International Journal of Molecular Sciences

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13 pages, 3807 KiB

Open AccessArticle

Comprehensive Bioinformatics Identifies Key microRNA Players in ATG7-Deficient Lung Fibroblasts

by Stevan D. Stojanović, Maximilian Fuchs, Jan Fiedler, Ke Xiao, Anna Meinecke, Annette Just, Andreas Pich, Thomas Thum and Meik Kunz

Int. J. Mol. Sci. 2020, 21(11), 4126; https://doi.org/10.3390/ijms21114126 - 9 Jun 2020

Cited by 10 | Viewed by 3283

Abstract

Background: Deficient autophagy has been recently implicated as a driver of pulmonary fibrosis, yet bioinformatics approaches to study this cellular process are lacking. Autophagy-related 5 and 7 (ATG5/ATG7) are critical elements of macro-autophagy. However, an alternative ATG5/ATG7-independent macro-autophagy pathway was recently discovered, its [...] Read more.

Background: Deficient autophagy has been recently implicated as a driver of pulmonary fibrosis, yet bioinformatics approaches to study this cellular process are lacking. Autophagy-related 5 and 7 (ATG5/ATG7) are critical elements of macro-autophagy. However, an alternative ATG5/ATG7-independent macro-autophagy pathway was recently discovered, its regulation being unknown. Using a bioinformatics proteome profiling analysis of ATG7-deficient human fibroblasts, we aimed to identify key microRNA (miR) regulators in autophagy. Method: We have generated ATG7-knockout MRC-5 fibroblasts and performed mass spectrometry to generate a large-scale proteomics dataset. We further quantified the interactions between various proteins combining bioinformatics molecular network reconstruction and functional enrichment analysis. The predicted key regulatory miRs were validated via quantitative polymerase chain reaction. Results: The functional enrichment analysis of the 26 deregulated proteins showed decreased cellular trafficking, increased mitophagy and senescence as the major overarching processes in ATG7-deficient lung fibroblasts. The 26 proteins reconstitute a protein interactome of 46 nodes and miR-regulated interactome of 834 nodes. The miR network shows three functional cluster modules around miR-16-5p, miR-17-5p and let-7a-5p related to multiple deregulated proteins. Confirming these results in a biological setting, serially passaged wild-type and autophagy-deficient fibroblasts displayed senescence-dependent expression profiles of miR-16-5p and miR-17-5p. Conclusions: We have developed a bioinformatics proteome profiling approach that successfully identifies biologically relevant miR regulators from a proteomics dataset of the ATG-7-deficient milieu in lung fibroblasts, and thus may be used to elucidate key molecular players in complex fibrotic pathological processes. The approach is not limited to a specific cell-type and disease, thus highlighting its high relevance in proteome and non-coding RNA research. Full article

(This article belongs to the Special Issue The Role of Non-Coding RNAs in Human Lung Health and Disease)

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11 pages, 1661 KiB

Open AccessCommunication

miR-9 Does Not Regulate Lamin A Expression in Metastatic Cells from Lung Adenocarcinoma

by Julien Guinde, Audrey Benoit, Diane Frankel, Stéphane Robert, Kevin Ostacolo, Nicolas Lévy, Philippe Astoul, Patrice Roll and Elise Kaspi

Int. J. Mol. Sci. 2020, 21(5), 1599; https://doi.org/10.3390/ijms21051599 - 26 Feb 2020

Viewed by 2314

Abstract

In lung adenocarcinoma, low lamin A expression in pleural metastatic cells has been proposed as a pejorative factor. miR-9 physiologically inhibits the expression of lamin A in neural cells and seems to be a central actor in the carcinogenesis and the metastatic process [...] Read more.

