The hepatocyte growth factor ( HGF) is a multifunctional growth factor, which produces multiple biological effects by binding to the c-Met acceptor. This article reviews the biological properties of HGF, particularly those correlated with male reproduction, including its abilities to promote testis embryonic development, spermatogenesis, and testosterone synthesis of Leydig cells. HGF may provide a new insight into the treatment of male hypogonadism and infertility.
Embryonic Development ; Hepatocyte Growth Factor ; physiology ; Humans ; Leydig Cells ; metabolism ; Male ; Proto-Oncogene Proteins c-met ; metabolism ; Reproduction ; physiology ; Spermatogenesis ; physiology ; Testis ; embryology ; Testosterone ; biosynthesis

Animals ; Carcinoma, Hepatocellular ; metabolism ; secondary ; Hepatocyte Growth Factor ; physiology ; Humans ; Liver Neoplasms ; metabolism ; pathology ; Neoplasm Metastasis ; Proto-Oncogene Proteins c-met ; physiology

The Met tyrosine kinase receptor is a widely expressed molecule, which mediates pleiotropic cellular responses following activation by its ligand, hepatocyte growth factor/scatter factor (HGF/SF). Previously, one of the authors identified an alternatively spliced form of Met (Met-SM) that lacked a single exon of a 47-amino-acid segment in the juxtamembrane domain. Here we report that Met-SM is a potent transforming gene in NIH3T3 mouse fibroblast cells. Met-SM-transfected NIH3T3 cells show stronger foci-forming activity than wild type-Met-transfected ones. In addition, Met-SM-transfected NIH3T3 cells form colonies in soft agar and are tumorigenic in athymic nu/nu mice. Furthermore, HGF/SF significantly increases the focus-forming activity of Met-SM comparing to wild type Met. The amount of protein and of tyrosine kinase activity of Met-SM accumulates to a high level following HGF/SF treatment. The accumulation of Met-SM correlated well with its delayed ubiquitination and increased stability. These results are consistent with the important role of the juxtamembrane domain in protein stability of Met receptor and suggest that the alternatively-spliced form may contribute to the development and progression of human cancer.
Proto-Oncogene Proteins c-met/*metabolism/*physiology ; Protein Isoforms/metabolism/physiology ; NIH 3T3 Cells ; Mutant Proteins/metabolism/physiology ; Mice, Nude ; Mice ; Hepatocyte Growth Factor/pharmacology ; Female ; Down-Regulation ; Carcinogens/*metabolism ; Carcinogenicity Tests ; Animals ; *Alternative Splicing

BACKGROUNDTo study the difference in gene expression between the EBV associated gastric carcinoma (EBVaGC) tissues. To explore the mechanism of gastric carcinoma pathogenesis initiated by EBV.

METHODSIn situ hybridization was used to study the frequencies of EBV small RNA expression in 155 cases of gastric carcinoma tissues. The expression levels of P53 protein and P21WAF1 protein were detected by immunohistochemistry in all gastric carcinoma tissues.

RESULTSThe expression of EBV small RNA was positive in 10 out of 155 cases (6.45%). The expression of P53 protein was weakly positive in 4 of the 10 cases. The expression level of P53 protein in EBVaGC was much lower than that in EBVnGC and was weakly positive in 30 of 145 cases with EBVnGC). P21WAF1 expression was detected in 7 of 10 cases with EBVaGC, but in 55 out of 145 cases with EBVaGC, P21WAF1 expression in EBVaGC was much higher than that in EBVnGC.

CONCLUSIONThere seems existing a special mechanism of pathogenesis in EBVaGC. In which P53 gene mutation may not play an important role.

Epstein-Barr Virus Infections ; metabolism ; pathology ; virology ; Herpesvirus 4, Human ; genetics ; physiology ; Host-Pathogen Interactions ; Humans ; Immunohistochemistry ; In Situ Hybridization ; Proto-Oncogene Proteins c-met ; metabolism ; RNA, Viral ; genetics ; Stomach Neoplasms ; metabolism ; pathology ; virology ; Tumor Suppressor Protein p53 ; metabolism

OBJECTIVETo investigate the expression of hepatocyte growth factor (HGF), and its receptor c-Met protein in nasopharyngeal carcinoma (NPC) and CNE-2 NPC cell line, to correlate their expression level with clinicopathologic features and to study the effect of HGF/c-Met system on the invasive and metastatic potential of NPC.

