High expression of CD34-positive sinusoidal endothelial cells is a risk factor for hepatocellular carcinoma in patients with HCV-associated chronic liver diseases

Ohmori, Shigeru; Shiraki, Katsuya; Sugimoto, Kazushi; Sakai, Takahisa; Fujikawa, Katsuhiko; Wagayama, Hidetaka; Takase, Koujiro; Nakano, Takeshi

doi:10.1053/hupa.2001.29678

Cited by 44 publications

(51 citation statements)

References 37 publications

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“…In fact, in the last 4 years, different studies have highlighted some interesting but conflicting scenarios. One of these studies suggested that the presence of HCV infection increased de facto the expression of VEGF (49,50). The second scenario suggested that in HCC samples infected by HCV, VEGF is down-regulated (51).…”

Section: Discussionmentioning

confidence: 99%

pRb2/p130, Vascular Endothelial Growth Factor, p27(KIP1), and Proliferating Cell Nuclear Antigen Expression in Hepatocellular Carcinoma

Claudio

Russo

Kumar

et al. 2004

Clinical Cancer Research

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Hepatocarcinoma (HCC) is the fifth most common cancer, with more than one million fatalities occurring annually worldwide. Multiple risk factors are associated with HCC disease etiology, the highest incidence being in patients with chronic hepatitis B virus and hepatitis C virus, although other factors such as genetic makeup and environmental exposure are involved. Multiple genetic alterations including the activation of oncogenes and inactivation of tumor suppressor genes are required for malignancy in human cancers and are correlated with increased stages of carcinogenesis and further tumor progression. In this study of 21 HCC patients, we analyzed pRb2/p130, vascular endothelial growth factor (VEGF), p27 (KIP1) , and proliferating cell nuclear antigen as potential HCC molecular biomarkers. In our sample set, we found that p27 (KIP1) was absent. Univariate survival analysis showed that proliferating cell nuclear antigen expression (diffuse staining >50% of positive cells in tumor) was confirmed as a significant HCC prognostic biomarker for determining patient survival agreeing with previous studies (P ‫؍‬ 0.0126, log-rank test). Lower pRb2/p130 expression was associated to a borderline P value of inverse correlation with tumor malignancy and to a positive correlation with respect to the time from HCC diagnosis (Spearman coefficient ‫؍‬ 0.568; P < 0.05). Conversely, higher VEGF expression was associated with a poor survival (P ‫؍‬ 0.0257, log-rank test). We demonstrate for the first time that pRb2/p130 is inversely correlated with VEGF expression and tumor aggressiveness (P < 0.05) in p27 (KIP1) -negative HCC patients. pRb2/p130 and VEGF expression are independent from tumor staging, suggesting their possible role as independent prognostic molecular biomarkers in HCC. Furthermore, we have evidence that VEGF together with pRb2/p130 may act as new HCC biomarkers in a p27 (KIP1) -independent manner. Additional studies with larger numbers of patient data would allow the use of multivariable techniques and would be able to further identify patients with poorer survival.

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Section: Discussionmentioning

confidence: 99%

pRb2/p130, Vascular Endothelial Growth Factor, p27(KIP1), and Proliferating Cell Nuclear Antigen Expression in Hepatocellular Carcinoma

Claudio

Russo

Kumar

et al. 2004

Clinical Cancer Research

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“…The FoxM1 transcription factor was identified as a novel inhibitory target of the mouse ARF tumor suppressor, and structure-function studies demonstrated that amino acid residues 26-46 of the mouse ARF protein were sufficient to inhibit FoxM1 (8). Furthermore, treatment of osteosarcoma U2OS cells with a cell-penetrating ARF [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] peptide containing 9 N-terminal d-arginine (D-Arg) residues (WT ARF [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] ) (32,33) significantly reduced FoxM1 function in this cancer cell line (8). Moreover, we previously developed Tg mice in which the Rosa26 promoter was used to drive ubiquitous expression of the human FoxM1b cDNA, and increased FoxM1b levels stimulated proliferation of pulmonary cells in response to lung injury (34) and stimulated development and progression of prostate cancers in both TRAMP/Rosa26-FoxM1b and LADY/Rosa26-FoxM1b double-Tg mice <...>…”

