p53 negatively regulates the hepatoma growth factor HDGF.

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.

[1]  M. Toyota,et al.  p53 Family Members Regulate the Expression of the Apolipoprotein D Gene* , 2009, Journal of Biological Chemistry.

[2]  M. Toyota,et al.  Identification of Flotillin-2, a Major Protein on Lipid Rafts, as a Novel Target of p53 Family Members , 2008, Molecular Cancer Research.

[3]  Sheng-Nan Lu,et al.  Hepatoma‐derived growth factor is a novel prognostic factor for gastrointestinal stromal tumors , 2007, International journal of cancer.

[4]  M. Toyota,et al.  Antitumor effect of adenovirus-mediated p53 family gene transfer on osteosarcoma cell lines , 2007, Cancer biology & therapy.

[5]  M. Monden,et al.  Hepatoma-Derived Growth Factor Is a Novel Prognostic Factor for Patients with Pancreatic Cancer , 2006, Clinical Cancer Research.

[6]  T. Stoops,et al.  Hepatoma-Derived Growth Factor Is Expressed after Vascular Injury in the Rat and Stimulates Smooth Muscle Cell Migration , 2006, Pediatric Research.

[7]  M. Toyota,et al.  Genetic, epigenetic, and clinicopathologic features of gastric carcinomas with the CpG island methylator phenotype and an association with Epstein–Barr virus , 2006, Cancer.

[8]  R. Mantovani,et al.  DNA Damage Promotes Histone Deacetylase 4 Nuclear Localization and Repression of G2/M Promoters, via p53 C-terminal Lysines* , 2006, Journal of Biological Chemistry.

[9]  M. Monden,et al.  Hepatoma-Derived Growth Factor Is a Novel Prognostic Factor for Hepatocellular Carcinoma , 2006, Annals of Surgical Oncology.

[10]  Y. Doki,et al.  Expression of Hepatoma-Derived Growth Factor Is Correlated with Lymph Node Metastasis and Prognosis of Gastric Carcinoma , 2006, Clinical Cancer Research.

[11]  P. Hall,et al.  An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Hideji Nakamura,et al.  Hepatoma-derived growth factor as a prognostic marker in completely resected non-small-cell lung cancer. , 2005, Oncology reports.

[13]  R. Mantovani,et al.  Direct p53 Transcriptional Repression: In Vivo Analysis of CCAAT-Containing G2/M Promoters , 2005, Molecular and Cellular Biology.

[14]  Edward A Fox,et al.  Insights into developmental mechanisms and cancers in the mammalian intestine derived from serial analysis of gene expression and study of the hepatoma-derived growth factor (HDGF) , 2005, Development.

[15]  F. Khuri,et al.  Expression of hepatoma-derived growth factor is a strong prognostic predictor for patients with early-stage non-small-cell lung cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  A. Tucker,et al.  Hepatoma-derived growth factor is a pulmonary endothelial cell-expressed angiogenic factor. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[17]  I. Kawase,et al.  Hepatoma-derived growth factor is involved in lung remodeling by stimulating epithelial growth. , 2004, American journal of respiratory cell and molecular biology.

[18]  C. Chen,et al.  Diverse cellular transformation capability of overexpressed genes in human hepatocellular carcinoma. , 2004, Biochemical and biophysical research communications.

[19]  I. McNeish,et al.  Gene Therapy Progress and Prospects: cancer gene therapy using tumour suppressor genes , 2004, Gene Therapy.

[20]  I. Kawase,et al.  Hepatoma‐derived growth factor induces tumorigenesis in vivo through both direct angiogenic activity and induction of vascular endothelial growth factor , 2003, Cancer science.

[21]  I. Kawase,et al.  Expression of hepatoma‐derived growth factor in hepatocarcinogenesis , 2003, Journal of gastroenterology and hepatology.

[22]  K. Resing,et al.  Functional proteomic analysis of melanoma progression. , 2003, Cancer research.

[23]  M. Tai,et al.  Expression of hepatoma‐derived growth factor in hepatocellular carcinoma , 2003, Cancer.

