Expression pattern of angiogenic factors and prognosis after hepatic resection in hepatocellular carcinoma: importance of angiopoietin‐2 and hypoxia‐induced factor‐1a

Wada, Hiroshi; Nagano, Hiroaki; Yamamoto, Hirofumi; Yang, Yubo; Kondo, Motoi; Ôta, Hideo; Nakamura, Masato; Yoshioka, Shinichi; Kato, Hitoshi; Damdinsuren, Bazarragchaa; Tang, Di; Marubashi, S.; Miyamoto, Atsushi; Takeda, Yutaka; Umeshita, Koji; Nakamori, Shoji; Sakon, Masato; Dono, Keizo; Wakasa, Kenichi; Monden, Morito

doi:10.1111/j.1478-3231.2006.01243.x

Cited by 118 publications

(113 citation statements)

References 41 publications

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“…Similarly, the expression levels of HIF-1a and vascular endothelial growth factor, and microvessel densities, are all significantly higher in HCC tumors than in paraneoplastic and normal liver tissue (Huang et al, 2005). The disease-free survival time of patients with high HIF-1a expression is significantly shorter than among those with the low expression (Wada et al, 2006). Because metastasis is one of the most important factors affecting prognosis, expression levels of MTA1/ HDAC1 proteins may serve as prognostic markers for HCC treatments such as hepatectomy and chemotherapy.…”

Section: Discussionmentioning

confidence: 96%

Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

et al. 2008

Oncogene

142

128

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Expression level of metastasis-associated protein 1 (MTA1) is closely related to tumor growth and metastasis in various cancers. Although increased expression level of MTA1 was observed in hepatocellular carcinoma (HCC), role of MTA1 complex containing histone deacetylase (HDAC) in hepatitis B virus (HBV)-associated hepatocarcinogenesis has not been studied. Here, we demonstrated that HBx strongly induced the expression of MTA1 and HDAC1 genes at transcription level. MTA1 and HDAC1/2 physically associated with hypoxia-inducible factor-1a (HIF-1a) in vivo in the presence of HBx, which was abolished by knockdown of MTA1 by short interfering RNA (siRNA). HBx induced deacetylation of the oxygen-dependent degradation domain of HIF-1a, which was accompanied with dissociation of prolyl hydroxylases and von Hippel-Lindau tumor suppressor from HIF-1a. These results indicate that HBx-induced deacetylation is important for proteasomal degradation of HIF-1a. Further, we observed that protein levels of MTA1 and HDAC1 were increased in the liver of HBxtransgenic mice. Also, there was a higher expression of HDAC1 in HCC than in the adjacent non-tumorous cirrhotic nodules in 10 out of 12 human HBV-associated HCC specimens. Together, our data indicate a positive cross talk between HBx and the MTA1/HDAC complex in stabilizing HIF-1a, which may play a critical role in angiogenesis and metastasis of HBV-associated HCC.

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Section: Discussionmentioning

confidence: 96%

Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

et al. 2008

Oncogene

142

128

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“…Most cases of HCC develop on a liver fibrosis/ cirrhosis background, which constitutes a very hypoxic environment for liver cells, and drives the production of numerous potent angiogenic factors [43] . In our HCC cohort, we monitored angiogenesis by measuring the expression of the endothelial cell marker; vWF and the angiogenic factor VEGF.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, we investigated further the expression of PK2/Bv8 in human liver, and its potential role in HCC angiogenesis. Our results show that Bv8/PK2 mRNA levels decrease significantly as the pathology evolves towards cancer.Most cases of HCC develop on a liver fibrosis/ cirrhosis background, which constitutes a very hypoxic environment for liver cells, and drives the production of numerous potent angiogenic factors [43] . In our HCC cohort, we monitored angiogenesis by measuring the expression of the endothelial cell marker; vWF and the angiogenic factor VEGF.…”

mentioning

confidence: 99%

Prokineticin 2/Bv8 is expressed in Kupffer cells in liver and is down regulated in human hepatocellular carcinoma

