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Transcriptomic studies provide insights into the tumor suppressive role of miR-146a-5p in non-small cell lung cancer (NSCLC) cells.

ABSTRACT: Non-small cell lung cancer (NSCLC) is a complex disease in need of new methods of therapeutic intervention. Recent interest has focused on using microRNAs (miRNAs) as a novel treatment method for various cancers. miRNAs negatively regulate gene expression post-transcriptionally, and have become attractive candidates for cancer treatment because they often simultaneously target multiple genes of similar biological function. One such miRNA is miR-146a-5p, which has been described as a tumor suppressive miRNA in NSCLC cell lines and tissues. In this study, we performed RNA-Sequencing (RNA-Seq) analysis following transfection of synthetic miR-146a-5p in an NSCLC cell line, A549, and validated our data with Gene Ontology and qRT-PCR analysis of known miR-146a-5p target genes. Our transcriptomic data revealed that miR-146a-5p exerts its tumor suppressive function beyond previously reported targeting of EGFR and NF-?B signaling. miR-146a-5p mimic transfection downregulated arachidonic acid metabolism genes, the RNA-binding protein HuR, and many HuR-stabilized pro-cancer mRNAs, including TGF-?, HIF-1?, and various cyclins. miR-146a-5p transfection also reduced expression and cellular release of the chemokine CCL2, and this effect was mediated through the 3' untranslated region of its mRNA. Taken together, our work reveals that miR-146a-5p functions as a tumor suppressor in NSCLC by controlling various metabolic and signaling pathways through direct and indirect mechanisms.

SUBMITTER: Iacona JR

PROVIDER: S-EPMC6844565 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Transcriptomic studies provide insights into the tumor suppressive role of miR-146a-5p in non-small cell lung cancer (NSCLC) cells.

Iacona Joseph R JR Monteleone Nicholas J NJ Lemenze Alexander D AD Cornett Ashley L AL Lutz Carol S CS

RNA biology 20190823 12

Non-small cell lung cancer (NSCLC) is a complex disease in need of new methods of therapeutic intervention. Recent interest has focused on using microRNAs (miRNAs) as a novel treatment method for various cancers. miRNAs negatively regulate gene expression post-transcriptionally, and have become attractive candidates for cancer treatment because they often simultaneously target multiple genes of similar biological function. One such miRNA is miR-146a-5p, which has been described as a tumor suppre ...[more]

PMID: 31425002

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Project description:Our previous study demonstrated that the expression of miR‑146a‑5p was downregulated in non‑small cell lung cancer (NSCLC) tissue, which affected the progression and prognosis of patients with NSCLC. Thus, the present study was conducted to investigate the functional mechanism of miR‑146a‑5p in tumorigenesis and angiogenesis in NSCLC. Following the construction of a H460 NSCLC cell line in which miR‑146a‑5p was overexpressed via lentivirus transduction, the NSCLC chick embryo chorioallantoic membrane (CAM) model was established by transplanting miR‑146a‑5p‑overexpressing NSCLC cells into the CAM. Then, the size of the neoplasms within the CAM was measured, the vessel ratio was calculated, and the cellular morphology, metastasis and inflammation of tumor cell was observed using hematoxylin and eosin staining. The target genes of miR‑146a‑5p were predicted by 12 online software programs; these genes were then subjected to Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway annotations using the Database for Annotation, Visualization and Integrated Discovery 6.7 as well as constructed into a protein interaction network using protein‑protein interaction from Search Tool for the Retrieval of Interacting Genes/Proteins. The xenograft tumor size and angiogenesis conditions of the miR‑146a‑5p‑overexpressing group (volume 6.340±0.066 mm3, vessel ratio 9.326±0.083) was obviously restricted (P<0.001) when compared with the low expression group (volume 30.13±0.06 mm3, vessel ratio 16.94±0.11). In addition, marked necrosis along with inflammatory cell infiltration was observed with the HE‑stained slices from the miR‑146a‑5p low expression group. Regarding the results of the target gene prediction, cancer and toll‑like receptor signaling were the two most significant pathways represented among the target genes, while JUN, EGFR and RAC1 were the most relevant proteins among the selected potential targets of miR‑146a‑5p. In a CAM xenograft tumor model, overexpression of miR‑146a‑5p inhibited the tumorigenesis and angiogenesis of an NSCLC cell line. miR‑146a‑5p may act as a tumor suppressor gene in NSCLC and have moderate prognostic value in lung cancer.

