miR-145-5p is associated with smoke-related chronic obstructive pulmonary disease via targeting KLF5
Introduction
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality every year globally and predicted to be the third leading cause of death by 2030 [1]. CPOD is characterized by chronic bronchiolitis and emphysema due to the abnormal inflammatory response triggered by pollutants such as virus infection and noxious gases exposure, of which cigarette smoking (CS) is considered as the predominant factor and attributed to approximately 80–90% of the COPD cases [2]. Airway epithelium serves as the first line of the innate immune defense against CS attack through the secretion of various pro-inflammatory mediators and production of airway mucus, whereas, the excessive accumulation of these immunological factors in chronic bronchiolitis caused by CS inhale contributes to the irreversible airflow limitation and airway remodeling, and COPD-related mortality occurs [3]. Furthermore, the CS-induced apoptosis in airway epithelial cells also accounts to the pathogenesis of COPD [4]. However, the molecular mechanism underlying the CS-induced inflammation and apoptosis in the progression of COPD remains largely unknown.
microRNAs (miRNAs) are a class of conserved and small non-coding RNAs (19-35 nucleotides in length) that negatively regulate gene expressions via complementary binding to the 3′-untranslated region (3′-UTR) of their target mRNAs, which results in the repression of protein synthesis and cleavage of mRNAs [5]. Emerging miRNA-microarray analysis has demonstrated that miRNAs play crucial roles in the pathogenesis of COPD [6]. miR-145-5p as a member of the miR-145 family has been widely verified to be involved in various human malignancies [7]. A recent study has illustrated that in myocardial ischemic injury, miR-145-5p functions as a cardiac-protective molecule by ameliorating apoptosis and inflammation [8]. Additionally, overexpression of miR-145 in airway smooth muscle cells from COPD patients has been manifested to suppress pro-inflammatory cytokines release when compared to the non-smoker controls [9]. However, the role and molecular mechanisms underlying the regulation of miR-145-5p on the inflammation and apoptosis of CS-stimulated airway epithelial cells are still poorly understood.
Kruppel-like 5 (KLF5, also named LKLF and BTEB2) is located at 13q21 chromosome and belongs to a family of zinc-finger (ZF) containing transcription factors. KLF5 is ubiquitously expressed at varying levels in different tissues, which facilitates the regulation of a wide range of genes involved in cell proliferation, apoptosis, stemness, inflammation, angiogenesis, migration, and differentiation [10]. A previous study has indicated that silencing of KLF5 prevents hypoxia-induced proliferation and migration, and promoted apoptosis in human pulmonary artery smooth muscle cells [11]. Specifically, KLF5 has been proved to be upregulated in the bronchial fibroblasts and pulmonary vessels of the patients and has a remarkably correlation with the severity of the airflow limitation [12]. Accordingly, we hypothesized that KLF5 might be involved in the progression of CS-induced COPD.
Whether the biological role of miR-145-5p in response to CS-induced airway epithelial cell dysfunction was mediated via KLF5 remain largely unknown. In this study, we identified miR-145-5p as a CS-induced apoptosis and inflammatory responsive miRNA in COPD patients and cells line. Further investigation revealed that miR-145-5p inhibited CS-induced apoptosis and inflammation in HBEC by negatively regulating of KLF5.
Section snippets
Human lung sample collection
Lung resection specimens were obtained from 31 patients underwent a pneumonectomy for a solitary non-small cell lung cancer (at least 5 cm away from the tumor regions) at The First Affiliated Hospital of Xi'an Jiaotong University. The subjects were divided into three groups: non-smokers without COPD (n = 8); smokers without COPD (n = 10), smokers with COPD (n = 13). The diagnosis of COPD was based on the criteria of the Global Initiative for Chronic Obstruct Lung Disease (GOLD). The
miR-145-5p was down-regulated in COPD tissues and CSE-mediated HBECs
The clinical characteristics including age and body mass index (BMI) among the three groups show no statistical difference except for lung function (Table 1). The expression of miR-145-5p in 31 cases of lung tissue samples were determined by qRT-PCR. Compared with specimens from non-smoker group, the expression level of miR-145-5p was remarkably reduced in lung tissues of smokers without or with COPD (P < 0.05 and P < 0.01, respectively, Fig. 1A). In addition, after exposure of HBECs to a
Discussion
Multiple studies have verified that persistent exposure to CSE contributed to the dysregulation of miRNAs in the lungs, which is associated with various respiratory disorders, such as pulmonary tuberculosis, asthma, lung cancers, as well as COPD [14]. Downregulation of miR-145 has been shown in the lungs of COPD rat model with CS exposure and miR-145 has been proposed to be closely associated with the diagnosis of COPD [9,15]. However, the function of miR-145-5p involved in the pathogenesis of
Conflicts of interest
The authors declare no conflicts of interest in this work.
Acknowledgement
This study was supported by “International Science and Technology Cooperation and Exchange Program Project of Shaanxi Province of China (2016KW-026).
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