The five amino acid-deleted isoform of hepatocyte growth factor promotes carcinogenesis in transgenic mice (original) (raw)
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Proceedings of the National Academy of Sciences, 1996
Overexpression of the c-myc oncogene is associated with a variety of both human and experimental tumors, and cooperation of other oncogenes and growth factors with the myc family are critical in the evolution of the malignant phenotype. The interaction of hepatocyte growth factor (HGF) with c-myc during hepatocarcinogenesis in a transgenic mouse model has been analyzed. While sustained overexpression of c-myc in the liver leads to cancer, coexpression of HGF and c-myc in the liver delayed the appearance of preneoplastic lesions and prevented malignant conversion. Furthermore, tumor promotion by phenobarbital was completely inhibited in the c-myc/HGF double transgenic mice, whereas phenobarbital was an effective tumor promoter in the c-myc single transgenic mice. The results indicate that HGF may function as a tumor suppressor during early stages of liver carcinogenesis, and suggest the possibility of therapeutic application for this cytokine.
Oncogene, 2002
Hepatocyte growth factor (HGF) is a mitogen for hepatocytes, but it is not clear whether HGF stimulates or inhibits hepatocarcinogenesis. We previously reported that HGF transgenic mice under the metallothionein gene promoter developed benign and malignant liver tumors spontaneously after 17 months of age. To elucidate the role of HGF in hepatocarcinogenesis, diethylnitrosamine (DEN) was administered to HGF transgenic mice. HGF overexpression accelerated DENinduced hepatocarcinogenesis, often accompanied by abnormal blood vessel formation. In this study, 59% of transgenic males (versus 20% of wild-type males) and 39% of transgenic females (versus 2% of wild-type females) developed either benign or malignant liver tumors by 48 weeks (P50.005, P50.001, respectively). Moreover, 33% of males and 23% of female transgenic mice developed hepatocellular carcinoma (HCC), while none of the wild-type mice developed HCC (P50.001, P50.005, respectively). Enhanced kinase activity of the HGF receptor, Met, was detected in most of these tumors. Expression of vascular endothelial growth factor (VEGF) was up-regulated in parallel with HGF transgene expression. Taken together, our results suggest that HGF promotes hepatocarcinogenesis through the autocrine activation of the HGF-Met signaling pathway in association with stimulation of angiogenesis by HGF itself and/or indirectly through VEGF.
International Journal of Molecular Sciences, 2015
The development of hepatocellular carcinoma (HCC) is an important complication of viral infection induced by hepatitis virus C, and our major research theme is to identify a new growth factor related to the progression of HCC. HDGF (hepatoma-derived growth factor) is a novel growth factor that belongs to a new gene family. HDGF was initially purified from the conditioned medium of a hepatoma cell line. HDGF promotes cellular proliferation as a DNA binding nuclear factor and a secreted protein acting via a receptor-mediated pathway. HDGF is a unique multi-functional protein that can function as a growth factor, angiogenic factor and anti-apoptotic factor and it participates in the development and progression of various malignant diseases. The expression level of HDGF may be an independent prognostic factor for predicting the disease-free and overall survival in patients with various malignancies, including HCC. Furthermore, the overexpression of HDGF promotes the proliferation of HCC cells, while a reduction in the HDGF expression inhibits the proliferation of HCC cells. This article provides an overview of the characteristics of HDGF and describes the potential role of HDGF as a growth-promoting factor for HCC.
2015
Abstract: The development of hepatocellular carcinoma (HCC) is an important complication of viral infection induced by hepatitis virus C, and our major research theme is to identify a new growth factor related to the progression of HCC. HDGF (hepatoma-derived growth factor) is a novel growth factor that belongs to a new gene family. HDGF was initially purified from the conditioned medium of a hepatoma cell line. HDGF promotes cellular proliferation as a DNA binding nuclear factor and a secreted protein acting via a receptor-mediated pathway. HDGF is a unique multi-functional protein that can function as a growth factor, angiogenic factor and anti-apoptotic factor and it participates in the development and progression of various malignant diseases. The expression level of HDGF may be an independent prognostic factor for predicting the disease-free and overall survival in patients with various malignancies, including HCC. Furthermore, the overexpression of HDGF promotes the proliferat...
A Mouse Model of Hepatocellular Carcinoma
American Journal of Pathology, 2002
Most mouse models of hepatocellular carcinoma have expressed growth factors and oncogenes under the control of a liver-specific promoter. In contrast, we describe here the formation of liver tumors in transgenic mice overexpressing human fibroblast growth factor 19 (FGF19) in skeletal muscle. FGF19 transgenic mice had elevated hepatic ␣-fetoprotein mRNA as early as 2 months of age, and hepatocellular carcinomas were evident by 10 months of age. Increased proliferation of pericentral hepatocytes was demonstrated by 5-bromo-2-deoxyuridine incorporation in the FGF19 transgenic mice before tumor formation and in nontransgenic mice injected with recombinant FGF19 protein. Areas of small cell dysplasia were initially evident pericentrally, and dysplastic/neoplastic foci throughout the hepatic lobule were glutamine synthetase-positive, suggestive of a pericentral origin. Consistent with chronic activation of the Wingless/ Wnt pathway, 44% of the hepatocellular tumors from FGF19 transgenic mice had nuclear staining for -catenin. Sequencing of the tumor DNA encoding -catenin revealed point mutations that resulted in amino acid substitutions. These findings suggest a previously unknown role for FGF19 in hepatocellular carcinomas.
