Macrophage migration inhibitory factor (MIF) may contribute to multiple aspects of tumor progression, including control of cell proliferation, differentiation, cell survival and angiogenesis. However, the potential roles of MIF in regulating hepatocellular carcinoma (HCC) tumor cell migration and the expression of angiogenic factors by HCC tumor cells have not been studied yet. In our study, we reported that intracellular MIF mRNA and protein were overexpressed in HCC tissues compared to nontumor tissues by using in situ hybridization and immunohistochemic staining. HCC tumor cell lines also secreted large amounts of MIF into the supernatants of tumor cell culture. To assess the role of MIF in HCC, we employed the transwell invasion chamber to study the effect of MIF on tumor cell migration. Our results showed that recombinant MIF and the supernatants of tumor cell line culture could enhance the invasion and migration of HCC cells. This effect can be inhibited by the addition of a neutralizing anti-MIF antibody. We observed that increased MIF serum levels correlated with higher levels of interleukin-8 (IL-8) in the sera of patients with HCC than in normal volunteers. We therefore hypothesized that MIF may regulate the production of angiogenic factors by HCC cells. To test this hypothesis, we examined the effect of MIF treatment on vascular endothelial growth factor (VEGF) and IL-8 expression by HCC cell lines. MIF induced a significant dose-dependent increase in IL-8 and VEGF production. Taken Key words: macrophage migration inhibitory factor; hepatocellular carcinoma; angiogenesis; metastasisHepatocellular carcinoma (HCC) is one of the most common human cancers in the world, and its incidence is particularly high among the Chinese. HCC has been the second largest cause of cancer death in China since the 1990s. 1 Although morbidity and mortality rates have decreased in patients with surgically treated HCC in recent years, the long-term prognosis remains unsatisfactory because of a high recurrence rate. 2 The high recurrence rate is related to a propensity of HCC for vascular invasion and metastasis. Although the risk factors of tumor recurrence in HCC are well known, the precise molecular mechanisms contributing to the invasiveness of HCC still remain unclear. Understanding of the molecular mechanisms of the complex multistep process of tumor invasion and metastasis could facilitate the development of better treatment modalities and preventive measures.Tumor growth and metastasis depend upon the ability of the tumor to induce its own blood supply. This process is dependent on the induction of angiogenesis mediated by angiogenic factors secreted by the tumor cells. Tumor cells secrete a wide variety of angiogenic factors that participate in the development of microvasculature in the tumor. 3,4 Among the identified angiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) are the most potent and representative angiogenic factors. [5][6][7][8] Other angiogenic factors such as basic fib...
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