Identification of the N-terminal residue of the heavy chain of both native and recombinant human hepatocyte growth factor

Yoshiyama, Yoshiko; Arakaki, Naokatu; Naka, Daiji; Takahashi, Kazuhiro; Hirono, Shuichi; Kondo, Jun; Nakayama, Hiroyuki; Gohda, Eiichi; Kitamura, Naomi; Tsubouchi, Hirohito; Ishii, Takuro; Hishida, Tadashi; Daikuhara, Yasushi

doi:10.1016/0006-291x(91)91616-k

Cited by 56 publications

(18 citation statements)

References 11 publications

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“…Recombinant human HGF (rhHGF) was prepared as described previously. 26 rhHGF was dissolved in 10 mmol/L phosphate buffer (pH 7.4), containing 0.7 mol/L NaCl and 0.05% bovine serum albumin (Sigma Chemical Co., St. Louis, MO), with the final concentration adjusted to 1 mg/mL. In this model, 70% hepatectomy was found to be lethal when performed within 5 days after the last DMN injection in our preliminary study.…”

Section: Animalsmentioning

confidence: 99%

Portal branch ligation with a continuous hepatocyte growth factor supply makes extensive hepatectomy possible in cirrhotic rats

et al. 1998

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In a cirrhotic liver, the regenerative ability and specific functions are so impaired that excessive resection easily complicates postoperative liver dysfunction, which frequently leads to life-threatening multiple-organ failure. Hepatocyte growth factor (HGF), first identified as the most potent stimulator of DNA synthesis in primary hepatocytes, not only stimulates liver regeneration, but also accelerates hepatic function, improves fibrosis, and protects liver cells against injury. Therefore, we investigated the efficacy of preoperative portal branch ligation (PBL) (which can induce compensatory hypertrophy of the unaffected lobes) combined with a continuous HGF supply in the performance of extensive hepatectomy in cirrhotic rats. Cirrhosis was induced by intraperitoneal injections of dimethylnitrosamine (DMN) three times per week for 3 weeks. Five days after the last injection, when 70% hepatectomy is lethal, the rats underwent portal ligation of the left lateral and median branches (corresponding to approximately 70% of the total volume of the liver). Simultaneously, they were continuously treated with either recombinant human HGF (rhHGF) or vehicle from an intraperitoneally implanted osmotic pump. Four days after the portal ligation, the occluded lobes were resected. The HGF treatment rapidly increased both the wet weight of the unoccluded lobes and the hepatocellular DNA synthesis. The blood chemical analysis indicated that HGF significantly suppressed the posthepatectomy liver dysfunction. Most importantly, the HGF treatment markedly improved the survival rate of the rats at 48 hours after the major hepatectomy. In conclusion, PBL combined with a continuous HGF supply makes extensive hepatectomy possible in cirrhotic rats, mainly by promoting the hypertrophy of the unaffected lobes. (HEPATOLOGY 1998;28:756-760.)Most of the primary hepatocellular carcinomas (HCC) reported in Japan are associated with chronic hepatitis or cirrhosis. 1 Although nonsurgical therapeutic options such as percutaneous ethanol injection therapy and transcatheter arterial embolization have been developed, surgical resection still plays a central role in the treatment of HCC. However, the regenerative ability and specific functions of a cirrhotic liver are so impaired that patients with HCC are at a high risk of postoperative liver failure, when resected over the extent of the safely resectable limit. 2 This serious complication, if uncontrolled, frequently leads to life-threatening multipleorgan failure. Although reducing the hepatic volume to be resected would lower the incidence of this complication, it might raise the risk of intrahepatic recurrence, and increase the number of patients who could not undergo curative surgeries. Therefore, the enlargement of the safely resectable limit in a cirrhotic liver has been an important goal to improve the survival rate of patients with HCC.Preoperative percutaneous transhepatic portal embolization (PTPE), a modification of portal branch ligation (PBL), [3][4][5] has been used clinically t...

