A positive feedback loop promotes HIF‐1α stability through miR‐210‐mediated suppression of RUNX3 in paraquat‐induced EMT

Abstract

Irreversible pulmonary fibrosis induced by paraquat (PQ) poisoning is the major cause of death in patients with PQ poisoning. The epithelial–mesenchymal transition (EMT) is postulated to be one of the main mechanisms of pulmonary fibrosis. Here, we investigated the role of miR‐210 in PQ‐induced EMT and its relationship with hypoxia‐inducible factor‐1α (HIF‐1α). Western blotting, immunofluorescence, immunoprecipitation and other methods were used in this study. We found that miR‐210 expression was significantly increased after PQ poisoning, and it may be regulated by HIF‐1α. Overexpression of miR‐210 further increased the HIF‐1α protein level and promoted EMT. Moreover, miR‐210 knock‐down reduced the HIF‐1α protein level and decreased the degree of EMT. Runt‐related transcription factor‐3 (RUNX3), a direct target of miR‐210, was inhibited by miR‐210 in response to PQ poisoning. RUNX3 increased the hydroxylation ability of prolyl hydroxylase domain‐containing protein 2 (PHD2), a key enzyme that promotes HIF‐1α degradation. PHD2 immunoprecipitated with RUNX3 and its level changed similarly to that of RUNX3. The expression of the HIF‐1α protein was significantly reduced when RUNX3 was overexpressed. HIF‐1α protein levels were markedly increased when RUNX3 was silenced. Based on these results, a positive feedback loop may exist between miR‐210 and HIF‐1α. The mechanism may function through miR‐210‐mediated repression of RUNX3, which further decreases the hydroxylation activity of PHD2, enhances the stability of HIF‐1α, and promotes PQ‐induced EMT, aggravating the progression of pulmonary fibrosis. This study further elucidates the mechanism of PQ‐induced pulmonary fibrosis and may provide a new perspective for the future development of therapies.

Low RUNX3 expression alters dendritic cell function in patients with systemic sclerosis and contributes to enhanced fibrosis

“…MiRNAs have also been shown to regulate of RUNX3 expression. miR-130b has been shown to decrease expression of RUNX3 in gastric tumour cells,24 and miR-210 was described to suppress RUNX3 expression in epithelial cells 25. However, we did not observe any significant correlation between mir-130b and mir-210 expression and RUNX3 expression levels in pDCs of these patients (see online supplementary table S2, supplementary figure S2).…”

A‐kinase‐interacting protein 1 facilitates growth and metastasis of gastric cancer cells via Slug‐induced epithelial‐mesenchymal transition

“…Recently, extensive evidence has demonstrated that epithelial‐mesenchymal transition (EMT) functions importantly in the invasion and metastasis of various epithelial tumours . The differentiation process that epithelial cells can down‐regulate epithelial properties and acquire mesenchymal features is commonly known as EMT.…”

Analysis of microRNA expression profiling during paraquat-induced injury of murine lung alveolar epithelial cells

“…Down-regulated miR-17-5p promoted PQ-induced degeneration of dopaminergic neurons in Neuro-2a cells (Wang et al, 2018a). Increased miR-210 expression after PQ poisoning aggravates the progression of pulmonary fibrosis through enhancing the stability of hypoxia-inducible factor-1 α, which promotes PQinduced epithelial-mesenchymal transition (Zhu et al, 2017). These studies indicate that miRNAs participate in different types of PQ-induced cell damage.…”