Regulation of Angiogenesis by Id-1 through Hypoxia-Inducible Factor-1α–Mediated Vascular Endothelial Growth Factor Up-regulation in Hepatocellular Carcinoma
Clinical Cancer Research, 2006•AACR
Purpose: 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. Experimental Design: We first showed that
overexpression of Id-1 was correlated with HCC metastasis (P< 0.001) and its expression …
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. Experimental Design: We first showed that
overexpression of Id-1 was correlated with HCC metastasis (P< 0.001) and its expression …
Abstract
Purpose: 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.
Experimental Design: 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.
Results: 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-1α protein. Down-regulation of Id-1 by antisense approach led to suppression of hypoxia-inducible factor-1α–mediated VEGF production. In addition, Id-1 suppression resulted in retardation of cell invasion through down-regulation of VEGF.
Conclusions: 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.
AACR
