Previous research in tissue fibrosis has revealed the expression of a protein called either Regulator of Cell Cycle (RGCC) or Response Gene to Complement 32 Protein plays a profibrotic role (RGC-32). In contrast, the examination of publicly available gene expression datasets demonstrated a consistent drop in RGCC mRNA levels in people with pulmonary fibrosis. Researchers discovered that activating primary adult human lung fibroblasts with TGF-β in cell culture increased collagen expression while attenuating RGCC mRNA and protein levels, which is consistent with this observation. Furthermore, overexpression of RGCC in cultured lung fibroblasts reduced the collagen-stimulating impact of TGF-β. They reduced RGCC levels in vivo in lung tissues of wild-type mice exposed to bleomycin in acute and chronic scenarios, similar to humans with pulmonary fibrosis. Mice with a constitutive RGCC gene deletion accumulated more collagen in their lungs than wild-type mice in response to a protracted bleomycin exposure. RGCC overexpression exhibited a minor transcriptome effect alone in lung fibroblasts, but when combined with TGF-β stimulation, generated significant transcriptomic changes that reversed TGF-β effects, particularly on extracellular matrix-related genes, according to RNA-Seq analysis.
RGCC overexpression delayed early TGF-β-induced Smad2/3 phosphorylation, increased total, and phosphorylated antifibrotic mediator STAT1, and suppressed the production of a profibrotic mediator STAT3 at the intracellular signaling level. They infer that RGCC protects against lung fibrosis and that its loss allows collagen to accumulate. In pulmonary fibrosis, restoring RGCC expression may have therapeutic promise.