Section: Figurementioning

confidence: 99%

A cell-penetrating ARF peptide inhibitor of FoxM1 in mouse hepatocellular carcinoma treatment

Gusarova¹,

Wang²,

Major³

et al. 2007

J. Clin. Invest.

144

150

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The forkhead box m1 (Foxm1) transcription factor is essential for initiation of carcinogen-induced liver tumors; however, whether FoxM1 constitutes a therapeutic target for liver cancer treatment remains unknown. In this study, we used diethylnitrosamine/phenobarbital treatment to induce hepatocellular carcinomas (HCCs) in either WT mice or Arf -/-Rosa26-FoxM1b Tg mice, in which forkhead box M1b (FoxM1b) is overexpressed and alternative reading frame (ARF) inhibition of FoxM1 transcriptional activity is eliminated. To pharmacologically reduce FoxM1 activity in HCCs, we subjected these HCC-bearing mice to daily injections of a cell-penetrating ARF 26-44 peptide inhibitor of FoxM1 function. After 4 weeks of this treatment, HCC regions displayed reduced tumor cell proliferation and angiogenesis and a significant increase in apoptosis within the HCC region but not in the adjacent normal liver tissue. ARF peptide treatment also induced apoptosis of several distinct human hepatoma cell lines, which correlated with reduced protein levels of the mitotic regulatory genes encoding polo-like kinase 1, aurora B kinase, and survivin, all of which are transcriptional targets of FoxM1 that are highly expressed in cancer cells and function to prevent apoptosis. These studies indicate that ARF peptide treatment is an effective therapeutic approach to limit proliferation and induce apoptosis of liver cancer cells in vivo.

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“…62,74 The pathophysiological significance of chronic viral hepatitis-associated angiogenesis is presently unclear; it has been proposed to exert a beneficial role by contributing to tissue repair and regeneration after liver damage. 62 It has also been suggested to represent a risk factor for progression to hepatocellular carcinoma in patients with chronic hepatitis C. 75 The molecular mechanisms involved in chronic viral hepatitis-associated angiogenesis have not been fully identified. However, many of the molecules that have been shown either in vitro or in experimental animals to participate in the angiogenic response are known to be overexpressed in the livers of such patients.…”

Section: -12 Dmentioning

confidence: 99%

Angiogenesis in chronic inflammatory liver disease

et al. 2004

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Intrahepatic hypoxia may occur during the inflammatory and fibrotic processes that characterize several chronic liver diseases of viral and autoimmune origin. As a consequence, new vascular structures are formed to provide oxygen and nutrients. Angiogenesis involves a tightly regulated network of cellular and molecular mechanisms that result in the formation of functional vessels. Of particular importance are growth factors, molecules involved in matrix remodeling and cell migration, and vessel maturation-related factors. In recent years, a number of studies have examined the expression and function of many pro-and antiangiogenic molecules in the setting of nontumoral chronic liver diseases and liver regeneration. This review examines the potential pathogenetic role of angiogenesis in the context of viral hepatitis, cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, and alcoholic liver disease. The future perspectives for research in this field are outlined.

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High expression of CD34-positive sinusoidal endothelial cells is a risk factor for hepatocellular carcinoma in patients with HCV-associated chronic liver diseases

Cited by 44 publications

References 37 publications

pRb2/p130, Vascular Endothelial Growth Factor, p27(KIP1), and Proliferating Cell Nuclear Antigen Expression in Hepatocellular Carcinoma

pRb2/p130, Vascular Endothelial Growth Factor, p27(KIP1), and Proliferating Cell Nuclear Antigen Expression in Hepatocellular Carcinoma

A cell-penetrating ARF peptide inhibitor of FoxM1 in mouse hepatocellular carcinoma treatment

Angiogenesis in chronic inflammatory liver disease

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