Expression Of Macrophage Migration Inhibitory Factor In Human Liver Cancer And Its Role In Tumor Cell Growth And Angiogenesis

OBJECTIVE: The purpose of this study was to determine whether expression of migration inhibitory factor (MIF), vascular endothelial growth factor (VEGF) and (IL-8) in liver cancers and whether it correlates with angiogenesis and growth.METHODS: The expression of MIF and VEGF in HCC tissue with adjacent liver tissue (n = 40) and in normal liver tissue(n = 10) were examined by immunochemistry.At the same time,we here demonstrated for expression of MIFmRNA, VEGFmRNA and IL-8mRNA by real time quantitative reverse transcription-polymerase chain reaction(RQ-PCR). In this study, we quantifyiedthere expression examined their relationship with clinicopathological factors. With treatment using rMIF,ELISA analysis determined the synthesis and secretion of VEGF and IL-8 by human liver(Bel-7402) cell carcinoma cells.Using RQ-PCR ,we studied expression of VEGFmRNA and IL-8mRNA.RESULTS:The results showed that the positive rates of MIF and VEGF in HCC tissue were 67.5% and 72.5% respectively, and in normal liver tissue were 20.00%and 30.00% respectively. The positive rates of MIF and VEGFin HCC were significantly higher than those in normal liver tissue(P < 0.05). MIF and VEGF in liver cancerwas related to its pathologic grade (P < 0.05), and MIF to tumor enveolp,but not to portal vein invasion, tumor size, TNM staging ,cirrhosis of liver,HbsAg,and so on (P > 0.05). The expressions of MIF and VEGF were strongly correlated (P < 0.05). Tumor/normal ratio(T/N ratio) of MIF / GAPDH (glyceraldehyde-3-phosphate dehydrogenase) , VEGF / GAPDH and IL-8/ GAPDH mRNA expression were respectively,andsignificantly different between liver cancer tissue (3.38 ±2.32, 12.28 ±1.84and 4.45 ±3.79) and normal liver tissue (5.20 ±1.96, 14.35 ±3.22 and 6.45 ±3.03, P < 0.05).A positive and significant correlation between MIFmRNA and VEGFmRNA, VEGFmRNA and IL-8mRNA expression was evidenced in connective tumor tissue.There was no relationship between MIF /GAPDH, VEGF / GAPDH and IL-8/ GAPDH expression and portal vein invasion, tumor size, TNM staging, cirrhosis of liver,HbsAg,and so on (P > 0.05). (T/N ratio) of MIF /GAPDH and VEGF / GAPDH expression was significantlyhigher in tumor pathologic grade III-IV liver cancer (2. 13 ±0. 91 and 11. 42 ± 1. 44) when compared with tumor pathologic grade I-II liver cancer(4. 50 ± 2. 64,13. 05 ± 1. 86 P<0.05).T/N ratio of IL-8/ GAPDH expression was signif-ycantly higher in tumor size > 5cm liver cancer and multiple liver cancer (3. 70 ±3. 41, 4. 20 ± 1. 99) when compared with tumor size=5cm liver cancer (9. 10 ±5. 73, P<0.05),respectively. T/N ratio of IL-8/ GAPDH expression was significantly higher in liver cancer with envelope (6. 27 ±4. 40) whencompared with liver cancer without envelope (3.65 ±3. 26, P<0.05). ThusMIF mRNA and VEGF mRNA, VEGF mRNA and IL-8 mRNA expression has been correlated with evidenceof tumor progression in terms of pathologic grade, tumor size and envelope of liver cancer.The concentration of VEGF in the supernatant of Bel-7402 was higher[(900.00 ±264.58)pg/ml] after rMIF treatment. It was also remarkably higherthan that in thesupernatant of Bel-7402 without rMIF treatment (P<0.01). However, there was no significant difference in the concentration variation of IL-8 in Bel-7402 (P >0.05). T/N ratio of VEGF / GAPDH expression withtreatment(9. 67 ±1.15) were respectively significantly different higher than without treatment (12. 67 ± 0. 58). There was no significant difference in T/N ratio of IL-8/ GAPDH expression between rMIF treatment (3. 67 ± 1. 53) andwithout rMIF treatment (4. 00 ± 1. 00) (P > 0.05).CONCLUSIONS: This study is the first to report MIF expression in the human liver and these findings support a role for MIF in tumor cell proliferation. MIF overexpression may play a crucial role in the carcinogenesis, angiogenesis and development of liver cancer.These new findings suggest that MIF may serve as a novel therapeutic treatment for liver carcinoma.