 knockdown against IPF-induced lung pathological manifestations, which could be reversed by THY1 knockdown. Our study demonstrates the important involvement of YY1/HSF1/miR-214/THY1 axis in the development of IPF.
特发性肺纤维化（IPF）是一种病因多样的进行性疾病，表现为肺成纤维细胞增殖和肺间质细胞外基质沉积增加。最近的研究表明，人类胚胎肺成纤维细胞（HEPFs）中存在 mRNA 和 microRNAs（miRNAs）的异常表达。在这项研究中，我们研究了 YY1/HSF1/miR-214/THY1 轴对 HEPF 功能和 IPF 的影响。通过失活和功能获得试验来确定 YY1、HSF1、miR-214 和 THY1 在 IPF 中的作用。通过 RT-qPCR 或 Western blot 分析，沉默 YY1 下调 HSF1 的表达，并减弱 HEPF 中促增殖和纤维化标志物的表达。同时，YY1 敲低抑制了 HEPF 的活力。通过双荧光素酶报告实验验证了 miR-214 和 THY1 之间的结合关系。在 HEPF 中，HSF1 的下调降低了 miR-214 的表达，从而抑制 HEPF 的增殖和纤维化转化，而 miR-214 的抑制通过上调 THY1 抑制 HEPF 的纤维化转化特性。随后，通过博来霉素处理诱导小鼠发生 IPF 模型。这些动物实验验证了 YY1 敲低对 IPF 诱导的肺病理表现的保护作用，而 THY1 敲低可逆转这种作用。我们的研究表明，YY1/HSF1/miR-214/THY1 轴在 IPF 的发生发展中具有重要作用。