Project description:Introduction: Acute graft vs. host disease (aGvHD) is a frequent complication following allogeneic haematopoeitic transplantation (HSCT). Despite recent advances, there are no universally accepted biomarkers to determine development of aGvHD. MicroRNAs miR-146a and miR-155 have been previously associated with aGvHD and show promise as clinically translatable biomarkers. In this study, we performed comprehensive expression profiling of miR-146a, miR-155, and miR-155* expression in aGvHD target tissue and biofluids and relate expression to post-HSCT outcomes. Materials and Methods: MicroRNA expression was assessed by qRT-PCR in gastrointestinal (n = 31) and skin (n = 31) biopsies as well as serum (exploratory cohort n = 34, verification cohort n = 81, diagnostic cohort n = 65) and urine (exploratory cohort n = 30, verification cohort n = 56, diagnostic cohort n = 20) biofluids, including extracellular vesicle (EV) cohorts (serum EV n = 15, urine EV n = 30). Expression was related to aGvHD incidence, severity and overall survival. Results: In GI samples, expression of miR-155 (p = 0.03) and miR-146a (p = 0.03) was higher at aGvHD onset compared to patients with no GvHD. In skin biopsies, expression of miR-155 (p = 0.004) was upregulated in aGvHD patients compared to normal control skin. Expression of miR-146a was higher in aGvHD compared to no aGvHD biopsies (p = 0.002). In serum, miR-155 (p = 0.03) and miR-146a (p = 0.02) expression was higher at day 14 (D14), while in urine expression was elevated at D7 post-HSCT in patients who developed aGvHD compared to those disease-free. This was verified in an independent serum (miR-155 p = 0.005, miR-146a p = 0.003) and urine (miR-155 p = 0.02, miR-146a p = 0.04) cohort, where both microRNAs were also associated with aGvHD by ROC analysis. In serum and urine samples taken at the time of aGvHD symptoms, expression of miR-155 and miR-146a was also elevated (serum miR-155 p = 0.03, miR-146a p < 0.001; urine miR-155 p = 0.02, miR-146a p = 0.02). In contrast, miR-146a and miR-155 were downregulated at D14 in serum EVs and at D7 in urine EVs in patients who developed aGvHD compared to those that remained disease-free, in both an exploratory (serum miR-155 p = 0.02, miR-146a p = 0.06; urine miR-155 p = 0.02, miR-146a p = 0.07) and an independent cohort (serum miR-155 p = 0.01, miR-146a p = 0.02). Conclusions: These results further support a role for miR-155 and miR-146a as non-invasive, clinically relevant biomarkers for aGvHD. However, the link between their involvement in generalized inflammation and in specific pathophysiology requires further investigation at a systemic level.

Project description:Hepatitis C virus (HCV)-induced chronic liver disease is one of the leading causes of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying HCC development following chronic HCV infection remain poorly understood. MicroRNAs (miRNAs) play an important role in cellular homeostasis within the liver and deregulation of the miRNome has been associated with liver disease including HCC. While host miRNAs are essential for HCV replication, viral infection in turn appears to induce alterations of intrahepatic miRNA networks. Although the cross-talk between HCV and liver cell miRNAs most likely contributes to liver disease pathogenesis, the functional involvement of miRNAs in HCV-driven hepatocyte injury and HCC remains elusive. Here, we combined a hepatocyte-like based model system, high-throughput small RNA-sequencing, computational analysis and functional studies to investigate HCV-miRNA interactions that may contribute to liver disease and HCC. Profiling analyses indicated that HCV infection differentially regulated the expression of 72 miRNAs by at least two-fold including miRNAs that were previously described to target genes associated with inflammation, fibrosis and cancer development. Further investigation demonstrated that miR-146a-5p was consistently increased in HCV-infected hepatocyte-like cells and primary human hepatocytes as well as in liver tissues from HCV-infected patients. Genome-wide microarray and computational analyses indicated that miR-146a-5p over-expression is related to liver disease and HCC development. Furthermore, we showed that miR-146a-5p positively impacts on late steps of the viral replication cycle thereby increasing HCV infection. Collectively, our data indicate that the HCV-induced increase in miR-146a-5p expression both promotes viral infection and is relevant for pathogenesis of liver disease. To explore the functional relevance of miR-146a-5p up-regulation, we performed a genome-wide transcriptomic analysis of hepatocyte-like cells upon ectopic miR-146a-5p expression.

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Transcriptomic studies provide insights into the tumor suppressive role of miR-146a-5p in non-small cell lung cancer (NSCLC) cells.

Publications

Transcriptomic studies provide insights into the tumor suppressive role of miR-146a-5p in non-small cell lung cancer (NSCLC) cells.

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