Expression of hepatoma‐derived growth factor in hepatocarcinogenesis

Yoshida, Kenya; Nakamura, Hitomi; Okuda, Yuji; Enomoto, Hirayuki; Kishima, Yoshihiko; Uyama, Hirokazu; Ito, Hiroaki; Hirasawa, Tsutomu; Inagaki, Soichi; Kawase, Ichiro

doi:10.1046/j.1440-1746.2003.03191.x

Cited by 43 publications

(48 citation statements)

References 42 publications

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“…Of the 57 specimens tested, 52 expressed higher levels of HDGF than adjacent noncancerous stomach tissue. This result suggests that the overexpression of HDGF is a frequent event in gastric cancer, which is consistent with results reported previously (10)(11)(12)(13). The relationship between HDGF expression and p53 mutational status was then investigated.…”

Section: Expression Of Hdgf and P53 Mutation In Human Cancer Tissuesupporting

confidence: 90%

“…Because HDGF possesses proliferative and angiogenic and activity (10,(30)(31)(32), the functional implication of HDGF in cancer cell growth was investigated. Colony formation assays revealed that the growth of HCT116 cells and HeLa cells was significantly enhanced in response to recombinant HDGF protein in a dose-dependent manner (Fig.…”

Section: Suppression Of Cancer Cell Growth By P53-mediated Repressionmentioning

confidence: 99%

“…Recent studies have suggested the involvement of HDGF in the development of the liver, lung, kidney, gut, and cardiovascular systems (5)(6)(7)(8)(9). HDGF expression is increased in several types of carcinomas compared with adjacent nontumorous areas in mouse and human (10). Several findings suggest that HDGF overexpression is associated with aggressive phenotypes of cancer cells, such as proliferation, invasiveness, and metastasis (11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

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p53 Negatively Regulates the Hepatoma Growth Factor HDGF

et al. 2011

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Hepatoma-derived growth factor (HDGF) is a secreted heparin-binding growth factor that has been implicated in cancer development and progression. Here, we report that HDGF is a critical target for transcriptional repression by the tumor suppressor p53. Endogenous HDGF expression was decreased in cancer cells with introduction of wild-type p53, which also downregulated HDGF expression after DNA damage. In support of the likelihood that HDGF is a critical driver of cancer cell growth, addition of neutralizing HDGF antibodies to culture media was sufficient to block cell growth, migration, and invasion. Similarly, these effects were elicited by conditioned culture medium from p53-expressing cells, and they could be reversed by the addition of recombinant human HDGF. Interestingly, we found that HDGF was overexpressed also in primary gastric, breast, and lung cancer tissues harboring mutant p53 genes. Mechanistic investigations revealed that p53 repressed HDGF transcription by altering HDAC-dependent chromatin remodeling. Taken together, our results reveal a new pathway in which loss of p53 function contributes to the aggressive pathobiological potential of human cancers by elevating HDGF expression. Cancer Res; 71(22); 7038-47. Ó2011 AACR.

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Section: Expression Of Hdgf and P53 Mutation In Human Cancer Tissuesupporting

confidence: 90%

Section: Suppression Of Cancer Cell Growth By P53-mediated Repressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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p53 Negatively Regulates the Hepatoma Growth Factor HDGF

et al. 2011

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“…Furthermore, HDGF is more abundantly expressed in HCC than in adjacent non-tumor liver tissues. 20) HDGF is a unique nuclear/growth factor, possibly playing an important role in the development and progression of cancer cells.…”

