In this aspect, the multikinase inhibitor Sorafenib has demonstrated some therapeutic benefits for patients with advanced HCC. This agent has been shown to exert an anti-angiogenic role by targeting major receptors for VEGF. Sorafenib also blocks tumor cell proliferation by inhibiting RAF/MEK/ERK signaling pathway. Although there were some studies mentioned that AFP, VEGF, MMP2 may associated with increased hepatoma cell infiltration and matastasis, but so far, no research studied on the regulation of VEGF/MMP-2/MMP-9 by AFP has been reported. In this study, we aim to investigate if AFP modulates the expression of VEGF and regulates angiogenesis. AFP is not only serves as a valuable tumor maker for patients with liver cancer, but it also possess important regulatory effect for several important biological processes such as cell differentiation, proliferation and apoptosis in embryogenesis and tumor growth. Our data show that silencing of AFP enhances apoptosis of Huh-7 cells, suggesting that under the physiological condition, AFP is essential for the maintenance of homeostasis. Previous studies have showed that AFP could regulate cell proliferation and apoptosis, and thus plays a role in liver cancer formation. Angiogenesis is essential for the initiation, progression, and metastasis of many solid tumors including liver cancer. Numerous angiogenic factors such as vascular endothelial growth factor and its receptors, PDGFs, placental growth factors, transforming growth factor, basic fibroblast growth factor, Epidermal Growth Factor, hepatocyte growth factor, angiopoietins and interleukin 4 and interleukin 8 are involved in the regulation of tumor angiogenesis, among which VEGF signaling through VEGFR-2 is the major angiogenic pathway in many cancer types. As such, blockade of VEGF/VEGFR-2 signalling is the first antiangiogenic strategy for cancer therapy. Guo and its colleagues also found expression of angiogenesis factors in HCC tissues could be regarded as a clinical indicator in estimating the prognosis of HCC patients. Previous studies by others have demonstrated that AFP itself may stimulate angiogenesis and induce metastasis of liver cancer. Increased serum AFP concentration was correlated with an enhanced VEGF-A protein expression in HCC tissue. AFP was also reported as a pro-angiogenesis factor, possibly in a VEGF dependent manner. In our study, silencing of AFP expression significantly reduced the expression levels of VEGF and VEGFR-2 in Huh-7 cells. By in vitro angiogenesis assay, we observed that silencing of AFP led to a reduced angiogenic ability of HUVECs. We postulate that AFP secreted by liver cancer cells may stimulate the tumor cells to produce VEGF which can then act on VEGFR-2, leading to increased tumor angiogenesis. Extracellular matrix forms a part of the body’s defense network. Degradation of important components of the extracellular matrix by metalloproteinases contributes to tumor invasion and distant metastasis. Previous studies have showed that VEGF secreted by the tumor cells could induce the expression of plasminogen activators and matrix metalloproteinases, contributing to the degradation of basement membranes.