Overexpression of c-met Protooncogene Product and Raised Ki67 Index in Hepatocellular Carcinomas With Respect to Benign Liver Conditions (original) (raw)

Liver hepatocyte growth factor does not always correlate with hepatocellular proliferation in human liver lesions: its specific receptor c-met does

Hepatology (Baltimore, Md.), 1996

Increased levels of expression of hepatocyte growth factor (HGF) and its specific receptor c-met have been shown in the liver of several benign and malignant pathologies, both in experimental models and humans. We investigated by immunohistochemistry the presence of both HGF and c-met protoocogene product (c-met pp) in 20 hepatocellular carcinomas (HCCs), 5 focal nodular hyperplasias (FNHs), 4 cases of fulminant hepatitis (FH), and 1 case of regenerated liver. The c-met protooncogene product was expressed in all cases with marked overexpression in the HCCs and in ductular metaplasia. HGF was detected in the Ito cells of all cases and in neoplastic hepatocytes of 9 of 20 HCCs (45%). The proliferative index of each lesion was evaluated by means of the polyclonal antibody anti-cyclin A. When the level of expression of HGF and c-met protooncogene product with the percentage of cyclin A+ nuclei were compared, the closest relationship was between c-met protooncogene product and cyclin A+ nuclei were compared, the closest relationship was between c-met protooncogene product and cyclin A. In 11 of 20 HCCs (55%), there wa no correlation between HGF positivity and cyclin A. This seems to suggest that, independently of the levels of native liver HGF, c-met protooncogene product is the most active modulator of liver cell proliferation.

u-PA and c-MET mRNA expression is co-ordinately enhanced while hepatocyte growth factor mRNA is down-regulated in human hepatocellular carcinoma

International Journal of Cancer, 2000

Hepatocyte growth factor/scatter factor (HGF/SF) is one of the most important humoral mediators of liver regeneration. It is potentially related to molecular mechanisms of hepatocarcinogenesis via a paracrine system involving its cellular receptor, c-met. In this study, the expression patterns of HGF and c-met were evidenced by multiplex RT-PCR in different specimens of human hepatic tissues (n ‫؍‬ 71). A significant increase of c-met mRNA expression was detected in hepatitis (P ‫؍‬ 0.001), cirrhosis (P ‫؍‬ 0.006), and hepatocellular carcinoma (HCC) tissue (P ‫؍‬ 0.003) compared with normal parenchyma and steatosis. HGF mRNA expression was significantly higher only in hepatitis (P ‫؍‬ 0.01). Overexpression of c-met mRNA and under-expression of HGF mRNA were detected in the HCCs compared with the corresponding peri-tumoral tissues. Neither HGF nor c-met expression was related to age, sex, tumor size, grading, presence of pseudocapsula, and proliferative activity of the malignant hepatocytes. A significant inverse correlation was found between c-met mRNA expression level and survival (in months) of patients (P ‫؍‬ 0.007), as previously shown for urokinase-type plasminogen activator (u-PA) mRNA (P ‫؍‬ 0.027). In addition, c-met mRNA expression was strictly associated with u-PA mRNA level in HCC samples (P ‫؍‬ 0.001). These data show that a loss of balance concerning HGF, c-met, and u-PA mRNA expression occurs during hepatocarcinogenesis. Particularly, up-regulation of c-met and u-PA mRNA transcription appears to be coordinately regulated, and their levels of expression are inversely correlated with survival; they must therefore play an important role in the development and progression of human HCC and may also be relevant prognostic markers. Int.

Tumorigenesis induced by coexpression of human hepatocyte growth factor and the human met protooncogene leads to high levels of expression of the ligand and receptor

Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research, 1993

We have previously shown that, in mouse NIH/3T3 cells, it is necessary to coexpress the gene for human hepatocyte growth factor/scatter factor (HGF/SFhu) with its receptor, the human met protooncogene (methu), to activate the transforming activity of the receptor (S. Rong, M. Bodescot, D. Blair, T. Nakamura, K. Mizuno, M. Park, A. Chan, S. Aaronson, and G. F. Vande Woude, Mol. Cell. Biol., 12: 5152-5158, 1992). In this study, we report that exceptionally high levels of the ligand and its receptor are expressed in tumor cell explants after several tumor passages through nude mice. Confluent tumor cells explanted after the second passage in nude mice can express 1700 units/ml/10(6) cells/72 h of scatter activity as determined in Madin-Darby canine kidney cell scatter assays. The motogenic factor produced by these cells is easily purified by heparin-Sepharose chromatography, and the purified factor efficiently induces tyrosine phosphorylation of Methu in YaOvBix2NMA human ovarian carci...

