Regulation of angiogenesis in human hepatomas: possible involvement of p53-inducible inhibitor of vascular endothelial cell proliferation

Tsukamoto, Ayumi; Kaneko, Yoshiyasu; Yoshida, Taku; Ichinose, Masakazu; Kimura, Satoshi

doi:10.1016/s0304-3835(99)00074-9

Cited by 13 publications

(7 citation statements)

References 12 publications

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“…Von Marschall reported that hypoxia induced upregulation of VEGF gene expression by at least two distinct molecular mechanisms: activation of VEGF gene transcription and an increase in VEGF mRNA stability in HCC (von Marschall et al 2001). On the other hand, VEGF expression was also under the control of p53 (Huang et al 2002;Tsukamoto et al 1999), SV40 (Catalano et al 2002 and ras (Rak and Kerbel 2001) in some cancers. In HCC, the HBx gene plays a critical role in the hypoxia-driven angiogenesis through transcriptional activation of VEGF during hepatocarcinogenesis (Lee et al 2000).…”

Section: Vegfmentioning

confidence: 95%

Angiogenesis in hepatocellular carcinoma: the retrospectives and perspectives

Sun

Tang

2004

Journal of Cancer Research and Clinical Oncology

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Hepatocellular carcinoma (HCC) is a typical hypervascular tumor. Many angiogenic factors have been studied in HCC, and several anti-angiogenic therapies have been tested in animal models and patients. This paper summarizes the latest findings, especially regarding the clinical significance of endothelial cell markers and angiogenic factors in HCC, and experimental and clinical anti-angiogenesis therapies. Further developments in this area, such as endothelial cell-oriented research and better experimental and clinical designs in the evaluation of anti-angiogenic therapies are discussed.

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Section: Vegfmentioning

confidence: 95%

Angiogenesis in hepatocellular carcinoma: the retrospectives and perspectives

Sun

Tang

2004

Journal of Cancer Research and Clinical Oncology

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“…HuH‐7 human hepatoma cells (purchased from the Health Science Research Resources Bank, Osaka, Japan) were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS). This cell line is known to produce IL‐8 24. Approximately 5×10 5 to 1×10 6 cells (at passage 46), in the exponential growth phase, were inoculated into the dorsal subcutaneous tissue of 4‐week‐old nude mice (male BALB/cAJclnu, Clea Japan, Inc., Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

The copper chelator trientine has an antiangiogenic effect against hepatocellular carcinoma, possibly through inhibition of interleukin‐8 production

Moriguchi

Nakajima

Kimura

et al. 2002

Intl Journal of Cancer

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Recent studies have revealed that copper is an important cofactor for several angiogenic agents. We examined the antiangiogenic effect against hepatocellular carcinoma (HCC) of the copper chelator trientine, especially focusing on the relationship between copper and interleukin-8 (IL-8), a potent angiogenic factor produced by hepatoma cells. HuH-7 hepatoma cells were transplanted into nude mice and the growth of xenograft tumors was compared to and without administration of trientine. Using the resected tumor, microvessel density, apoptotic potential and proliferative activity were analyzed histologically and IL-8 mRNA was semiquantified by RT-PCR. In addition, HuH-7 cells were cultured in control medium, medium supplemented with copper, medium supplemented with trientine and medium supplemented with both copper and trientine. Human IL-8 levels were measured in the supernatants by ELISA. Using the extracts from cultured cells, IL-8 mRNA was semiquantified by RT-PCR. Trientine suppressed the growth of xenograft tumors significantly. Histologically, apoptotic potential was increased significantly and microvessel density, decreased. The production of IL-8 from the tumor was suppressed by trientine. In vitro, IL-8 production by HuH-7 cells in coppercontaining medium was significantly greater than that in copper-free medium, and this effect was weakened when trientine was added. However, no significant change was apparent when trientine was added to the medium alone. In conclusion, the chelating effect of trientine prevented copper from functioning as a cofactor in angiogenesis, which resulted in reduced IL-8 production from HuH-7 cells.

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“…This response was validated using real-time PCR. VEGF is known to be produced by HuH7 cells and has pro-proliferative in addition to its well-characterised angiogenic effects (42)(43)(44)(45). Network 3 was unusual in converging on a single nuclear target, FOS.…”

Section: Discussionmentioning

confidence: 99%

Proteolysis-inducing factor core peptide mediates dermcidin-induced proliferation of hepatic cells through multiple signalling networks

Lowrie

Dickinson²,

Wheelhouse

et al. 2011

Int J Oncol

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Abstract. Dermcidin is a candidate oncogene capable of increasing the number of cultured neuronal, breast cancer and prostate cancer cells and improving the survival of hepatic cells. The dermcidin gene encodes the proteolysis-inducing factor core peptide (PIF-CP) and the skin antimicrobial peptide DCD-1. The peptide responsible for inducing proliferation of cells and the mechanisms involved are unknown. In this study, we confirmed a proliferative effect of dermcidin overexpression of 20% (p<0.02) in the HuH7 human hepatic cell line. Proliferation was abrogated by prevention of PIF-CP translation or inactivation of its calcineurin-like phosphatase domain by site-directed mutagenesis. Prevention of DCD-1 translation had no effect. Treatment of cells with a 30 amino acid synthetic PIF-CP induced an analogous increase in proliferation of 14%. Microarray analysis of PIF-CP-treated cells revealed low but significant changes in 111 potential mediator genes. Pathway analysis revealed several gene networks involved in the cellular response to the peptide, one with VEGFB as a hub and two other networks converging on FOS and MYC. Quantitative PCR confirmed direct upregulation of VEGFB. These data reveal PIF-CP as the key mediator of dermcidin-induced proliferation and demonstrate induction of key oncogenic pathways.

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Regulation of angiogenesis in human hepatomas: possible involvement of p53-inducible inhibitor of vascular endothelial cell proliferation

Cited by 13 publications

References 12 publications

Angiogenesis in hepatocellular carcinoma: the retrospectives and perspectives

Angiogenesis in hepatocellular carcinoma: the retrospectives and perspectives

The copper chelator trientine has an antiangiogenic effect against hepatocellular carcinoma, possibly through inhibition of interleukin‐8 production

Proteolysis-inducing factor core peptide mediates dermcidin-induced proliferation of hepatic cells through multiple signalling networks

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