LncRNA HOXA11-AS通过海绵吸附miR-148a-3p并调控SMAD2促进特发性肺纤维化进展
LncRNA HOXA11-AS promotes idiopathic pulmonary fibrosis progression via sponging miR-148a-3p and regulating SMAD2.
摘要(中文译文)
特发性肺纤维化(IPF)主要以进行性肺组织瘢痕形成为特征。本研究旨在探讨HOXA11-AS/miR-148a-3p/SMAD2轴在IPF中的分子机制。研究招募了60例IPF患者和70例健康对照者。采用RT-qPCR检测mRNA表达。使用转化生长因子-β1(TGF-β1)诱导A549细胞和MRC-5细胞建立IPF模型。分别采用细胞计数试剂盒-8(CCK-8)、流式细胞术和酶联免疫吸附试验(ELISA)评估细胞增殖、凋亡、氧化应激水平及纤维化标志物。通过双荧光素酶报告基因实验验证调控相互作用。在IPF患者中，HOXA11-AS表达显著上调。其表达与肺功能参数及6分钟步行试验(6MWT)距离呈负相关。相反，其与纤维化相关血清标志物如透明质酸(HA)和层粘连蛋白(LN)呈正相关。这些发现提示HOXA11-AS可能作为IPF有前景的诊断生物标志物。此外，HOXA11-AS促进增殖、抑制凋亡、通过降低超氧化物歧化酶(SOD)活性和增加丙二醛(MDA)水平增强氧化应激，并上调关键纤维化标志物的表达，包括α-平滑肌肌动蛋白(α-SMA)、I型胶原蛋白和纤连蛋白。HOXA11-AS直接结合miR-148a-3p，后者反过来靶向调控SMAD2。值得注意的是，抑制miR-148a-3p可逆转HOXA11-AS敲低对TGF-β1诱导的A549细胞增殖、氧化应激和纤维化表型的抑制作用，同时恢复SMAD2表达。在MRC-5成纤维细胞中观察到一致的结果：HOXA11-AS敲低显著减弱TGF-β1诱导的增殖、促进凋亡，并降低α-SMA、I型胶原蛋白和纤连蛋白的表达。这些效应被miR-148a-3p抑制部分逆转，证实了HOXA11-AS/miR-148a-3p/SMAD2轴在肺成纤维细胞中的功能作用。HOXA11-AS通过海绵吸附miR-148a-3p上调SMAD2表达，从而促进IPF进展。
Abstract
Idiopathic Pulmonary Fibrosis (IPF) is characterized primarily by progressive lung tissue scarring. This study aimed to explore the molecular mechanism of the HOXA11-AS/miR-148a-3p/SMAD2 axis in IPF. Sixty IPF patients and 70 healthy controls were recruited. mRNA expression was measured by RT-qPCR. An IPF model was established in A549 cells and MRC-5 cells using transforming growth factor-beta 1 (TGF-β1) induction. Cell proliferation, apoptosis, oxidative stress levels, and fibrosis markers were assessed using the cell counting kit-8 (CCK-8), flow cytometry, and enzyme-linked immunosorbent assay (ELISA), respectively. A dual-luciferase reporter assay was conducted to confirm the regulatory interaction. In IPF patients, HOXA11-AS expression was significantly upregulated. Its expression was negatively correlated with lung function parameters as well as with the 6-minute walk test (6MWT) distance. Conversely, it was positively associated with fibrosis-related serum markers, such as hyaluronic acid (HA) and laminin (LN). These findings suggested that HOXA11-AS may serve as a promising diagnostic biomarker for IPF. Moreover, HOXA11-AS promoted the proliferation, suppressed apoptosis, enhanced oxidative stress by reducing superoxide dismutase (SOD) activity and increasing malondialdehyde (MDA) levels, and upregulated the key fibrosis markers expression, including alpha-smooth muscle actin (α-SMA), Collagen I, and Fibronectin. HOXA11-AS directly binds to miR-148a-3p, which in turn targets and regulates SMAD2. Notably, inhibition of miR-148a-3p reversed the suppressive effects of HOXA11-AS knockdown on TGF-β1-induced proliferation, oxidative stress, and fibrotic phenotypes in A549 cells, while restoring SMAD2 expression. Consistent results were observed in MRC-5 fibroblasts: HOXA11-AS knockdown significantly attenuated TGF-β1-induced proliferation, promoted apoptosis, and decreased the expression of α-SMA, Collagen I, and Fibronectin. These effects were partially reversed by miR-148a-3p inhibition, confirming the functional role of the HOXA11-AS/miR-148a-3p/SMAD2 axis in lung fibroblasts. HOXA11-AS promoted the IPF progression by upregulating SMAD2 expression through the sponging of miR-148a-3p.
如何引用
AMA
Lidong Wang, Xing Ding, Ran Tang, Heping Jiang. LncRNA HOXA11-AS promotes idiopathic pulmonary fibrosis progression via sponging miR-148a-3p and regulating SMAD2.. Hereditas. 2026; doi:10.1186/s41065-026-00684-9.
APA
Lidong Wang, Xing Ding, Ran Tang, Heping Jiang (2026). LncRNA HOXA11-AS promotes idiopathic pulmonary fibrosis progression via sponging miR-148a-3p and regulating SMAD2.. Hereditas. https://doi.org/10.1186/s41065-026-00684-9
GB/T 7714
Lidong Wang, Xing Ding, Ran Tang, Heping Jiang. LncRNA HOXA11-AS promotes idiopathic pulmonary fibrosis progression via sponging miR-148a-3p and regulating SMAD2.[J]. Hereditas, 2026 doi:10.1186/s41065-026-00684-9.
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