[24]  J. Bushweller,et al.  Hepatoma derived growth factor is a nuclear targeted mitogen. , 2003, Current drug targets.

[25]  S. Benchimol,et al.  Transcriptional repression mediated by the p53 tumour suppressor , 2003, Cell Death and Differentiation.

[26]  A. Miyajima,et al.  Hepatoma‐derived growth factor is highly expressed in developing liver and promotes fetal hepatocyte proliferation , 2002, Hepatology.

[27]  Xin Lu,et al.  Live or let die: the cell's response to p53 , 2002, Nature Reviews Cancer.

[28]  Yusuke Nakamura,et al.  The p53 Family Member Genes Are Involved in the Notch Signal Pathway* , 2002, The Journal of Biological Chemistry.

[29]  Y. Sasaki,et al.  Adenovirus-mediated transfer of the p53 family genes, p73 and p51/p63 induces cell cycle arrest and apoptosis in colorectal cancer cell lines: potential application to gene therapy of colorectal cancer , 2001, Gene Therapy.

[30]  R. A. Johnson,et al.  Transcriptional Repression by p53 through Direct Binding to a Novel DNA Element* 210 , 2001, The Journal of Biological Chemistry.

[31]  A. Levine,et al.  Surfing the p53 network , 2000, Nature.

[32]  Hideji Nakamura,et al.  Hepatoma-derived growth factor stimulates smooth muscle cell growth and is expressed in vascular development. , 2000, The Journal of clinical investigation.

[33]  Y. Nakamura,et al.  Recombinant adenovirus expressing wild-type p53 is antiangiogenic: a proposed mechanism for bystander effect. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[34]  T. Liu,et al.  Bystander effect in the adenovirus-mediated wild-type p53 gene therapy model of human squamous cell carcinoma of the head and neck. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[35]  Q. Al-Awqati,et al.  An endothelial growth factor involved in rat renal development. , 1998, The Journal of clinical investigation.

[36]  A. Yang,et al.  p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. , 1998, Molecular cell.

[37]  Chikashi Ishioka,et al.  Cloning and functional analysis of human p51, which structurally and functionally resembles p53 , 1998, Nature Medicine.

[38]  L. Ellis,et al.  Adenovirus-mediated wild-type p53 gene transfer down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human colon cancer. , 1998, Cancer research.

[39]  S. Schreiber,et al.  A role for histone deacetylase activity in HDAC1-mediated transcriptional repression. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[40]  K. Struhl Histone acetylation and transcriptional regulatory mechanisms. , 1998, Genes & development.

[41]  A. Yang,et al.  Monoallelically Expressed Gene Related to p53 at 1p36, a Region Frequently Deleted in Neuroblastoma and Other Human Cancers , 1997, Cell.

[42]  S. Stass,et al.  Parenteral gene therapy with p53 inhibits human breast tumors in vivo through a bystander mechanism without evidence of toxicity. , 1997, Human gene therapy.

[43]  T. Kishimoto,et al.  Molecular cloning of complementary DNA for a novel human hepatoma-derived growth factor. Its homology with high mobility group-1 protein. , 1994, Journal of Biological Chemistry.

[44]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[45]  K. Kinzler,et al.  Definition of a consensus binding site for p53 , 1992, Nature Genetics.

[46]  J. Sato,et al.  Partial purification and characterization of human hepatoma-derived growth factor. , 1989, Clinica chimica acta; international journal of clinical chemistry.

[47]  大嶋 雄一郎 Antitumor effect of adenovirus-mediated p53 family gene transfer on osteosarcoma cell lines , 2007 .

[48]  L. Mao,et al.  Down-regulation of hepatoma-derived growth factor inhibits anchorage-independent growth and invasion of non-small cell lung cancer cells. , 2006, Cancer research.

[49]  Y. Nakamura,et al.  The role of p53-target genes in human cancer. , 2000, Critical reviews in oncology/hematology.

[50]  J. Levine,et al.  Surfing the p53 network , 2000, Nature.

[51]  W. El-Deiry,et al.  Regulation of p53 downstream genes. , 1998, Seminars in cancer biology.