USP15 Enhances the Proliferation, Migration, and Collagen Deposition of Hypertrophic Scar-Derived Fibroblasts by Deubiquitinating TGF-beta R1 In Vitro

Background: Hypertrophic scar is a fibroproliferative disorder caused by skin injury. The incidence of hypertrophic scar following trauma or burns is 40 to 70 percent or 70 percent, respectively. It has been shown that transforming growth factor (TGF) beta 1/Smad signaling plays a crucial role in hypertrophic scar, and that USP15 can regulate the activity of TGF beta 1/Smad signaling to affect the progression of the disease. However, the underlying mechanism of USP15 in hypertrophic scar remains unclear. The authors hypothesized that USP15 was up-regulated and enhanced the proliferation, migration, invasion, and collagen deposition of hypertrophic scar-derived fibroblasts by deubiquitinating TGF-beta receptor I (T beta RI) in vitro. Methods: Fibroblasts were isolated from human hypertrophic scars in vitro. The knockdown and overexpression of USP15 in hypertrophic scar-derived fibroblasts were performed using lentivirus infection. The effect of USP15 on hypertrophic scar-derived fibroblast proliferation, migration, and invasion, and the expression of T beta RI, Smad2, Smad3, alpha-SMA, COL1, and COL3, were detected by Cell Counting Kit-8, scratch, invasion, quantitative real-time polymerase chain reaction, and Western blot assays. The interaction between USP15 and T beta RI was detected by co-immunoprecipitation and ubiquitination assays. Results: The authors demonstrated that USP15 knockdown significantly inhibited the proliferation, migration, and invasion of hypertrophic scar-derived fibroblasts in vitro and down-regulated the expression of T beta RI, Smad2, Smad3, alpha-SMA, COL1, and COL3; in addition, USP15 overexpression showed the opposite trends (p < 0.05). Co-immunoprecipitation and ubiquitination assays revealed that USP15 interacted with T beta RI and deubiquitinated T beta RI. Conclusion: USP15 enhances the proliferation, migration, invasion, and collagen deposition of hypertrophic scar-derived fibroblasts by deubiquitinating T beta RI in vitro.