Abstract
Emerging evidence suggests that microRNA (miRNA) and long noncoding RNA (lncRNA) play important roles in disease development. However, the mechanism underlying mRNA interaction with miRNA and lncRNA in idiopathic pulmonary fibrosis (IPF) remains unknown. This study presents a novel lnc-PCF that promotes the proliferation of TGF-β1-activated epithelial cells through the regulation of map3k11 by directly targeting miR-344a-5p during pulmonary fibrogenesis. Bioinformatics and in vitro translation assay were performed to confirm whether or not lnc-PCF is an actual lncRNA. RNA fluorescent in situ hybridization (FISH) and nucleocytoplasmic separation showed that lnc-PCF is mainly expressed in the cytoplasm. Knockdown and knockin of lnc-PCF indicated that lnc-PCF could promote fibrogenesis by regulating the proliferation of epithelial cells activated by TGF-β1 according to the results of xCELLigence real-time cell analysis system, flow cytometry, and western blot analysis. Computational analysis and a dual-luciferase reporter system were used to identify the target gene of miR-344a-5p, whereas RNA pull down, anti-AGO2 RNA immunoprecipitation, and rescue experiments were conducted to confirm the identity of this direct target. Further experiments verified that lnc-PCF promotes the proliferation of activated epithelial cells that were dependent on miR-344a-5p, which exerted its regulatory functions through its target gene map3k11. Finally, adenovirus packaging sh-lnc-PCF was sprayed into rat lung tissues to evaluate the therapeutic effect of lnc-PCF. These findings revealed that lnc-PCF can accelerate pulmonary fibrogenesis by directly targeting miR-344a-5p to regulate map3k11, which may be a potential therapeutic target in IPF.
Highlights
The majority of genomes are transcribed using modern molecular biology techniques, such as deep sequencing; only 2% of the transcribed genome codes are attributed to proteins
Lnc-MD1 ‘sponges’ miR-133 and miR-135 to regulate the expression of MAML1 and MEF2C, thereby activating muscle-specific gene expression.[5] lnc-APF is identified as the competitive endogenous RNAs (ceRNAs) that can regulate autophagic cell death by targeting miR-188-3p and ATG7.6 the mechanism underlying mRNA interaction with miRNA and long noncoding RNAs (lncRNAs) in idiopathic pulmonary fibrosis (IPF) remains unknown
Received 08.5.17; revised 10.8.17; accepted 31.8.17; Edited by E Candi lnc-PCF promotes pulmonary fibrosis H Liu et al which revealed its function
Summary
The majority of genomes are transcribed using modern molecular biology techniques, such as deep sequencing; only 2% of the transcribed genome codes are attributed to proteins. NcRNAs can be divided into small (o200 nt) ncRNAs, such as microRNAs (miRNAs) and transfer RNAs, and long RNAs(4200 nt), such as long noncoding RNAs (lncRNAs) and ribosomal RNAs.[1] miRNAs and lncRNAs play important roles in the development and progression of diseases,[2,3] the interaction of mRNAs with miRNAs and lncRNAs to form an interrelated regulatory network in diseases remains unknown. IPF is defined as a specific form of chronic and progressive interstitial pneumonia of an unknown cause, and this disease leads to the progressive loss of lung function, respiratory failure, and death.[7] To date, lung transplant is the only effective treatment available for IPF.[8] a comprehensive understanding of the molecular mechanisms of fibrogenesis is required in developing specific therapies toward this disease.[9]. We described the differentially expressed miRNAs, lncRNAs, and mRNAs in IPF; the molecular mechanisms of these RNAs are poorly elucidated.[10,11] In the present work, we defined a novel lnc-PCF, its function, and the crosstalk between lnc-PCF and the map3k11 target miR-344a-5p in the regulation of fibrogenesis
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