METHODSForty-five biopsies were collected from pre-treatment NPC patients during the period from 1999 to 2003. Immunohistochemical staining was used to detect the expression of HGF-alpha subunit and c-Met protein in NPC tissues. The association between expression of these proteins and clinicopathologic features was statistically analyzed. The expression of HGF and c-Met, as detected by flow cytometry, in CNE-2 NPC cell line (with or without exogenous HGF) was compared. Western blot analysis and reverse transcriptase-polymerase chain reaction (RT-PCR) were also applied to evaluate the protein and mRNA expression of c-Met in CNE-2 cells.

RESULTSIn the 45 cases studied, the expression rate of c-Met was 91.1% (41/45). Only 1 case (2.2%, 1/45) showed positive signal for HGF in neoplastic cells. Instead, HGF was expressed in surrounding lymphocytes. The expression of c-Met positively correlated with lymph node metastasis (P = 0.024). There was also a positive correlation between expression of c-Met by tumor cells and expression of HGF by surrounding lymphocytes (r(s) = 0.450, P = 0.002). Moreover, the expression of c-Met was higher if there was a higher expression of HGF by lymphocytes (P = 0.009). However, there was no association between expression of c-Met and clinicopathologic features, such as age, gender, histopathologic type and clinical stage. After treatment with HGF for 24 hours, the percentage of c-Met-positive cells was significantly increased in CNE-2 cell line, from (46.6 +/- 9.02)% to (85.8 +/- 6.05)% (P = 0.003). The c-Met protein expression and c-Met mRNA level were also enhanced in CNE-2 cells with HGF treatment. However, endogenous HGF was not detected in CNE-2 cells, regardless of HGF treatment.

CONCLUSIONSHGF may play an important role in the development of NPC metastasis by inducing the expression of c-Met in tumor cells via a paracrine, instead of an autocrine, pathway.

Adult ; Aged ; Carcinoma, Squamous Cell ; metabolism ; secondary ; Cell Line, Tumor ; Female ; Hepatocyte Growth Factor ; biosynthesis ; physiology ; Humans ; Lymphatic Metastasis ; Lymphocytes ; metabolism ; Male ; Middle Aged ; Nasopharyngeal Neoplasms ; metabolism ; pathology ; Proto-Oncogene Proteins c-met ; biosynthesis ; genetics ; RNA, Messenger ; biosynthesis ; genetics

BACKGROUNDVascular endothelial growth factor plays a key role in human colorectal carcinoma invasion and metastasis. However, the regulation mechanism remains unknown. Recent studies have shown that several cytokines can regulate the expression of vascular endothelial growth factor in tumor cells. In this study, we investigated whether hepatocyte growth factor can regulate the expression of vascular endothelial growth factor in colorectal carcinoma cells.

METHODSHepatocyte growth factor and vascular endothelial growth factor in human serum were measured by ELISA. The mRNA level of vascular endothelial growth factor was analyzed by reverse transcription-PCR. Western blot assay was performed to evaluate levels of c-Met and several other proteins involved in the MAPK and PI3K signaling pathways in colorectal carcinoma cells.

RESULTSSerum hepatocyte growth factor and vascular endothelial growth factor were significantly increased in colorectal carcinoma subjects. In vitro extraneous hepatocyte growth factor markedly increased protein and mRNA levels of vascular endothelial growth factor in colorectal carcinoma cells. Hepatocyte growth factor induced phosphorylation of c-Met, ERK1/2 and AKT in a dose-dependent manner. Specific inhibitors on MEK and PI3K inhibited the hepatocyte growth factor-induced expression of vascular endothelial growth factor in colorectal carcinoma cells.

CONCLUSIONThis present study indicates that hepatocyte growth factor upregulates the expression of vascular endothelial growth factor in colorectal carcinoma cells via the MEK/ERK and PI3K/AKT signaling pathways.

