Overexpressed Id‐1 is associated with a high risk of hepatocellular carcinoma development in patients with cirrhosis without transcriptional repression of p16

Matsuda, Yasunobu; Yamagiwa, Satoshi; Takamura, Masaaki; Honda, Yutaka; Ishimoto, Yuiko; Ichida, Takafumi; Aoyagi, Yoshinobu

doi:10.1002/cncr.21259

Cited by 41 publications

(30 citation statements)

References 36 publications

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“…Taken together, the above data suggested a novel regulatory mechanism of VEGF by Id-1 leading to HCC progression. Recently, there have been reports showing Id-1 to be involved in early HCC carcinogenesis (43,44). Instead of viewing this as a mutually exclusive event, we speculated that this may provide additional evidence to our finding that Id-1 is involved in HCC angiogenesis and angiogenesis plays a crucial role in tumor devilment in the early stage.…”

Section: Discussionsupporting

confidence: 52%

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

Lee¹,

Poon²,

Yuen³

et al. 2006

Clinical Cancer Research

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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.

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Section: Discussionsupporting

confidence: 52%

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

Lee¹,

Poon²,

Yuen³

et al. 2006

Clinical Cancer Research

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“…The level of ID1 protein correlates significantly with both cancer progression and overall prognosis of a number of human malignancies (15). ID1 is commonly overexpressed in HCC, where a functional role in the regulation of HCC cell growth and hepatic fibrogenesis has been suggested (37,38). Increased expressions of ID1 have also been implicated with increased risk of HCC development in patients with liver cirrhosis (38).…”

Section: Discussionmentioning

confidence: 99%

“…ID1 is commonly overexpressed in HCC, where a functional role in the regulation of HCC cell growth and hepatic fibrogenesis has been suggested (37,38). Increased expressions of ID1 have also been implicated with increased risk of HCC development in patients with liver cirrhosis (38). Inhibition of ID1 expression, on the other hand, could result in a suppressed cell proliferation possibly through the induction of cellular senescence and G 2 -M cell cycle arrest (39).…”

Section: Discussionmentioning

confidence: 99%

Re-Expression of Transcription FactorATF5in Hepatocellular Carcinoma Induces G2-M Arrest

Gho

Ip²,

Chan³

et al. 2008

Cancer Research

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Transcription factors represent an important class of genes that play key roles in controlling cellular proliferation, cell cycle modulation, and attractive targets for cancer therapy. Here, we report on the novel finding of common ATF5 downregulations in hepatocellular carcinoma (HCC), a highly malignant tumor with a dismal clinical course. Array-based mapping in HCC highlighted a high and consistent incidence of transcription factor ATF5 repressions on regional chr.19q13. By quantitative reverse transcription-PCR, profound down-regulations of ATF5 were further suggested in 78% of HCC tumors (60 of 77 cases) compared to their adjacent nontumoral liver (P = 0.0004). Restoration of ATF5 expression in 3 nonexpressing HCC cell lines demonstrated a consistent growth inhibitory effect (P < 0.029) but minimal induction on cellular apoptosis. Subsequent flow cytometric investigations revealed a G 2 -M cell cycle arrest in HCC cells that were ectopically transfected with ATF5 (P < 0.002). The differential expressed genes from the functional effects of ATF5 were examined by array profiling. Over a hundred genes were identified, among which ID1 contains the ATF/CREB target binding sequences within its promoter region. An inverse relationship between ATF5 expressions with ID1 transcriptions was verified in HCC (P = 0.019), and a direct interaction of ATF5 on the promoter of ID1 was further demonstrated from electromobility shift assay. Examination of causal events underlying the silencing of ATF5 in HCC suggested copy number losses, promoter hypermethylation, histone deacetylation, and DNA mutations to be the likely inactivating mechanisms. In conclusion, our finding supports a tumor suppressive role for ATF5 in HCC, and highlighted ID1 as a potential downstream target. [Cancer Res 2008; 68(16):6743-51]

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“…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).…”

mentioning

confidence: 99%

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

Tsunedomi

Iizuka

Tamesa

et al. 2008

Clinical Cancer Research

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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...

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Overexpressed Id‐1 is associated with a high risk of hepatocellular carcinoma development in patients with cirrhosis without transcriptional repression of p16

Cited by 41 publications

References 36 publications

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

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

Re-Expression of Transcription FactorATF5in Hepatocellular Carcinoma Induces G2-M Arrest

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

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