Abstract
Metastasis is commonly associated with poor prognosis of hepatocellular carcinoma (HCC). Being an important angiogenic factor, vascular endothelial growth factor (VEGF) plays a central role in HCC growth and metastasis. Recently, Id-1 (inhibitor of differentiation/DNA synthesis) has been suggested to be a key factor in cancer progression but the molecular mechanism remains unknown. We first showed that overexpression of Id-1 was correlated with HCC metastasis (P < 0.001) and its expression was significantly correlated with VEGF expression by tissue microarray. By ectopic transfection of Id-1 into HCC cells, Id-1 was able to induce VEGF secretion through activation of VEGF transcription. Increased VEGF secretion in Id-1 transfectants induced morphologic change and proliferation of human umbilical vascular endothelial cell resulting in promotion of angiogenesis. Id-1 induced transcriptional activation of VEGF by stabilizing hypoxia-inducible factor-1alpha protein. Down-regulation of Id-1 by antisense approach led to suppression of hypoxia-inducible factor-1alpha-mediated VEGF production. In addition, Id-1 suppression resulted in retardation of cell invasion through down-regulation of VEGF. Id-1 is a novel angiogenic factor for HCC metastasis and down-regulation of Id-1 may be a novel target to inhibit HCC metastasis through suppression of angiogenesis.
Highlights
Metastasis is commonly associated with poor prognosis of hepatocellular carcinoma (HCC)
We first showed significant up-regulation of Id-1 in human metastatic HCCs compared with primary ones by tissue microarray (TMA), and its expression was significantly correlated with vascular endothelial growth factor (VEGF) expression
HCC metastasis is commonly associated with poor prognosis because of the lack of effective systemic chemotherapy [3]
Summary
Metastasis is commonly associated with poor prognosis of hepatocellular carcinoma (HCC). Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that plays a central role in angiogenesis in various cancer types [8]. Poor vascularization resulting from generation of Id-1 and Id-3 double knockout mice is a convincing evidence showing the central role of Id-1 overexpression in tumor metastasis [21]. We first showed significant up-regulation of Id-1 in human metastatic HCCs compared with primary ones by tissue microarray (TMA), and its expression was significantly correlated with VEGF expression. Ectopic Id-1 expression promotes HCC angiogenesis through hypoxia-inducible factor-1a (HIF-1a) – mediated VEGF promoter activation in PLC cell. Down-regulation of Id-1 expression by antisense approach significantly inhibits HCC angiogenesis both in vitro and in vivo This line of evidence strongly provides an insight on the novel regulatory mechanism of VEGF in HCC by Id-1. Down-regulation of Id-1 may provide a novel target to inhibit HCC angiogenesis and metastasis
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