Partial blockage of hepatocyte maturation in hepatoma-derived growth factor transgenic mice
World journal of hepatology, 2009
To investigate the role of hepatoma-derived growth factor (HDGF) in liver development, especially in the hepatocyte differentiation. We generated transgenic mice which overexpressed HDGF in hepatocytes under the transcriptional control of mouse albumin promoter/enhancer. To examine the effects of HDGF overexpression on hepatocyte differentiation, we investigated the expression patterns of the differentiation marker genes. The HDGF transgenic mice developed normally and showed no apparent abnormality in the liver. However, the gene expression patterns of the liver in adult transgenic mice were similar to those of the neonatal liver in control mice. These findings suggest that HDGF-overexpression partially suppresses hepatocyte maturation.
Hepatoma-derived growth factor is induced in liver regeneration
Hepatology Research, 2009
Aim: Hepatoma-derived growth factor (HDGF) is a heparinbinding protein, which has been suggested to be involved in the development of kidneys, the cardiovascular system and the liver. We have shown that HDGF is highly expressed in parenchymal hepatocytes in the developing liver and promotes fetal hepatocyte proliferation. In the present study, we asked whether HDGF expression was related to liver regeneration.
Molecular Mechanisms of Hepatocarcinogenesis in Transgenic Mouse Models of Liver Cancer
Toxicologic Pathology, 2005
Overexpression of c-myc and transforming growth factor-alpha (TGF-α) has been frequently observed in human hepatocellular carcinoma (HCC), suggesting a pivotal role played by these protooncogenes in liver oncogenesis. In order to investigate the molecular events underlying human hepatic malignant transformation, we have generated c-myc and c-myc/ TGF-α transgenic mice that are prone to liver cancer. These transgenic mice develop HCCs with different incidence, kinetics and histopathological features. Indeed, co-expression of c-myc and TGF-α transgenes results in a dramatic synergistic effect on liver tumor development when compared with respective single transgenic lines, including a shorter latency period and a more aggressive phenotype. The more malignant histopathological features characteristic of c-myc/ TGF-α HCCs are the result of the increased proliferation and reduced apoptosis in this model of liver cancer when compared with single parental lines. Accordingly, c-myc and c-myc/ TGF-α transgenic mice display a different molecular pathogenesis of HCC. Importantly, the genetic and molecular mechanisms that are involved in c-myc and c-myc/ TGF-α liver cancer development are major oncogenic events in human hepatocarcinogenesis, indicating that these mouse models represent a useful tool to dissect and elucidate the molecular basis of human HCC.
Cancer Research, 1994
Transforming growth factor a (TGF-a) is a polypeptide closely asso elated with hepatocyte proliferation in vivo and in vitro. In order to inves tigate the mechanisms by which TGF-a contributes to hepatocyte repli cation and transformation, we isolated hepatocytes from mice bearing a human TGF-a transgene and examined their growth properties and gene expression in defined, serum-free culture. The transgenic hepatocytes continued to overexpress human TGF-a mRNA and pepfide, and were able to proliferate without exogenous growth factors in primary culture, in contrast to nontransgenic mouse hepatocytes. In short-term culture the transgenic hepatocytes underwent 1 wave of DNA replication at 72â€"96 h in culture before senescing, similar to nontransgenic hepatocytes supple mented with epidermal growth factor. Constitufive expression of TGF-a rendered the transgenic hepatocytes unresponsive to further growth sUm ulation by exogenous TGF-a, as well as other mitogens such as epidermal growth factor and hepntocyte growth factor. However, it did not alter their sensitivity to growth inhibition by TGFfi1, 2 and 3. The addition of nicotinamide to the culture medium enabled both transgenic and epider mal growth factor-supplemented normal hepatocytes to replicate repeat edly and survive for 2 months in primary culture while maintaining differentiated traits. From these long-term primary cnitures of transgenic and nontransgenic hepatocytes, we established immortalized cell lines (designated TAMH and NMH lines, respectively) Both lines continued to express differentiated adult hepatocytic markers such as albumin, a-iantitrypsin, transferrin, and connexin 26 and 32 mRNAs, but also ex p1-eased mRNAs for the oncofetal markers a-fetoprotein and insulin-like growth factor II. Unlike the near-diploid NMH hepatocyte line, the trans genic TAMH hepatocyte line was quasl-tetrnploid, strongly expressed human TGF-a mRNA, and was highly tumorigenic in nude mice. Well differentiated hepatocellular carcinomas developed in nude mice given injecions of the TAMH line, and these appeared similar to the primary liver tumors seen in TGF-a transgemc mice with regard to histology and strong expression of mouse and human TGF-a, insulin-like growth factor H, and a-fetoprotein mRNAs. Our data show that TGF-a overexpression causes autonomous hepatocyte proliferation and contributes to neoplasia but that additional cellular alterations must occur for carcinogenesis. Inappropriate expression of insulin-like growth factor H may constitute one of these steps. The TGF-a transgenlc mouse hepatocyte line TAMH appears to undergo transformation in n similar manner to that of hepa tocytes overexpressing TGF-a in vivo, and should serve as an ideal system in which to study hepatocarcinogenesis.