Abstract: Objective To investigate the effect of WNK2 on the expression of SHP2 (tyrosine phosphatase) in HCC and to explore the effect on the proliferation and migration of HCC. Methods HepG2 cells were transfected with WNK2-mimic, WNK2-inhibitor, and corresponding negative control. The effect of WNK2 on the proliferation of HCC was examined by subcutaneous tumorigenesis assay in Balb/c nude mice. The expressions of WNK2, p-SHP2, p-AKT, and p-ERK1/2 in tumor tissues were detected by Western blot. After treatment with SHP2 inhibitor PHPS1, the expressions of WNK2, p-SHP2, p-AKT, and p-ERK1/2 in HepG2 cells were detected by Western blot. The migration ability and invasion ability of HepG2 cells were detected by cell scratch assay and Transwell. The proliferation ability of HepG2 cells was detected by monoclonal proliferation assay. Results Compared with the NC group, the tumor volume of nude mice in the sh-RNA WNK2 group was significantly increased (p<0.01), while that of nude mice in the WNK2-mimic group was significantly decreased (p<0.01). Western blot results showed that compared with the NC group, the expression of WNK2 in the sh-RNA WNK2 group was significantly decreased (p<0.01), while the expressions of p-SHP2, p-AKT, and p-ERK1/2 were significantly increased (p<0.01). However, the expression of WNK2 was significantly increased in the WNK2-mimic group (p<0.01), and the expressions of p-SHP2, p-AKT, and p-ERK1/2 were significantly decreased (p<0.01). In vitro experiment, compared with the NC group, the expression of WNK2 was significantly decreased in the WNK2-inhibitor group (p<0.01), while the expressions of p-SHP2, p-AKT and p-ERK1/2 were significantly increased in the WNK2-inhibitor group (p<0.01). Compared with the NC PHPS1 group, the expression of WNK2 was significantly decreased in the WNK2-inhibitor PHPS1 group (p<0.01), while the expressions of p-SHP2, p-AKT, and p-ERK1/2 were reversed and had no significant differences compared with the NC PHPS1 group (p>0.05). The cell scratch assay and Transwell results showed that the migration and invasion ability of HepG2 cells in the WNK2-inhibitor group was significantly increased compared with the NC group (p<0.01). The migration and invasion ability of HepG2 cells in the NC PHPS1 group and WNK2-inhibitor PHPS1 group were significantly decreased with no significant difference (p>0.05). The results of the monoclonal proliferation experiment showed that the proliferation capacity of HepG2 cells in the WNK2-inhibitor group was significantly increased compared with the NC group (p<0.01), while the proliferation ability of HepG2 cells in the NC PHPS1 group and WNK2-inhibitor PHPS1 group was significantly decreased with no significant difference (p>0.05). Conclusion WNK2 inhibits the expression of SHP2 in HCC by regulating the level of oxidative stress, delaying the proliferation and migration of HCC.