Abstract: Objective To investigate the expression of suppressor of cytokine signaling 2 (SOCS2) in hepatocellular carcinoma (HCC) and its effects on the proliferation, metastasis and angiogenesis of HCC. Methods A total of 40 pathological samples of HCC removed by surgery were collected. The expression difference of SOCS2 between cancer tissue and paracancerous tissue was detected by Western blot. In addition, 40 healthy physical examination population were collected, and the difference of serum SOCS2 levels between HCC patients and healthy controls were compared. The HCC cell lines (MHCC97H, HepG2, Huh-7, Hep3B) and normal liver cell line L02 were cultured in vitro, and the expression levels of SOCS2 in the lines were detected by Western blot. The MHCC97H cell line was selected for SOCS2 expression knockdown experiment, and the Hep3B cell was selected for SOCS2 over-expression experiment. The effects of SOCS2 expression changes on the expression levels of epithelial-mesenchymal transition related proteins, proliferation, migration and invasion of HCC cells were observed by Western blot, clone formation, scratch and Transwell experiments, respectively. Subsequently, the treated HCC cells were co-cultured with human umbilical vein endothelial cells to observe the effects of SOCS2 expression changes on HCC angiogenesis. Results Compared with the paracancerous tissues, the expression level of SOCS2 was decreased in HCC cancerous tissues (0.31±0.14 vs. 0.71±0.10, t=13.079, P<0.001). Similarily, compared with L02 cells (0.88±0.04), the expression level of SOCS2 was decreased in HCC cell lines (MHCC97H: 0.63±0.03, Hep3B: 0.31±0.03, Huh7: 0.38±0.02, HepG2: 0.48±0.02) (F=198.600, P<0.001). Compared with healthy people, the SOCS2 levels in the serum of HCC patients were decreased (16.24±7.95 ng/L vs. 37.85±10.17 ng/L, t=10.590, P<0.001). Knockdown of SOCS2 expression led to enhanced proliferation (69.33±4.04 vs. 122.00±11.14, t=7.700, P=0.002), migration (70.36%±2.08% vs. 92.00%±1.73%, t=13.860, P<0.001), and invasion (259.33±12.22 vs. 390.00±21.07, t=9.297, P<0.001) abilities of MHCC97H cells, with increased levels of Vimentin (0.52±0.04 vs. 0.83±0.02, t=18.402, P<0.001) and N-cadherin (0.61±0.03 vs. 0.93±0.03, t=13.867, P<0.001), and decreased levels of E-cadherin (0.42±0.03 vs. 0.11±0.02, t=17.762, P<0.001) and ZO-1 (0.33±0.02 vs. 0.15±0.01, t=13.754, P<0.001). Overexpression of SOCS2 led to decreased proliferative (86.67±5.69 vs. 46.33±8.51, t=6.828, P=0.002), migratory (94.03%±1.71% vs. 72.50%±2.18%, t=12.770, P<0.001), and invasive (327.67±20.11 vs. 206.00±17.06, t=7.992, P=0.001) ability of Hep3B cells, decreased levels of Vimentin (0.42±0.02 vs. 0.14±0.02, t=22.451, P<0.001) and N-cadherin (0.53±0.02 vs. 0.20±0.03, t=16.810, P<0.001), and increased levels of E-cadherin (0.30±0.03 vs. 0.70±0.03, t=15.904, P<0.001) and ZO-1 (0.23±0.02 vs. 0.62±0.03, t=19.402, P<0.001). Knockdown of SOCS2 expression led to enhanced angiogenesis ability of HCC (total tube length: 12 566.67±632.76 μm vs. 15 102.27±265.06 μm, t=6.402, P=0.003; branch point number: 130.00±3.00 vs. 151.33±4.16, t=7.201, P=0.002), and overexpression of SOCS2 led to decreased angiogenesis ability of HCC (total tube length: 15 226.44±1 047.37 μm vs. 11 124.58±936.63 μm, t=5.057, P=0.007; branch point number: 136.00±3.61 vs. 106.72±4.04, t=9.487, P<0.001). Conclusion The expression level of SOCS2 is decreased in HCC, and its over-expression can inhibit the proliferation, metastasis and angiogenesis of HCC cells.

Key words: Recombinant suppressor of cytokine signaling 2, Hepatocellular carcinoma, Proliferation, Metastasis, Angiogenesis