Cancer-suppressing Molecule May Be PF Therapeutic Target
The levels of a cancer-suppressing molecule called microRNA-326 (miR-326) are reduced significantly in the lungs of a mouse model of silica-induced pulmonary fibrosis (PF), a study shows.
Increasing the levels of miR-326 in these mice lessened lung scarring (fibrosis) and suppressed the production of pro-fibrotic molecules, highlighting miR-326 as a potential therapeutic target for silica-induced PF, the researchers noted.
The study also identified other potential targets that directly interact with miR-326, including its suppressor, long non-coding RNA SNHG1 (lnc-SNHG1), and its target, specificity protein 1 (SP1).
More studies are needed to confirm these findings in people with silica-induced PF, the researchers stated.
The study, “Long non-coding RNA SNHG1 promotes fibroblast-to-myofibroblast transition during the development of pulmonary fibrosis induced by silica particles exposure,” was published in the journal Ecotoxicology and Environmental Safety.
Silicosis, one of the most common occupational causes of PF, results from repeatedly inhaling fine particles of silica, a common mineral found in sand, quartz, and many other types of rock. The condition usually is linked to construction, sandblasting, and mining.
“Due to the lack of effective biomarkers and specific treatment, silicosis patients often endure delayed diagnosis and the progressive process of disease,” the researchers wrote, adding there is an urgent need for new therapeutic targets and approaches.
Now, a team of researchers in China discovered that two RNA molecules, lnc-SNHG1 and miR-326, are involved, in opposite ways, in lung fibrosis caused by exposure to silica particles.
Both molecules work by regulating the activity of other genes and were shown previously to have a role in cell growth, migration, and epithelial-to-mesenchymal transition (EMT) — processes whose dysregulation is key for cancer cell growth, as well as the development and progression of fibrosis.
EMT is the process by which epithelial cells, such as those that line the lungs’ airways, gain properties resembling those of fibroblasts or myofibroblasts, two cell types that play a key role in lung fibrosis.
While lnc-SNHG1 is known to promote such processes, miR-326 suppresses them and is known as a tumor-suppressing molecule.
Researchers first found that lnc-SNHG1 levels were increased significantly in the lungs of a mouse model of silica-induced PF relative to healthy mice, and in lab-grown human lung fibroblasts exposed to TGF-beta-1, a major pro-fibrotic molecule.
Additional analysis in lab-grown human fibroblasts revealed that lnc-SNHG1 promoted cells’ maturation into myofibroblasts, the main drivers of lung fibrosis, and the production of pro-fibrotic molecules.
Given that long non-coding RNAs can act as microRNA sponges, sequestering these molecules and ultimately preventing their activity, the team analyzed three databases to look for potential miRNA targets of lnc-SNHG1 and found that miR-326 was a direct target.
Notably, miR-326 showed an opposite dynamic to lnc-SNHG1, as it was significantly reduced in the lungs of the mouse model and in lab-grown lung fibroblasts exposed to TGF-beta, compared with their counterparts. Also, increasing the levels of miR-326 reversed lnc-SNHG1’s pro-fibrotic effects in lung fibroblasts.
Moreover, treating mice with a miR-326-mimicking molecule at a stage of established silica-induced PF effectively lessened fibrosis and reduced the levels of pro-fibrotic molecules in the lungs.
Further analysis revealed that SP1, a protein known to be involved in fibrosis, was a direct target of miR-326, indicating that lnc-SNHG1’s effects were based on the sequestration of miR-326, thereby preventing it from suppressing SP1.
These findings “provide evidence that the lnc-SNHG1/miR-326/SP1 axis is involved in silica particles exposure-induced pulmonary fibrosis, and further suggest new targets for the treatment of pulmonary fibrosis,” the researchers wrote.
“Further studies of lnc-SNHG1 and miR-326 levels in blood samples or exhaled breath condensate from [silica-exposed] workers are necessary to evaluate the potential of lnc-SNHG1 and miR-326 as biomarkers of silica particles exposure,” they concluded.