In lung adenocarcinoma, low lamin A expression in pleural metastatic cells has been proposed as a pejorative factor. miR-9 physiologically inhibits the expression of lamin A in neural cells and seems to be a central actor in the carcinogenesis and the metastatic process in lung cancer. Thus, it could be a good candidate to explain the reduction of lamin A expression in lung adenocarcinoma cells. miR-9 expression was analyzed in 16 pleural effusions containing metastatic cells from lung adenocarcinoma and was significantly reduced in patients from the ‘Low lamin A expression’ group compared to patients from the ‘High lamin A expression’ group. Then, carcinoma cells selection by fluorescence-activated cell sorting (FACS) was performed according to epithelial membrane antigen (EMA) expression, reflecting lamin A expression. miR-9 was underexpressed in lamin A− carcinoma cells compared to lamin A+ carcinoma cells in patients from the ‘Low lamin A expression’ group, whereas there was no difference of miR-9 expression between lamin A+ and lamin A− carcinoma cells in patients from the ‘High lamin A expression’ group. These results suggest that miR-9 does not regulate lamin A expression in metastatic cells from lung adenocarcinoma. On the contrary, miR-9 expression was shown to be reduced in lamin A-negative carcinoma cells. Full article

(This article belongs to the Special Issue The Role of Non-Coding RNAs in Human Lung Health and Disease)

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14 pages, 1000 KiB

Open AccessArticle

Current Smoking is Associated with Decreased Expression of miR-335-5p in Parenchymal Lung Fibroblasts

by Jennie Ong, Anke van den Berg, Alen Faiz, Ilse M Boudewijn, Wim Timens, Cornelis J Vermeulen, Brian G Oliver, Klaas Kok, Martijn M Terpstra, Maarten van den Berge, Corry-Anke Brandsma and Joost Kluiver

Int. J. Mol. Sci. 2019, 20(20), 5176; https://doi.org/10.3390/ijms20205176 - 18 Oct 2019

Cited by 17 | Viewed by 3202

Abstract

Cigarette smoking causes lung inflammation and tissue damage. Lung fibroblasts play a major role in tissue repair. Previous studies have reported smoking-associated changes in fibroblast responses and methylation patterns. Our aim was to identify the effect of current smoking on miRNA expression in [...] Read more.

Cigarette smoking causes lung inflammation and tissue damage. Lung fibroblasts play a major role in tissue repair. Previous studies have reported smoking-associated changes in fibroblast responses and methylation patterns. Our aim was to identify the effect of current smoking on miRNA expression in primary lung fibroblasts. Small RNA sequencing was performed on lung fibroblasts from nine current and six ex-smokers with normal lung function. MiR-335-5p and miR-335-3p were significantly downregulated in lung fibroblasts from current compared to ex-smokers (false discovery rate (FDR) <0.05). Differential miR-335-5p expression was validated with RT-qPCR (p-value = 0.01). The results were validated in lung tissue from current and ex-smokers and in bronchial biopsies from non-diseased smokers and never-smokers (p-value <0.05). The methylation pattern of the miR-335 host gene, determined by methylation-specific qPCR, did not differ between current and ex-smokers. To obtain insights into the genes regulated by miR-335-5p in fibroblasts, we overlapped all proven miR-335-5p targets with our previously published miRNA targetome data in lung fibroblasts. This revealed Rb1, CARF, and SGK3 as likely targets of miR-335-5p in lung fibroblasts. Our study indicates that miR-335-5p downregulation due to current smoking may affect its function in lung fibroblasts by targeting Rb1, CARF and SGK3. Full article

(This article belongs to the Special Issue The Role of Non-Coding RNAs in Human Lung Health and Disease)

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29 pages, 5912 KiB

Open AccessArticle

Transforming Growth Factor-β1 Selectively Recruits microRNAs to the RNA-Induced Silencing Complex and Degrades CFTR mRNA under Permissive Conditions in Human Bronchial Epithelial Cells

by Nilay Mitash, Fangping Mu, Joshua E. Donovan, Michael M. Myerburg, Sarangarajan Ranganathan, Catherine M. Greene and Agnieszka Swiatecka-Urban

Int. J. Mol. Sci. 2019, 20(19), 4933; https://doi.org/10.3390/ijms20194933 - 5 Oct 2019

Cited by 14 | Viewed by 4338

Abstract

<p>Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (<italic>CFTR</italic>) gene lead to cystic fibrosis (CF). The most common mutation F508del inhibits folding and processing of CFTR protein. FDA-approved correctors rescue the biosynthetic processing of F508del-CFTR protein, while potentiators improve the rescued CFTR channel [...] Read more.