Monnier¹,

Piquet‐Pellorce²,

Feige³

et al. 2008

WJG

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as expected. In addition, out of all isolated liver cells examined, only Kupffer cells (liver resident macrophages) express significant levels of PK2/Bv8 and its receptors, prokineticin receptor 1 and 2. CONCLUSION:In nor mal l ive r P K2/ B v8 a n d i t s receptors were specifically expressed by Kupffer cells. PK2/Bv8 expression decreased as the liver evolves t o wa r d s c a n c e r a n d d i d n o t c o r r e l a t e w i t h H C C angiogenesis. INTRODUCTIONIn vivo, a solid tumor can not progress beyond a few cubic millimeters without oxygen and nutrients supplied by an adequate vascular support [1] . The creation of novel vascular vessels in the tumor microenvironment resulting from an over expression of pro-angiogenic factors plays a central role in tumor invasion and metastasis [2] . Hepatocellular carcinoma (HCC) present typical neo vascularization [3] . Among the soluble factors responsible for the shift towards tumor neo vascularization, vascular endothelial growth factor (VEGF) is thought to play an important role in HCC. This factor is synthesized essentially during hypoxic stress [4] and promotes the growth, migration, morphogenesis of vascular endothelial cells and increases vascular permeability [5,6] . Furthermore, the VEGF/VEGF receptor system is thought to be closely related to the histological grade of hepatocellular carcinoma [7] and strongly expressed in well differentiated HCC [8] . Several other potent angiogenic factors have been reported to be Abstract AIM:To study the implication of prokineticin 1 (PK1/EG-VEGF) and prokineticin 2 (PK2/Bv8) in hepatocellular carcinoma angiogenesis. METHODS:The gene induction of PK1/EG-VEGF and PK2/Bv8 was investigated in 10 normal, 28 fibrotic and 28 tumoral livers by using real time PCR. Their expression was compared to the expression of VEGF (an angiogenesis marker), vWF (an endothelial cell marker) and to CD68 (a monocyte/macrophage marker). Furthermore, the mRNA levels of PK1/EG-VEGF, PK2/Bv8, prokineticin receptor 1 and 2 were evaluated by real time PCR in isolated liver cell populations. Finally, PK2/Bv8 protein was detected in normal liver paraffin sections and in isolated liver cells by immunohistochemistry and immunocytochemistry.RESULTS: PK2/Bv8 mRNA but not PK1/EG-VEGF was expressed in all types of normal liver samples examined. In the context of liver tumor development, we reported that PK2/Bv8 correlates only with CD68 and showed a significant decrease in expression as the pathology evolves towards cancer. Whereas, VEGF and vWF mRNA were significantly upregulated in both fibrosis and HCC, involved in HCC angiogenesis, notably basic fibroblast growth factor (bFGF) [9,10] , angiopoietin 1 (Ang1) and angiopoietin 2 (Ang2) [11] . Interestingly, inflammatory cytokines like Interleukin 8 (IL-8) and tumor necrosis factoralpha (TNF-α) have also been shown to be implicated in the maintenance of HCC angiogenesis but also in chronic hepatitis [12,13] . P r o k i n e t i c i n 1 , a l s o n a m e d e n d o c r i n e g l a n dvascular endothelial gro...

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“…In total, there were four tissue OS studies (Chow et al, 1997;Jeng et al, 2004a;Deli et al, 2005;Sheen et al, 2005), six tissue DFS studies (Jeng et al, 2004a;Sheen et al, 2005;Guo et al, 2006;Wada et al, 2006;Zhang et al, 2006;Ho et al, 2007), seven serum OS studies (Poon et al, 2001(Poon et al, , 2004a(Poon et al, , b, 2007Chao et al, 2003;Kim et al, 2004;Jeng et al, 2004b;Treiber et al, 2006), and five serum DFS studies (Poon et al, 2001(Poon et al, , 2007Chao et al, 2003;Jeng et al, 2004b;Treiber et al, 2006). Pooled HRs were then calculated for all groups.…”

Section: Summary Estimates Of Primary Studiesmentioning

confidence: 99%

Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: systematic review and meta-analysis

et al. 2009

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Hepatocellular carcinoma (HCC) is a highly vascular tumour that expresses vascular endothelial growth factor (VEGF). Various studies have evaluated the prognostic value of VEGF levels in HCC. Its overall test performance remains unclear, however. The aim was to perform a systematic review and meta-analysis of prognostic cohort studies evaluating the use of VEGF as a predictor of survival in patients with treated HCC. Eligible studies were identified through multiple search strategies. Studies were assessed for quality using the Newcastle–Ottawa Tool. Data were collected comparing disease-free and overall survival in patients with high VEGF levels as compared to those with low levels. Studies were pooled and summary hazard ratios were calculated. A total of 16 studies were included for meta-analysis (8 for tissue and 8 for serum). Methodological analysis indicated a trend for higher study quality with serum studies as compared to tissue-based investigations. Four distinct groups were pooled for analysis: tissue overall survival ( n =251), tissue disease-free survival ( n =413), serum overall survival ( n =579), and serum disease-free survival ( n =439). High tissue VEGF levels predicted poor overall (HR=2.15, 95% CI: 1.26–3.68) and disease-free (HR=1.69, 95% CI: 1.23–2.33) survival. Similarly, high serum VEGF levels predicted poor overall (HR=2.35, 95% CI: 1.80–3.07) and disease-free (HR=2.36, 95% CI 1.76–3.16) survival. A high degree of inter-study consistency was present in three of four groups analysed. Tissue and serum VEGF levels appear to have significant predictive ability for estimating overall survival in HCC and may be useful for defining prognosis in HCC.

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Expression pattern of angiogenic factors and prognosis after hepatic resection in hepatocellular carcinoma: importance of angiopoietin‐2 and hypoxia‐induced factor‐1a

Abstract: Our study showed that the expression of VEGF and Ang-2 correlated with MVD. Strong Ang-2 expression and/or high nuclear expression of HIF-1alpha is a significant predictive factor for recurrence after curative resection in HCC patients.

Cited by 118 publications

References 41 publications

Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

Prokineticin 2/Bv8 is expressed in Kupffer cells in liver and is down regulated in human hepatocellular carcinoma

Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: systematic review and meta-analysis

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