Senin , 29 Mar 2021 14:12:38
microRNA-mRNA regulatory networks underlying chronic mucus hypersecretion in COPD


Abstract

Chronic mucus hypersecretion (CMH) is a common feature in COPD and associated with worse prognosis and quality of life. This study aimed to identify microRNA (miRNA)-mRNA regulatory networks underlying CMH.

miRNA and mRNA expression profiles in bronchial biopsies from 63 COPD patients were associated with CMH using linear regression. Potential mRNA targets of each CMH-associated miRNA were identified using Pearson correlations. GSEA and STRING analyses were used to identify key genes and pathways.

Twenty miRNAs and 539 mRNAs were differentially expressed with CMH in COPD. The expression of 10 miRNAs was significantly correlated with the expression of one or more mRNAs. Of these, miR-134-5p, miR146a-5p and the let-7 family had the highest representation of CMH-associated mRNAs among their negatively correlated predicted targets. KRAS and EDN1 were identified as key regulators of CMH and were negatively correlated predicted targets of miR-134-5p and the let-7a/d/f-5p, respectively. GSEA suggested involvement of MUC5AC-related genes and several other relevant gene sets in CMH. The lower expression of miR-134-5p was confirmed in primary airway fibroblasts from COPD patients with CMH.

We identified miR-134-5p, miR-146a-5p and let-7 family, along with their potential target genes including KRAS and EDN1, as potential key miRNA-mRNA networks regulating CMH in COPD.

Footnotes

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: Dr. Tasena has nothing to disclose.

Conflict of interest: Dr. Faiz has nothing to disclose.

Conflict of interest: Dr. Timens reports grants from Merck, during the conduct of the study; personal fees from Pfizer, personal fees from GSK, personal fees from Chiesi, personal fees from Roche Diagnostics / Ventana, grants from Dutch Asthma Fund, personal fees from Biotest, personal fees from Merck Sharp Dohme, personal fees from Novartis, personal fees from Lilly Oncology, personal fees from Boehringer Ingelheim, outside the submitted work.

Conflict of interest: Dr. Noordhoek has nothing to disclose.

Conflict of interest: Dr. Hylkema has nothing to disclose.

Conflict of interest: Dr. Gosens reports grants from Boehringer Ingelheim, grants from Chiesi Farmaceutici, grants and other from Aquilo, grants and other from Holaira, outside the submitted work.

Conflict of interest: Dr. Hiemstra reports grants from Galapagos N.V., grants from Boehringer Ingelheim, outside the submitted work.

Conflict of interest: Dr. Spira reports personal fees from Veracyte Inc, personal fees from janssen pharma, outside the submitted work.

Conflict of interest: Dirkje S. Postma: The University of Groningen has received money for Professor Postma regarding a grant for research from Astra Zeneca, Chiesi, Genentec, GSK and Roche. Fees for consultancies were given to the University of Groningen by Astra Zeneca, Boehringer Ingelheim, Chiesi, GSK, Takeda and TEVA.

Conflict of interest: Dr. Tew reports other from Genentech Inc, during the conduct of the study.

Conflict of interest: Dr. Grimbaldeston reports other from Genentech Inc, during the conduct of the study.

Conflict of interest: Dr. van den Berge reports grants paid to the University from Astra Zeneca, TEVA, GSK, Chiesi, outside the submitted work.

Conflict of interest: Dr. Heijink has nothing to disclose.

Conflict of interest: Dr. Brandsma has nothing to disclose.

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