<p>Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (<italic>CFTR</italic>) gene lead to cystic fibrosis (CF). The most common mutation F508del inhibits folding and processing of CFTR protein. FDA-approved correctors rescue the biosynthetic processing of F508del-CFTR protein, while potentiators improve the rescued CFTR channel function. Transforming growth factor (TGF-β1), overexpressed in many CF patients, blocks corrector/potentiator rescue by inhibiting CFTR mRNA in vitro. Increased TGF-β1 signaling and acquired CFTR dysfunction are present in other lung diseases. To study the mechanism of TGF-β1 repression of CFTR, we used molecular, biochemical, and functional approaches in primary human bronchial epithelial cells from over 50 donors. TGF-β1 destabilized CFTR mRNA in cells from lungs with chronic disease, including CF, and impaired F508del-CFTR rescue by new-generation correctors. TGF-β1 increased the active pool of selected micro(mi)RNAs validated as CFTR inhibitors, recruiting them to the RNA-induced silencing complex (RISC). Expression of F508del-CFTR globally modulated TGF-β1-induced changes in the miRNA landscape, creating a permissive environment required for degradation of F508del-CFTR mRNA. In conclusion, TGF-β1 may impede the full benefit of corrector/potentiator therapy in CF patients. Studying miRNA recruitment to RISC under disease-specific conditions may help to better characterize the miRNAs utilized by TGF-β1 to destabilize CFTR mRNA. Full article

(This article belongs to the Special Issue The Role of Non-Coding RNAs in Human Lung Health and Disease)

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18 pages, 4069 KiB

Open AccessArticle

Involvement of Dual Strands of miR-143 (miR-143-5p and miR-143-3p) and Their Target Oncogenes in the Molecular Pathogenesis of Lung Adenocarcinoma

by Hiroki Sanada, Naohiko Seki, Keiko Mizuno, Shunsuke Misono, Akifumi Uchida, Yasutaka Yamada, Shogo Moriya, Naoko Kikkawa, Kentaro Machida, Tomohiro Kumamoto, Takayuki Suetsugu and Hiromasa Inoue

Int. J. Mol. Sci. 2019, 20(18), 4482; https://doi.org/10.3390/ijms20184482 - 11 Sep 2019

Cited by 47 | Viewed by 3378

Abstract

Our analyses of tumor-suppressive microRNAs (miRNAs) and their target oncogenes have identified novel molecular networks in lung adenocarcinoma (LUAD). Moreover, our recent studies revealed that some passenger strands of miRNAs contribute to cancer cell malignant transformation. Downregulation of both strands of the miR-143 [...] Read more.

Our analyses of tumor-suppressive microRNAs (miRNAs) and their target oncogenes have identified novel molecular networks in lung adenocarcinoma (LUAD). Moreover, our recent studies revealed that some passenger strands of miRNAs contribute to cancer cell malignant transformation. Downregulation of both strands of the miR-143 duplex was observed in LUAD clinical specimens. Ectopic expression of these miRNAs suppressed malignant phenotypes in cancer cells, suggesting that these miRNAs have tumor-suppressive activities in LUAD cells. Here, we evaluated miR-143-5p molecular networks in LUAD using genome-wide gene expression and miRNA database analyses. Twenty-two genes were identified as potential miR-143-5p-controlled genes in LUAD cells. Interestingly, the expression of 11 genes (MCM4, RAD51, FAM111B, CLGN, KRT80, GPC1, MTL5, NETO2, FANCA, MTFR1, and TTLL12) was a prognostic factor for the patients with LUAD. Furthermore, knockdown assays using siRNAs showed that downregulation of MCM4 suppressed cell growth, migration, and invasion in LUAD cells. Aberrant expression of MCM4 was confirmed in the clinical specimens of LUAD. Thus, we showed that miR-143-5p and its target genes were involved in the molecular pathogenesis of LUAD. Identification of tumor-suppressive miRNAs and their target oncogenes may be an effective strategy for elucidation of the molecular oncogenic networks of this disease. Full article

