Regulation of angiogenesis by Id-1 through hypoxia-inducible factor-1alpha-mediated vascular endothelial growth factor up-regulation in hepatocellular carcinoma.
OBJECTIVE
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.


METHODS
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.
Lee
Terence K
TK
Department of Surgery, The University of Hong Kong, Hong Kong, China.
Poon
Ronnie T P
RT
Yuen
Anthony P
AP
Ling
Ming Tat
MT
Wang
Xiang Hong
XH
Wong
Yong Chuan
YC
Guan
Xin Yuan
XY
Man
Kwan
K
Tang
Zao You
ZY
Fan
Sheung Tat
ST
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000503:physiopathology* / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051798:Inhibitor of Differentiation Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000503:physiopathology* / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D046888:Tissue Array Analysis; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051798:Inhibitor of Differentiation Protein 1; D020319:Oligodeoxyribonucleotides, Antisense; D042461:Vascular Endothelial Growth Factor A