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-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. 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.
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-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. 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.
Authors: Jan Harder; Michael J Müller; Matthias Fuchs; Vera Gumpp; Annette Schmitt-Graeff; Richard Fischer; Melanie Frank; Oliver Opitz; Jens Hasskarl Journal: World J Gastroenterol Date: 2013-12-28 Impact factor: 5.742
Authors: Ida G Lunde; Siobhan L Anton; Jo C Bruusgaard; Zaheer A Rana; Stian Ellefsen; Kristian Gundersen Journal: J Physiol Date: 2011-01-24 Impact factor: 5.182
Authors: Vincent W Keng; Augusto Villanueva; Derek Y Chiang; Adam J Dupuy; Barbara J Ryan; Ilze Matise; Kevin A T Silverstein; Aaron Sarver; Timothy K Starr; Keiko Akagi; Lino Tessarollo; Lara S Collier; Scott Powers; Scott W Lowe; Nancy A Jenkins; Neal G Copeland; Josep M Llovet; David A Largaespada Journal: Nat Biotechnol Date: 2009-02-22 Impact factor: 54.908