(This article belongs to the Special Issue The Role of Non-Coding RNAs in Human Lung Health and Disease)

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Review

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56 pages, 3530 KiB

Open AccessReview

Exosomal Long Non-Coding RNAs in Lung Diseases

by Christophe Poulet, Makon-Sébastien Njock, Catherine Moermans, Edouard Louis, Renaud Louis, Michel Malaise and Julien Guiot

Int. J. Mol. Sci. 2020, 21(10), 3580; https://doi.org/10.3390/ijms21103580 - 19 May 2020

Cited by 71 | Viewed by 8649

Abstract

Within the non-coding genome landscape, long non-coding RNAs (lncRNAs) and their secretion within exosomes are a window that could further explain the regulation, the sustaining, and the spread of lung diseases. We present here a compilation of the current knowledge on lncRNAs commonly [...] Read more.

Within the non-coding genome landscape, long non-coding RNAs (lncRNAs) and their secretion within exosomes are a window that could further explain the regulation, the sustaining, and the spread of lung diseases. We present here a compilation of the current knowledge on lncRNAs commonly found in Chronic Obstructive Pulmonary Disease (COPD), asthma, Idiopathic Pulmonary Fibrosis (IPF), or lung cancers. We built interaction networks describing the mechanisms of action for COPD, asthma, and IPF, as well as private networks for H19, MALAT1, MEG3, FENDRR, CDKN2B-AS1, TUG1, HOTAIR, and GAS5 lncRNAs in lung cancers. We identified five signaling pathways targeted by these eight lncRNAs over the lung diseases mentioned above. These lncRNAs were involved in ten treatment resistances in lung cancers, with HOTAIR being itself described in seven resistances. Besides, five of them were previously described as promising biomarkers for the diagnosis and prognosis of asthma, COPD, and lung cancers. Additionally, we describe the exosomal-based studies on H19, MALAT1, HOTAIR, GAS5, UCA1, lnc-MMP2-2, GAPLINC, TBILA, AGAP2-AS1, and SOX2-OT. This review concludes on the need for additional studies describing the lncRNA mechanisms of action and confirming their potential as biomarkers, as well as their involvement in resistance to treatment, especially in non-cancerous lung diseases. Full article

(This article belongs to the Special Issue The Role of Non-Coding RNAs in Human Lung Health and Disease)

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37 pages, 3464 KiB

Open AccessReview

Non-Coding RNAs in Lung Tumor Initiation and Progression

by Ruben Mercado Santos, Cerena Moreno and Wen Cai Zhang

Int. J. Mol. Sci. 2020, 21(8), 2774; https://doi.org/10.3390/ijms21082774 - 16 Apr 2020

Cited by 32 | Viewed by 6860

Abstract

Lung cancer is one of the deadliest forms of cancer affecting society today. Non-coding RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), through the transcriptional, post-transcriptional, and epigenetic changes they impose, have been found to be dysregulated to [...] Read more.

