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

Abstract

Purpose: We aimed to explore the molecular and biological functions of Inhibitor of DNA binding/differentiation 2 (ID2), which was found to be responsible for portal vein invasion of hepatocellular carcinoma (HCC). Experimental Design: We measured ID2 mRNA levels in 92 HCC patients by real-time reverse transcription-PCR and examined the relation to clinicopathologic features. To clarify the precise roles of ID2, we did in vitro analysis with expression vectors and small interfering RNAs. Effects of ID2 on cell invasive potential and expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1a were analyzed by Matrigel-coated invasion chamber, ELISA, and Western blot analysis, respectively.Results: ID2 mRNA level correlated inversely with portal vein invasion (P < 0.001), tumor-nodemetastasis stage (P < 0.001), tumor size (P < 0.001), and early intrahepatic recurrence (P < 0.05). When limited to a cohort of hepatitis C virus^related HCCs, patients with low levels of ID2 had significantly shorter disease-free survival time than those with high levels of ID2. Invasive potential of cells transfected with ID2 expression vector was lower than that of empty vector^transfected cells. Cells overexpressing ID2 also showed decreased VEGF secretion and hypoxia-inducible factor-1a protein levels. The results of ID2-knockdown experiments were opposite to those of ID2 overexpression experiments. Conclusions: On the basis of our clinical and in vitro data, we suggest that ID2 plays a significant role in the metastatic process during progression of HCC. This action might be explained, at least in part, by altered cell mobility due to decreased secretion of VEGF.Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor worldwide and accounted for 5.7% of new cancer cases in 2002 (1). HCC is caused mainly by chronic liver inflammation due to hepatitis B virus, hepatitis C virus (HCV), alcohol abuse, or hemochromatosis (2). Despite resection with curative intent and recent advances in treatments, the clinical course of HCC is variable, and recurrence occurs in a large number of patients after surgery. The poor prognosis can be explained largely by the high rate of intrahepatic recurrence (IHR) attributable to intrahepatic dissemination of tumor cells (3). Among the many factors responsible for IHR, venous invasion, particularly portal vein invasion (PVI), is one of the most significant pathologic factors (4). Thus, identification of key genes involved in PVI may improve therapies for HCC.Hepatitis B virus and HCV contribute differently to the molecular pathogenesis of HCC (2). This concept was supported by our previous genome-wide studies (5, 6). We examined HCV-related HCC and identified a gene, inhibitor of DNA binding/differentiation 2 (ID2), whose levels were significantly lower in HCV-related, well-differentiated HCC than in HCV-related liver disease (7). More recently, we found that ID2 is a PVI-related gene specific for HCV-related HCC (8). ID proteins (ID1-ID4), which belong...

Overexpressed DNA-binding protein inhibitor 2 as an unfavorable prognosis factor promotes cell proliferation in nasopharyngeal carcinoma

“…Furthermore, the decreased ID2 mRNA level correlated inversely with tumor invasion, tumor-node-metastasis stage, tumor size, and early intrahepatic recurrence. When limited to a cohort of hepatitis C virus-related HCCs, patients with low levels of ID2 had significantly shorter disease-free survival time than those with high levels of ID2 [22]. Interestingly, similar results were reported in breast cancer.…”

“…ID2 also is an oncogenic factor to promote tumors progression [8,13,[16][17][18][19][20][21]. On the contrary, ID2 acts as a tumor suppressor participating in the pathogenesis of some tumors including liver cancer, breast cancer, and ocular cancer [22][23][24]. However, the expression pattern and functional mechanism of ID2 in NPC is still unclear.…”

An Accurate, Clinically Feasible Multi-Gene Expression Assay for Predicting Metastasis in Uveal Melanoma

“…20 The bHLH inhibitor ID2 functions as a tumor suppressor in uveal melanoma and some other cancers. 9,21,22 MTUS1 is a tumor suppressor protein.…”

Id4 suppresses MMP2-mediated invasion of glioblastoma-derived cells by direct inactivation of Twist1 function

“…Specifically, Id1 has been shown to upregulate MMP14, while both Id1 and Id3 increase the expression of MMP2 and MMP9. [10][11][12] The action of Id2, however, may be context dependent because it inhibits the invasion of hepatocellular carcinoma and an aggressive breast cancer cell line, 13,14 while promoting the invasion of other tumor types including GBM. 15,16 Additionally, Id2 has been shown to enhance or repress MMP9 expression in different contexts.…”