Hepatoma-Derived Growth Factor Is Involved in Lung Remodeling by Stimulating Epithelial Growth

Mori, Masahide; Morishita, Hiroshi; Nakamura, Hitomi; Matsuoka, Hiroto; Yoshida, Kenya; Kishima, Yoshihiko; Zhou, Zhiwei; Kida, Hiroshi; Funakoshi, Tadanao; Goya, Sho; Yoshida, Mitsuhiro; Kumagai, Toru; Tachibana, Isao; Yamamoto, Yoichi; Kawase, Ichiro; Hayashi, Seiji

doi:10.1165/rcmb.2003-0013oc

Cited by 38 publications

(38 citation statements)

References 31 publications

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“…Although HDGF can stimulate DNA synthesis and cell proliferation in vascular or bronchial epithelial cells has been previously reported (8,9,13), our results are consistent with our clinical observation that the expression levels of HDGF was not associated with Ki67 labeling indices in primary NSCLC (10). In fact, HDGFmediated cell growth was observed only when the cells were cultured in serum-free condition (13,14); the presence of serum would have masked HDGF stimulation because of the effect of other growth stimulators in serum.…”

Section: Resultssupporting

confidence: 91%

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Down-regulation of Hepatoma-Derived Growth Factor Inhibits Anchorage-Independent Growth and Invasion of Non–Small Cell Lung Cancer Cells

Zhang

Ren²,

Yuan³

et al. 2006

Cancer Research

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We recently reported that a high level of hepatoma-derived growth factor (HDGF) expression in tumors correlates with a high incidence of tumor relapse or distant metastasis and shortened survival time in patients with non-small cell lung cancer (NSCLC). However, the mechanisms of the HDGFassociated aggressive biological behavior are unknown. In this study, we knocked down HDGF expression in NSCLC cells to determine the biological consequences. Transfection with HDGF-specific small interfering RNA (siRNA) resulted in down-regulation of HDGF expression in four NSCLC cell lines. Down-regulation of HDGF resulted in no detectable effect on anchorage-dependent cell growth as determined with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, a microelectronic cell sensor system, and flow cytometry. In contrast, cells transfected with HDGF-siRNA grew more slowly and formed significantly fewer colonies in soft agar than did cells treated with LipofectAMINE alone or transfected with negative control siRNA. In an in vitro invasion assay, significantly fewer cells transfected with HDGF-siRNA than cells treated with LipofectAMINE alone were able to invade across a Matrigel membrane barrier. In an in vivo mouse model, A549 cells treated with HDGF-siRNA grown significantly slower than the cells treated with LipofectAMINE alone or negative control siRNA. Morphologically, HDGF-siRNAtreated tumors exhibited markedly reduced blood vessel formation and increased necrosis, whereas the Ki67 labeling indices were similar in tumors treated with controls. Our results suggest that HDGF is involved in anchorage-independent growth, cell invasion, and formation of neovasculature of NSCLC. These qualities may contribute to the HDGF-associated aggressive biological behavior of NSCLC. (Cancer Res 2006; 66(1): 18-23)

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Section: Resultssupporting

confidence: 91%

“…In fact, HDGFmediated cell growth was observed only when the cells were cultured in serum-free condition (13,14); the presence of serum would have masked HDGF stimulation because of the effect of other growth stimulators in serum.…”

Section: Resultsmentioning

confidence: 99%

Down-regulation of Hepatoma-Derived Growth Factor Inhibits Anchorage-Independent Growth and Invasion of Non–Small Cell Lung Cancer Cells

Zhang

Ren²,

Yuan³

et al. 2006

Cancer Research

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“…HDGF has been reported to be highly expressed in fetal tissues, and an association with the aggressive biological potential of cancer cells, such as proliferation, has been proposed (5,6,11,12). Whether cell growth arrest resulted in a decrease in HDGF expression was, therefore, tested.…”

Section: P53 Family Downregulates Expression Of the Hdgf Mrna And Promentioning

confidence: 99%

“…HDGF stimulates the proliferation of fibroblasts, endothelial cells, vascular smooth muscle cells, and some liver cancer cells. 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).…”

Section: Introductionmentioning

confidence: 99%

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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“…In contrast, the length and amino acid sequences of carboxyl-terminal regions of HRPs vary considerably, suggesting a modular structure of these proteins, which is supported by NMR data analysis of human HDGF (10). Expression of HDGF mRNA as well as protein is developmentally regulated, and various results point to an important function of HDGF during tissue development, protection, and repair (6,(11)(12)(13)(14)(15)(16)(17)(18). In addition, studies on different types of cancers suggest a possible role of this growth factor in cancer development and neovascularization (19 -24).…”

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confidence: 91%

Hepatoma-derived Growth Factor

Abouzied

Eltahir

Prenner

et al. 2005

Journal of Biological Chemistry

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Hepatoma-derived growth factor (HDGF) has proliferative, angiogenic, and neurotrophic activity. It plays a putative role in the development and progression of cancer. When expressed in cells, the mitogenic activity of HDGF depends on its nuclear localization, but it also stimulates proliferation when added to the cell culture medium. A cell surface receptor for HDGF has not been identified so far. We investigated the interaction of various purified recombinant HDGF fusion proteins with the cell surface of NIH 3T3 fibroblasts. We showed that binding of a HDGF-␤-galactosidase fusion protein to the cell surface of NIH 3T3 fibroblasts was saturable, occurred with high affinity (K D ‫؍‬ 14 nM), and had a proliferative effect. We identified a peptide comprising amino acid residues 81-100 within the amino-terminal part of HDGF that bound to the cell surface of NIH 3T3 cells with saturation and affinity values similar to those of HDGF. When added to primary human fibroblasts, this peptide stimulated proliferation. Substitution of a single amino acid (K96A) within this peptide was sufficient to abolish its binding to the cell surface and its proliferative activity. In contrast, when expressed transiently in NIH 3T3 cells, a HDGF-␤-galactosidase fusion protein in which amino acid residues 81-100 were deleted still had proliferative activity, whereas a fusion protein containing only the 81-100 peptide did not. Our results suggest the existence of a plasma membrane-located HDGF receptor for which signaling depends on amino acid residues 81-100 of HDGF. This region differs from the one that has been recently identified to be essential for mitogenic activity depending on the nuclear localization of HDGF. Thus, HDGF exerts its proliferative activity via two different pathways.

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Hepatoma-Derived Growth Factor Is Involved in Lung Remodeling by Stimulating Epithelial Growth

Cited by 38 publications

References 31 publications

Down-regulation of Hepatoma-Derived Growth Factor Inhibits Anchorage-Independent Growth and Invasion of Non–Small Cell Lung Cancer Cells

Down-regulation of Hepatoma-Derived Growth Factor Inhibits Anchorage-Independent Growth and Invasion of Non–Small Cell Lung Cancer Cells

p53 Negatively Regulates the Hepatoma Growth Factor HDGF

Hepatoma-derived Growth Factor

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