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miR150 Is Upregulated by TGF-Beta and Promotes Pulmonary Fibrosis Through Downregulation of OGR1 Expression

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A2210 - miR150 Is Upregulated by TGF-Beta and Promotes Pulmonary Fibrosis Through Downregulation of OGR1 Expression
Author Block: D. Nagel1, J. L. Judge2, R. Clough1, W. Narrow1, P. J. Sime1, R. M. Kottmann1; 1Pulmonary and Critical Care, University of Rochester Medical Center, Rochester, NY, United States, 2University of Michigan, Ann Arbor, MI, United States.
Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a median survival of less than 3 years. Transforming Growth Factor-beta (TGF-β) is a key pro-fibrotic cytokine responsible for generating excess scar tissue. We have shown that TGF-β downregulates expression of Ovarian Cancer G-Protein Coupled Receptor 1 (OGR1) and that OGR1 protects against the development of pulmonary fibrosis. Micro Ribonucleic Acids (miRNA) are small non-coding RNAs that regulate the function of coding RNA. We identified several novel miRNAs that are upregulated in patients with IPF and are predicted to negatively regulate OGR1. We hypothesize that one of these miRNAs is upregulated by TGF-β and negatively regulates OGR1.
Methods: We utilized existing databases (www.targetscan.org) to identify miRNAs that were predicted to target OGR1 and were upregulated in the lung tissue of patients with IPF and found three potential miRNAs; miR21, miR125, and miR150. To determine the significance of these miRNAs, human lung fibroblasts were treated with TGF-β. The expression of the target miRNAs was then measured with quantitative real-time polymerase chain reaction (qRT-PCR). Subsequently, fibroblasts were transfected with control miRNA or candidate miRNAs and the expression of OGR1 and Col1A1 was assessed with qRT-PCR.
Results: TGF-β induced a time-dependent, 5-fold increase in miR150 expression in healthy human lung fibroblasts. In a cell line derived from a patient with IPF, TGF-β did not cause an increase in miR150. However, TGF-β induced a 2.5-fold increase in miR21 expression and a 2-fold increase in miR125 in this cell line. When healthy fibroblasts were transfected with miR150, there was an approximate 2-fold decrease in OGR1 expression, and a 2 fold increase in collagen gene expression.
Conclusions: These data suggest that TGF-β induces expression of miR150, a miRNA found to be upregulated in patients with IPF. Overexpression of miR150 caused a significant decrease in OGR1 expression and induced collagen gene expression. In conjunction with our prior work, we hypothesize that one possible mechanism by which TGF-β downregulates OGR1 expression is via upregulation of miR150. Additional work is required to determine the interplay between OGR1 and miR150. We did not identify a significant increase in miR150 in a fibrotic fibroblast cell line, however miR21 and miR125 were both upregulated by TGFβ. Interrogation of the differential expression of miRNAs in healthy and fibrotic fibroblasts may help define key mechanistic differences in these cell populations. MicroRNAs such as miR150 may represent novel therapeutic targets for treating pulmonary fibrosis.
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