Lung cancer is one of the deadliest forms of cancer affecting society today. Non-coding RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), through the transcriptional, post-transcriptional, and epigenetic changes they impose, have been found to be dysregulated to affect lung cancer tumorigenesis and metastasis. This review will briefly summarize hallmarks involved in lung cancer initiation and progression. For initiation, these hallmarks include tumor initiating cells, immortalization, activation of oncogenes and inactivation of tumor suppressors. Hallmarks involved in lung cancer progression include metastasis and drug tolerance and resistance. The targeting of these hallmarks with non-coding RNAs can affect vital metabolic and cell signaling pathways, which as a result can potentially have a role in cancerous and pathological processes. By further understanding non-coding RNAs, researchers can work towards diagnoses and treatments to improve early detection and clinical response. Full article

(This article belongs to the Special Issue The Role of Non-Coding RNAs in Human Lung Health and Disease)

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16 pages, 2329 KiB

Open AccessReview

miRNAs in Lung Development and Diseases

by Eistine Boateng and Susanne Krauss-Etschmann

Int. J. Mol. Sci. 2020, 21(8), 2765; https://doi.org/10.3390/ijms21082765 - 16 Apr 2020

Cited by 25 | Viewed by 4790

Abstract

The development of the lung involves a diverse group of molecules that regulate cellular processes, organ formation, and maturation. The various stages of lung development are marked by accumulation of small RNAs that promote or repress underlying mechanisms, depending on the physiological environment [...] Read more.

The development of the lung involves a diverse group of molecules that regulate cellular processes, organ formation, and maturation. The various stages of lung development are marked by accumulation of small RNAs that promote or repress underlying mechanisms, depending on the physiological environment in utero and postnatally. To some extent, the pathogenesis of various lung diseases is regulated by small RNAs. In this review, we discussed miRNAs regulation of lung development and diseases, that is, COPD, asthma, pulmonary fibrosis, and pulmonary arterial hypertension, and also highlighted possible connotations for human lung health. Full article

(This article belongs to the Special Issue The Role of Non-Coding RNAs in Human Lung Health and Disease)

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18 pages, 2671 KiB

Open AccessReview

Radon Biomonitoring and microRNA in Lung Cancer

by Rakhmet Bersimbaev, Alessandra Pulliero, Olga Bulgakova, Assiya Kussainova, Akmara Aripova and Alberto Izzotti

Int. J. Mol. Sci. 2020, 21(6), 2154; https://doi.org/10.3390/ijms21062154 - 20 Mar 2020

Cited by 28 | Viewed by 5725

Abstract

Radon is the number one cause of lung cancer in non-smokers. microRNA expression in human bronchial epithelium cells is altered by radon, with particular reference to upregulation of miR-16, miR-15, miR-23, miR-19, miR-125, and downregulation of let-7, miR-194, miR-373, miR-124, miR-146, miR-369, and [...] Read more.

Radon is the number one cause of lung cancer in non-smokers. microRNA expression in human bronchial epithelium cells is altered by radon, with particular reference to upregulation of miR-16, miR-15, miR-23, miR-19, miR-125, and downregulation of let-7, miR-194, miR-373, miR-124, miR-146, miR-369, and miR-652. These alterations alter cell cycle, oxidative stress, inflammation, oncogene suppression, and malignant transformation. Also DNA methylation is altered as a consequence of miR-29 modification induced by radon. Indeed miR-29 targets DNA methyltransferases causing inhibition of CpG sites methylation. Massive microRNA dysregulation occurs in the lung due to radon expose and is functionally related with the resulting lung damage. However, in humans this massive lung microRNA alterations only barely reflect onto blood microRNAs. Indeed, blood miR-19 was not found altered in radon-exposed subjects. Thus, microRNAs are massively dysregulated in experimental models of radon lung carcinogenesis. In humans these events are initially adaptive being aimed at inhibiting neoplastic transformation. Only in case of long-term exposure to radon, microRNA alterations lead towards cancer development. Accordingly, it is difficult in human to establish a microRNA signature reflecting radon exposure. Additional studies are required to understand the role of microRNAs in pathogenesis of radon-induced lung cancer. Full article

(This article belongs to the Special Issue The Role of Non-Coding RNAs in Human Lung Health and Disease)

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