Butadienes ; pharmacology ; Cell Line, Tumor ; Chromones ; pharmacology ; Colorectal Neoplasms ; metabolism ; pathology ; Gene Expression Regulation ; drug effects ; Hepatocyte Growth Factor ; blood ; pharmacology ; Humans ; MAP Kinase Signaling System ; physiology ; Morpholines ; pharmacology ; Nitriles ; pharmacology ; Phosphatidylinositol 3-Kinases ; physiology ; Phosphorylation ; Proto-Oncogene Proteins c-met ; metabolism ; RNA, Messenger ; analysis ; Signal Transduction ; physiology ; Vascular Endothelial Growth Factor A ; genetics

PURPOSE: Hepatocyte growth factor (HGF) and its receptor (HGFR/c-Met) regulate motility, mitogenesis, and morphogenesis in a cell type-dependent fashion. We report the role of HGF and c-Met on stress-induced ARPE-19 human retinal pigment epithelial (RPE) cells in this study. METHODS: The cells were cultured either with or without serum. Southern and Western blot analyses were done to determine the expression patterns of HGF/c-Met in serum-starved ARPE-19 cells. The cell proliferation pattern in serum-starved condition was analyzed using MTS assay. Inhibition level of cell proliferation was analyzed using a neutralizing monoclonal antibody against c-Met (2 microgram/ml). RESULTS: Abnormal cell proliferation and scattering of ARPE-19 cells was observed under serum starvation. HGF/c-Met were expressed in serum-starved ARPE-19 cells. ARPE-19 cell proliferation was also enhanced with recombinant HGF treatment. Neutralization against c-Met inhibited the proliferation of serum-deprived ARPE-19 by 64.5% (n=9, S.D. 5.5%). Serum starvation appears to induce epithelial-mesenchymal transition of ARPE-19 cells, resulting in scatter, and the expression of alpha-smooth muscle actin (alpha-SMA), a marker for fibrosis. CONCLUSIONS: In conclusion, c-Met induced under non-physiologic conditions has significant effects on the activation of RPE cells.
Blotting, Southern ; Blotting, Western ; Cell Movement/physiology ; Cell Proliferation ; Cells, Cultured ; Culture Media, Serum-Free ; *Gene Expression ; Hepatocyte Growth Factor/biosynthesis/*genetics ; Humans ; Mitosis/physiology ; Pigment Epithelium of Eye/cytology/*metabolism ; Polymerase Chain Reaction ; Proto-Oncogene Proteins c-met/biosynthesis/*genetics ; RNA/*genetics

OBJECTIVETo investigate the effect of ursodeoxycholic acid (UDCA) on liver regeneration after 70% partial hepatectomy (PH) in bile duct obstructive (BDO) rats.

METHODSWistar rats were randomly divided into N-PH group in which normal rats were operated with 70% PH, BDO-PH group in which 70% PH were operated after two week's BDO, and BDO-PH UDCA or sterile saline treatment group in which UDCA (15mg kg(-1) d(-1)) or saline was administrated during BDO and after 70% PH. The hepatic pathological changes were observed. BrdU labeling of hepatocytes, the mRNA expression of intrahepatic hepatocyte growth factor (HGF) and its receptor (Met gene) after 70% PH were measured by immunohistochemical analysis and RT-PCR, respectively.

RESULTSImprovements of hepatic function and pathological changes were induced by UDCA administration after BDO. The expression of hepatic HGF/Met mRNA after 70% PH in BDO-PH UDCA treatment group rats was significantly increased compared with N-PH group rats (P<0.05), BrdU peak labelling of hepatocytes (59.39% +/- 10.82%) in BDO-PH UDCA treatment group rats was significantly higher than that (36.22% +/- 8.37%) in BDO-PH group rats (t=4.149, P<0.01) and without significance compared with N-PH group rats (68.64% +/- 11.26%, t=1.451, P >0.05).

CONCLUSIONSUDCA promotes liver regeneration after 70% PH in BDO rats by remission of hepatic pathological changes and elevating hepatic mRNA expression of HGF and Met.

Animals ; Cholestasis ; genetics ; physiopathology ; surgery ; Gene Expression Regulation ; drug effects ; Hepatectomy ; Hepatocyte Growth Factor ; genetics ; Liver ; physiology ; surgery ; Liver Regeneration ; drug effects ; Male ; Proto-Oncogene Proteins c-met ; genetics ; RNA, Messenger ; drug effects ; genetics ; metabolism ; Rats ; Rats, Wistar ; Ursodeoxycholic Acid ; pharmacology