Influences of Changes in Protein Tyrosine Phosphatase SHP2 Expression on Liver Fibrosis via Regulating the Cell Cycle of Activated Hepatic Stellate Cells

Introduction/Objective: Accumulating evidence has shown that the carcinogenic src-homology domain 2-containing protein tyrosine phosphatase-2 (SHP2) is involved in hepatic fibrosis. Nevertheless, it is still unclear whether SHP2 expression changes affect liver fibrosis by regulating the cell cycle of activated hepatic stellate cells (HSC). The study aimed to investigate the mechanism by which SHP2 affects liver fibrosis, with special emphasis on the cell cycle of activated HSC. Methods: Short hairpin RNA targeting SHP2 and the wild-type SHP2 gene were imported into human hepatic stellate cell LX-2 and rats with liver fibrosis through adenovirus. Pathological changes, collagen deposition, type I and III collagen, and alpha-smooth muscle actin (α-SMA), an activated HSC marker in rat liver, were detected using hematoxylin- eosin staining, Masson trichrome staining, immunohistochemical staining, and western blotting, respectively. Proliferation, cell cycle, cyclin D1, cyclin-dependent kinase 4 (CDK4), and p27kip1 in LX-2 cells were analyzed using Cell Counting Kit-8, flow cytometry, and western blotting, respectively. Results: It was found that SHP2 overexpression promoted the proliferation of activated HSC by accelerating cell cycle progression via upregulating cyclin D1 and CDK4 expressions and downregulating p27kip1 expression, thereby exacerbating liver fibrosis. Conversely, downregulated SHP2 expression inhibited the proliferation of activated HSC by arresting cell cycle progression via downregulating cyclin D1 and CDK4 expressions and upregulating p27kip1 expression, and then alleviating liver fibrosis. Discussion: We identified that overexpression of SHP2 exacerbates liver fibrosis, whereas low SHP2 expression mitigates it. SHP2 overexpression was found to promote the proliferation of activated HSC in vitro and in vivo; downregulating SHP2 expression inhibits proliferation, suggesting that SHP2 affects liver fibrosis by regulating HSC proliferation. Furthermore, it was found that SHP2 overexpression accelerates the cell cycle of activated HSC by increasing the expression of cyclin D1 and CDK4 and decreasing p27kip1 expression; downregulating SHP2 expression has the opposite effect, revealing the mechanism by which changes in SHP2 expression affect the proliferation of activated HSC. This study provides insight into the mechanism by which SHP2 affects liver fibrosis. Conclusion: The present study suggested that SHP2 participates in the pathological progression of liver fibrosis by regulating the cell cycle of activated HSC, and highlights SHP2 as a potential therapeutic target for liver fibrosis.