Aberrant MicroRNAomics in Pulmonary Complications: Implications in Lung Health and Diseases

Abstract

Over the last few decades, evolutionarily conserved molecular networks have emerged as important regulators in the expression and function of eukaryotic genomes. Recently, miRNAs (miRNAs), a large family of small, non-coding regulatory RNAs were identified in these networks as regulators of endogenous genes by exerting post-transcriptional gene regulation activity in a broad range of eukaryotic species. Dysregulation of miRNA expression correlates with aberrant gene expression and can play an essential role in human health and disease. In the context of the lung, miRNAs have been implicated in organogenesis programming, such as proliferation, differentiation, and morphogenesis. Gain- or loss-of-function studies revealed their pivotal roles as regulators of disease development, potential therapeutic candidates/targets, and clinical biomarkers. An altered microRNAome has been attributed to several pulmonary diseases, such as asthma, chronic pulmonary obstructive disease, cystic fibrosis, lung cancer, and idiopathic pulmonary fibrosis. Considering the relevant roles and functions of miRNAs under physiological and pathological conditions, they may lead to the invention of new diagnostic and therapeutic tools. This review will focus on recent advances in understanding the role of miRNAs in lung development, lung health, and diseases, while also exploring the progress and prospects of their application as therapeutic leads or as biomarkers.

Keywords: COPD; antagomiR; aptamer; asthma; cystic fibrosis; idiopathic pulmonary fibrosis; lung cancer; microRNA dysregulation.

Figure 1

Mechanism of MicroRNA Processing and Their Inhibitory Mechanism The microRNA (miRNA) processing pathway begins with transcription of their genes with the help of RNA polymerase II (Pol II) or polymerase III (Pol III) to produce pri-miRNAs in the nucleus. Then a microprocessor complex, composed of RNA-binding protein DGCR8 and type III RNase Drosha, cleaves pri-miRNA into a ∼85-nt stem-loop structure called pre-miRNA. The exportin 5-RAN/GTP complex mediates the transport of pre-miRNA from the nucleus into the cytoplasm. The RNase DICER in complex with double-stranded RNA-binding protein TRBP cleaves the pre-miRNA hairpin to a ∼20- to 22-nt miRNA/miRNA duplex. After the duplex is unwound, the functional strand of the mature miRNA (the guide strand) is loaded into the miRISC-containing DICER1, TRBP, and Argonaute (AGO) proteins. This miRISC silences/inhibits the target mRNAs expression/function through mRNA cleavage, translational repression, or deadenylation. The passenger strand of the miRNA is degraded. AGO, Argonaute proteins; DGCR8, DiGeorge syndrome critical region gene 8; m7G cap, 7-methylguanosine; miRISC, miRNA-induced silencing complex; miRNA, microRNA; pre-miRNA, miRNA precursor; pri-miRNA, primary miRNA; RAN-GTP, Ras-related nuclear protein coupled with guanosine-5′-triphosphate; TRBP, transactivating response RNA-binding protein.

Figure 2

Schematic of MicroRNAs Implicated in Lung Pathophysiology in Different Lung Diseases (A) Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease that causes obstructed airflow from the lungs and attenuates mucociliary clearance (MCC), leading to mucous obstruction, and provides a nutrient-rich environment for bacterial reproduction, leading to pulmonary infections and chronic inflammation. (B) Asthma, characterized by the hallmarks of airway inflammation, airway remodeling, airway hyperresponsiveness, and reversible airway obstruction. (C) Lung cancer is associated with excessive pulmonary cell proliferation, apoptosis, angiogenesis, and epithelial-mesenchymal transition. (D) In idiopathic pulmonary fibrosis, the normal lung tissue is replaced by more heavily scarred lung tissue, which makes it difficult for the patient to breathe and deliver needed oxygen to the body. This causes the aberrantly activated lung epithelium to produce mediators of fibroblast migration, proliferation, and differentiation into active myofibroblasts. (E) In cystic fibrosis, aberrant or nonexistent CFTR function compromises the airway surface liquid, leading to mucous impaction and sub-optimal ciliary beating. This results in microbial colonization and chronic inflammation, which further compromise mucociliary clearance. microRNAs in red and green indicate whether the miRNA is elevated or reduced in lung-associated diseases, respectively. CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; IPF, idiopathic pulmonary fibrosis.

Figure 3

Therapeutic Approaches to Rescue miRNA Dysfunction Exosome/liposome, viral vectors (lentivirus [LV], adeno-associated virus [AAV], adeno, and plasmid), nanoparticles/polymers, aptamer-mediated antagomiR, and miRNA mimic delivery into the pulmonary cells. (A) Small molecules bind to Drosha and Dicer processing sites of human miRNAs that are disease associated and inhibit their biogenesis. (B) miRNA mimics function like endogenous miRNAs restoring the activity of a miRNA. (C and D) Binding of single-stranded antagomiRs having complementary sequences to the target endogenous miRNA genome sequence and inhibiting the synthesis of disease-causing miRNAs (C), and antagomiRs having seed sequence sequesters the endogenous free miRNA target inhibiting the activity (D). AGO, Argonaute proteins; DGCR8, DiGeorge syndrome critical region gene 8; m7G cap, 7-methylguanosine; miRISC, miRNA-induced silencing complex; miRNA, microRNA; pre-miRNA, miRNA precursor; pri-miRNA, primary miRNA; RAN-GTP, Ras-related nuclear protein coupled with guanosine-5′-triphosphate; T, inhibitory effect; TRBP, transactivating response RNA-binding protein.