Co-expression and regulation ofMet andRon proto-oncogenes in human hepatocellular carcinoma tissues and cell lines

Hepatology, 1997

The met proto-oncogene was originally identified as a Met and ron proto-oncogenes encode the cell surface receptransforming gene activated after in vitro treatment of a hutors for hepatocyte growth factor (HGF) and hepatocyte man osteosarcoma cell line with the chemical carcinogen growth factor-like (HLP) protein, respectively, and induce mi-N-methyl-N-nitro-N-nitrosoguanidine. 1 Molecular cloning togenesis, motogenesis, morphogenesis, and metastatic activstudies revealed that it encodes a protein tyrosine kinase that ity in various cell types. Overexpression of met in human is now known as the cell surface receptor for hepatocyte carcinoma has been reported by several groups including ours; growth factor (HGF). 2,3 The mature Met protein is a heterohowever, the mechanisms that control met gene expression dimeric protein of approximately 190 kd, containing an a are thus far unclear. The present study focuses on the expresand a b chain, the latter of which is the transmembrane sion and regulation of the Met and Ron receptors in human subunit possessing an extracellular domain and a cytoplasmic hepatocellular carcinoma (HCC). We report here that abnordomain that contributes to the tyrosine kinase activity upon mal expression of met and ron proteins occurs in some cases activation. After binding to its ligand HGF, Met mediates of human HCC. Using several HCC cell lines as a model diverse biological responses such as mitogenesis, motogensystem, we show that HGF, as well as other cytokines, such esis, or morphogenesis as well as cytotoxicity or growth inhias epidermal growth factor (EGF), interleukin-1 (IL-1), inbition, on a broad spectrum of cellular targets. 4,5 Under physterleukin-6 (IL-6), and tumor necrosis factor a (TNF-a), iniological conditions, met is mainly expressed in the epithelial duce met and ron expression. Using several chimeric concompartment of various tissues. The HGF ligand, on the structs consisting of various lengths of the met promoter other hand, is a factor of mesenchymal origin. Therefore, region fused to the reporter gene of chloramphenicol acetyl HGF and Met constitute a paracrine signaling system that is transferase (CAT), and by performing transient transfection of these constructs into HepG2 cells, we show that induction believed to play a crucial role in development and organogenof met gene expression by HGF and other cytokines is, at esis. 6-8 Met expression is induced in response to tissue releast in part, through up-regulation of met gene promoter moval or damage such as liver regeneration or renal and lung activity. The DNA region conferring responsiveness to cytoinjury, and met is considered to be an important mediator kine induction was located within 0.2 kb of the met core in the wound healing and tissue repair processes. 9-11 Overexpromoter. Interestingly, EGF did not stimulate met promoter pression of the met gene has been observed in several human activity in any of the met-CAT chimeric constructs. These tumors of epithelial origin as well as in sarcoma tissues and results provide evidence that met and ron are modulated in cell lines. It is overexpressed and amplified in a gastric carcithe liver by a similar cytokine network. In the case of met noma cell line, GTL-16, and its expression is enhanced in expression, the 0.2-kb region in the met gene promoter may pancreatic, colorectal, gastric and thyroid cancer, and in melplay an important role in mediating its gene induction in anomas. 12-16 Co-transfection of met with its ligand HGF into response to HGF and other cytokines. Our results also suggest NIH3T3 cells was reported to provoke the transformation of that unregulated expression of met and ron may be associated these cells via an autocrine mechanism. 17-19 In the study of with pathological conditions, such as HCC, in the liver. (HEPAhepatocellular carcinoma (HCC), researchers focused on the TOLOGY 1997;26:59-66.) expression of met in HCC and the potential role of this tyrosine kinase receptor in tumor development and progression. 20-22 Some groups have reported that met expression (messenger RNA [mRNA]/protein) is higher in certain cases Abbreviations: HGF, hepatocyte growth factor; HCC, hepatocellular carcinoma; mRNA, messenger RNA; HLP, hepatocyte growth factor-like protein; MSP, macro-of HCC and have suggested that met expression may be correphage-stimulating protein; EGF, epidermal growth factor; IL-1, interleukin-1; IL-6, lated with cancer cell differentiation. interleukin-6; TNF-a; tumor necrosis factor a; MEM, minimum essential medium; Recently, several other genes have been identified that cDNA, complementary DNA; RT-PCR, reverse-transcription polymerase chain reaction; share structural similarities with met and are proposed to be CAT, chloramphenicol acetyl transferase.

Hepatoma-Derived Growth Factor: Its Possible Involvement in the Progression of Hepatocellular Carcinoma

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.

Hepatoma-Derived Growth Factor Is a Novel Prognostic Factor for Hepatocellular Carcinoma

Annals of Surgical Oncology, 2006

Proliferating activity as mitotic count is generally accepted as a major prognostic indicator for gastrointestinal stromal tumors (GISTs). Hepatoma-derived growth factor (HDGF) is a novel growth factor and elevated in several types of cancer. Our study was designed to elucidate the expression and prognostic role of HDGF in GISTs. A total 178 surgically resected CD117-positive GISTs specimens were collected for immunohistochemical analysis using antibodies against HDGF. The immunoreactivities were scored as labeling index (LI) and correlated with clinicopathologic parameters of GIST patients. The HDGF immunoreactivities were detected in both nucleus and cytoplasm of GISTs tissues. Besides, the nuclear and cytoplasmic HDGF was parallely upregulated in GISTs (p < 0.001). The nuclear HDGF LI were positively correlated with that of PCNA (p < 0.001) and Ki-67 (p < 0.001), tumor mitosis (p < 0.001), tumor sizes (p 5 0.007) and NIH risk categories (p < 0.001). In addition, the cytoplasmic HDGF LI were also positively correlated with that of PCNA (p 5 0.031) and Ki-67 (p 5 0.038), tumor sizes (p 5 0.003) and tumor mitosis (p 5 0.015). Patients with higher HDGF levels had earlier tumor recurrence and unfavorable outcome (p < 0.05). In addition to standard prognostic factors (NIH risk categories), the nuclear HDGF LI is an independent prognostic factor for disease free and overall survivals of GIST patients after operation. We conclude that HDGF is a novel prognostic factor for GIST patients.