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Silicosis is a disease characterized by lung inflammation and fibrosis caused by long-term inhalation of free silicon dioxide (SiO2). Recent studies have found that a large number of lymphatic hyperplasia occurs during the occurrence and development of silicosis. miRNAs play an important role in lymphangiogenesis. However, the regulation and mechanism of miRNAs on lymphangiogenesis in silicosis remain unclear. In this study, lymphangiogenesis was observed in silicosis rats, and VEGF-C-targeted miRNAs were screened, and the effect of miRNAs on the formation of human lymphatic endothelial cells (HLECs) tubular structure was investigated in vitro. The results showed that SiO2 promoted the expressions of Collagen Ι and α-SMA, TNF-α, IL-6 and VEGF-C increased first and then decreased, and promoted the formation of lymphatic vessels. Bioinformatics methods screened miR-455–3p for targeted binding to VEGF-C, and dual luciferase reporter genes confirmed VEGF-C as the target gene of miR-455–3p, and miR-455–3p was down-regulated in the lung tissue of silicosis rats. Transfection of miR-455–3p Inhibitors down-regulated the expression level of miR-455–3p and up-regulated the expression levels of VEGF-C and VEGFR-3 in HLECs, enhanced migration ability and increased tube formation. Transfection of miR-455–3p Mimics showed an opposite trend. These results suggest that miR-455–3p further regulates the tubular structure formation of HLECs by regulating VEGF-C/VEGFR3. Therefore, targeting miR-455–3p may provide a new therapeutic strategy for SiO2-induced silicosis injury.

Background: Long noncoding RNA (lncRNA) is widely acknowledged for its crucial role in the biological processes of various human cancers. MCF2L antisense RNA 1 (MCF2L-AS1) is a newly identified lncRNA, which remains unexplored in the context of cancer. Methods: MCF2L-AS1 expression was examined using qRT-PCR analysis. The impact of MCF2L-AS1 on LUAD cell growth was assessed through CCK-8, colony formation, EdU, caspase-3 activity, TUNEL, Western blot, and transwell assays. The interaction between miR-874-3p and MCF2L-AS1 or STAT3 was confirmed by RIP, luciferase reporter, and RNA pull-down assays. Results: Our study demonstrated the overexpression of MCF2L-AS1 in LUAD cells. Functionally, the silencing of MCF2L-AS1 hindered cell proliferation, migration, and invasion, while promoting cell apoptosis. Notably, the depletion of MCF2L-AS1 was associated with decreased cisplatin resistance. Mechanistically, MCF2L-AS1 was identified as an upstream gene of miR-874-3p, negatively regulating its expression. Following this, STAT3, the downstream target of miR-874-3p, was identified. Additionally, the expression of STAT3 was inversely related to miR-874-3p and positively regulated by MCF2L-AS1. A restoration assay suggested that MCF2L-AS1 promoted LUAD cell growth by sponging miR-874-3p and modulating STAT3 expression. Intriguingly, STAT3 was subsequently confirmed as a transcription factor that binds to the MCF2L-AS1 promoter, thereby enhancing its transcription. Conclusions: The MCF2L-AS1/miR-874-3p/STAT3 feedback loop plays a significant role in LUAD cell growth and cisplatin resistance.

Silicosis is a fibrotic disease caused by long-term inhalation of SiO2 particles that currently has no effective treatment. Earlier studies have suggested that pulmonary lymphatic vessels play a key role in the transport of silica but have not address the long-term effects of altered pulmonary lymphatic drainage on silicosis. Here, we investigated the impact of impaired pulmonary lymphatic drainage on silicosis. In the past, lymphatic drainage disorders were established mainly through the use of VEGF inhibitors. For the first time, we established a model of pulmonary lymphatic drainage disorder by ligating the thoracic duct in rats. Impaired pulmonary lymphatic drainage was found to aggravate inflammation and oxidative damage in silicosis rats and accelerate silicosis progression. Next, we investigated the effect of pulmonary lymphatic drainage on silicosis. We have demonstrated the effect of sodium tanshinone IIA sulfonate(STS) on lymphangiogenesis, which revealed that STS promotes lymphangiogenesis and can delay inflammation, oxidative damage, and fibrosis progression in silicosis rats by promoting the pulmonary lymphatic drainage response, and this effect is mediated by the VEGFR-3/PI3K/AKT signaling pathway. These findings suggest that pulmonary lymphogenesis plays an important role in silicosis pathogenesis, and targeted intervention in pulmonary lymphangiogenesis may be a potential strategy for treating of silicosis in the future.