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confidence: 99%

Hepatoma‐derived growth factor induces tumorigenesis in vivo through both direct angiogenic activity and induction of vascular endothelial growth factor

et al. 2003

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Hepatoma-derived growth factor (HDGF) is highly expressed in tumor cells, and stimulates their proliferation. In the present study, we investigated the role of HDGF in tumorigenesis and elucidated the mechanism of action. Stable transfectants of NIH3T3 cells overexpressing HDGF did not show significant anchorage-independent growth in soft agar assay. However, these stable transfectants overexpressing HDGF generated sarcomatous tumors in nude mice. These tumors were red-colored macroscopically, and histologically showed a rich vascularity. Immunohistochemical analysis using CD31 antibody showed new vessel formation. Recombinant HDGF stimulated proliferation of human umbilical vein endothelial cells in a dose-dependent manner, and stimulated tubule formation. ncogenesis is induced by genetic alterations of various proteins involved in the cell cycle and cellular proliferation, especially by up-regulation of oncogenic genes and/or down-regulation of tumor suppressor genes. Overexpression of growth factors, receptors for growth factors, proteins related to signal transduction from the respective receptors and positive transcriptional regulatory factors, and suppressed expression of growth-inhibitory genes, including negative signal transducers and transcriptional regulatory factors, have all been associated with tumor formation in nude mice. [1][2][3][4][5][6][7][8][9] Hepatoma-derived growth factor (HDGF) is a heparin-binding protein purified from the conditioned media of Huh-7 hepatoma cells, which proliferate autonomously in a serum-free chemically defined medium.10, 11) HDGF contains a well-conserved N-terminal amino acid sequence, which is called the hath (homologous to amino terminus of HDGF) region. 11,12) HDGF is translocated to the nucleus via nuclear localization signals and its nuclear translocation is essential for induction of cell growth activity. 13,14) It is highly expressed in fetal tissues and may be involved in development of organs, including the cardiovascular system, kidney and liver. [15][16][17][18] HDGF has mitogenic activity for some hepatocellular carcinoma (HCC) cells, in addition to fibroblasts, endothelial cells, vascular smooth muscle cells and fetal hepatocytes. 10,11,13,15,16,18,19) It is abundantly expressed in tumor cell lines, and HDGF antisense oligonucleotides suppress the proliferation of hepatoma cells expressing HDGF endogenously. 19) In human and murine models of HCC, HDGF expression increases at an early stage, even before tumor formation. Furthermore, HDGF is more abundantly expressed in HCC than in adjacent non-tumor liver tissues.20) HDGF is a unique nuclear/growth factor, possibly playing an important role in the development and progression of cancer cells.Increasing evidence suggests that HDGF might be implicated in tumorigenesis. However, whether HDGF really induces transformation of cells and tumor formation in vivo is not known. Therefore, we established stable cell lines overexpressing HDGF from NIH3T3 fibroblasts by transfection, and investigated their oncogenic p...

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“…It has been reported that HDGF participates in the development of liver cancer and gastric cancer (27,28). Overexpression of HDGF results in tumorigenesis by NIH 3T3 cells, and dowregulation of HDGF inhibits the tumorigenicity of NSCLC cells in vivo (10,20).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of hepatoma-derived growth factor suppresses the malignant phenotype of U87 human glioma cells

et al. 2012

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Abstract. Hepatoma-derived growth factor (HDGF) has been shown to correlate with increased malignancy of different types of tumors and could be an independent prognostic index for human cancers. We previously found that HDGF is overexpressed in glioma tissues and that its expression level may correlate with the clinical pathological grade. In the present study, we investigated the effects of HDGF downregulation on the biological behaviors of U87 glioma cells. Our results showed that HDGF knockdown significantly inhibited the malignant phenotype of U87 cells, including the colony formation, migration and invasion in vitro, as well as tumorigenesis in vivo. Our data also suggest that hepatocyte growth factor/scatter factor (HGF/SF) may contribute to the HDGFassociated aggressive behavior of glioma cells.

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Expression of hepatoma‐derived growth factor in hepatocarcinogenesis

Abstract: The present findings suggest that HDGF plays an important role in the development or progression of HCC in humans and rodents.

Cited by 43 publications

References 42 publications

p53 Negatively Regulates the Hepatoma Growth Factor HDGF

p53 Negatively Regulates the Hepatoma Growth Factor HDGF

Hepatoma‐derived growth factor induces tumorigenesis in vivo through both direct angiogenic activity and induction of vascular endothelial growth factor

Downregulation of hepatoma-derived growth factor suppresses the malignant phenotype of U87 human glioma cells

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