CircHECTD1 mediates pulmonary fibroblast activation via HECTD1

Abstract

Background:Circular RNA (circRNA), a new class of noncoding RNA, has been shown to be important in silicosis due to its unique role as a transcription regulator or as a sponge of small RNA regulators. Here, the mechanisms underlying circHECTD1/HECTD1 in fibroblast activation and subsequent fibrosis induced by SiO2 were investigated.Methods:Primary human pulmonary fibroblasts (HPF-a) were utilized, combined with quantitative real-time PCR (qRT-PCR) and fluorescence in situ hybridization (FISH) assays. LC3B-LV-RFP lentivirus was used to evaluate the role of autophagy. The CRISPR/Cas9 system was applied to specifically knock down HECTD1, combined with MTT, BrdU, and migration assays, to explore the functional changes induced by SiO2.Results:After exposure to SiO2, the circHECTD1 level was decreased, which was associated with an increase in HECTD1 in HPF-a cells. SiO2-induced autophagy was reversed by either circHECTD1 overexpression or HECTD1 knockdown in HPF-a cells, with restored SiO2-induced fibroblast activation, proliferation, and migration via downstream autophagy. The lungs of mice exposed to SiO2 confirmed the upregulation of HECTD1 in pulmonary fibroblasts.Conclusions:Our data suggested a link between circHECTD1/HECTD1 and fibroblast activation with subsequent fibrosis induced by SiO2, providing novel insight into the potential of circHECTD1/HECTD1 to be a therapeutic target for silicosis.

Hsa_circ_0018818 knockdown suppresses tumorigenesis in non-small cell lung cancer by sponging miR-767-3p

“…Moreover, circRNAs are stable and widely expressed in many tumor tissues [14,15]. Some circRNAs have important biological functions and can be considered as biomarkers for diagnosis of multiple diseases [4,16,17]. This suggests the possibility that circRNAs, like miRNAs, may be involved in paracrine signaling or cell-to-cell crosstalk.…”

Circular RNAs: Novel Players in the Oxidative Stress‐Mediated Pathologies, Biomarkers, and Therapeutic Targets

“…circHECTD1 was upregulated in the mouse model of silicosis. Their studies included the direct role of circHECTD1/HECTD1 axis in fibroblast [ 81 ] and its indirect effect through endothelial cells [ 82 ] and macrophages [ 83 ], leading to induction of lung fibrosis after stimulation with SiO. An additional study by the same group confirmed the role of circ_012091 in mediating the silicosis-induced lung fibrosis as it was downregulated in the mouse model of silicosis and after induction of lung cells with SiO in vitro [ 35 ].…”

Circular RNA and tumor microenvironment

“…In primary human pulmonary fibroblasts (HPF-a) exposed to SiO, circHECTD1 was downregulated, thus inducing an increase in HECTD1, which subsequently caused fibroblast activation and accumulation via the EMT and endothelial-mesenchymal transition (EndMT) processes [97,103,104]. CircRNAs also help fibroblasts overcome stress.…”