Regulation of Angiogenesis by Id-1 through Hypoxia-Inducible Factor-1α–Mediated Vascular Endothelial Growth Factor Up-regulation in Hepatocellular Carcinoma

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: IncreasedVEGF secretion in Id-1transfectants 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-1a protein. Down-regulation of Id-1 by antisense approach led to suppression of hypoxia-inducible factor1a^mediated VEGF production. In addition, Id-1 suppression resulted in retardation of cell invasion through down-regulation of VEGF. Conclusions: Id-1is 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.

Decreased ID2 Promotes Metastatic Potentials of Hepatocellular Carcinoma by Altering Secretion of Vascular Endothelial Growth Factor

“…Thus, it is possible that ID1 and ID2 have opposite effects on HCC metastasis. Lee et al (32) used a cohort consisting mostly of hepatitis B virus -related HCC. In contrast, our cohort consisted of many HCV-related HCCs.…”

“…Interestingly, it is likely that ID1 and ID2 function differently in progression of breast cancer (21,25,29). In the case of HCC, expression of ID1 is increased at early stages of hepatocarcinogenesis (31), and high ID1 expression increases the metastatic potential of HCC (32). It is known that ID2 is expressed at high levels in both human adult and fetal liver tissues (33) but that expression of ID2 decreases in more advanced HCC (34).…”

Liver sinusoidal endothelial cells and liver regeneration

“…Id1 activates VEGF by enhancing the stability and activity of HIF-1α (52)(53)(54), and conversely the VEGF/VEGFR2 pathway may activate Id1 (4). Studies in Id1 -/-mice have demonstrated impaired mobilization and recruitment of bone marrow EPCs, leading to impaired tumor angiogenesis and tumor growth (55).…”

Concerted Potent Humoral Immune Responses to Autoantigens Are Associated with Tumor Destruction and Favorable Clinical Outcomes without Autoimmunity

“…It is also known to bind to phosphorylated Rb. Id1 has recently been associated with transcriptional regulation in the radial growth phase of primary melanomas (29), functions as an angiogenic factor through hypoxia-inducible factor-1a in hepatocellular carcinoma (30), and is implicated into transforming growth factor-h1 suppression of prostate cancer cells (31).…”