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Section: Animalsmentioning

confidence: 99%

Portal branch ligation with a continuous hepatocyte growth factor supply makes extensive hepatectomy possible in cirrhotic rats

et al. 1998

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“…Recombinant human HGF was prepared and purified as described previously (33). Other materials used in this study were described previously (2,22).…”

Section: Methodsmentioning

confidence: 99%

Involvement of Oxidative Stress in Tumor Cytotoxic Activity of Hepatocyte Growth Factor/Scatter Factor

Arakaki¹,

Kajihara²,

Arakaki³

et al. 1999

Journal of Biological Chemistry

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In this study, we show that N-acetylcysteine (NAC), a precursor of glutathione and an intracellular free radical scavenger, almost completely prevented hepatocyte growth factor (HGF)-suppressed growth of Sarcoma 180 and Meth A cells, and HGF-induced apoptosis, assessed by DNA fragmentation, and increase in caspase-3 activity, in Sarcoma 180 cells. The reduced form of glutathione also prevented HGF-suppressed growth of the cells as effective as NAC. Ascorbic acid partially prevented the effect of HGF, but other antioxidants such as superoxide dismutase, catalase, and vitamin E, and the free radical spin traps N-t-butyl-␣-phenylnitrone and 3,3,5,5-tetramethyl-1-pyrroline-1-oxide did not have protective effects. HGF caused morphological changes of the cells, many cells showing condensation and rounding, and enhanced the generation of intracellular reactive oxygen species (ROS) as judged by flow cytometric analysis using 2,7-dichlorofluorescein diacetate. NAC completely prevented both HGF-induced morphological changes and the enhancement of ROS generation in the cells. However, NAC did not prevent the HGF-induced scattering of Madin-Darby canine kidney cells. To our knowledge, this is the first report that HGF stimulates the production of ROS, and our results suggest the involvement of oxidative stress in the mechanism by which HGF induces growth suppression of tumor cells.Hepatocyte growth factor (HGF), 1 which was initially isolated as a potent mitogen of hepatocytes in primary culture (1, 2), is now known to be a broad-spectrum mitogen of a variety of cell types including melanocytes and endothelial and epithelial cells (3). HGF has been found to be identical with the "scatter factor" (4), which dissociates and increases the motility of epithelial cells. In addition to these activities, HGF induces branching tubule formation of Madin-Darby canine kidney epithelial cells in a three-dimensional collagen gel matrix (5). HGF is a potent angiogenic factor in vivo (6, 7) and is involved in organ regeneration (8) and tumorigenesis (9). All these effects of HGF are mediated by the HGF receptor, identified as the product of the c-met proto-oncogene (10, 11). During embryogenesis, c-met is expressed in epithelial components of various organs, while hgf is expressed in the adjacent mesenchyme (12). Embryos of mutant mice homozygous for the hgf gene die due to abnormal development of the placenta or both the placenta and liver (13,14). Likewise, c-met-deficient embryos lack muscles of the limbs, diaphragm, and tip of the tongue, all derived from migratory precursors (15). Thus, HGF is now understood as a multifunctional cytokine that mediates epithelial-mesenchymal interactions.In addition to its mitogenic activity, HGF has tumor cytotoxic activity, which suppresses growth of several tumor cell lines including Sarcoma 180 cells, Meth A mouse sarcoma cells, and Hep G2 human hepatoblastoma cells (16 -18). Moreover, HGF has been shown to inhibit the growth of hepatocellular carcinoma cells in vivo and c-myc-induced hepatocarcin...

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“…Recently, cytotoxic and cytostatic activities of SF/HGF have been reported (15)(16)(17). Mature SF/HGF of human fibroblasts is a 92-kDa disulfide-linked heterodimer that is translated as a single-chain precursor and then proteolyzed at a dibasic site; the heavy chain (62 kDa) consists of an N-terminal region that could form a hairpin structure followed by four kringle modules; the light chain (32/34 kDa) is homologous to serine proteases but has no demonstrable protease activity due to the absence of two of three critical residues within the catalytic site (2,4,6,7,(18)(19)(20). In human fibroblasts two major transcripts of SF/HGF [6 and 3 kilobases (kb)] exist due to differential poly(A) site usage (4).…”

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confidence: 99%

A functional domain in the heavy chain of scatter factor/hepatocyte growth factor binds the c-Met receptor and induces cell dissociation but not mitogenesis.

Hartmann¹,

Naldini²,

Weidner³

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

208

153

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Identification of the N-terminal residue of the heavy chain of both native and recombinant human hepatocyte growth factor

Cited by 56 publications

References 11 publications

Portal branch ligation with a continuous hepatocyte growth factor supply makes extensive hepatectomy possible in cirrhotic rats

Portal branch ligation with a continuous hepatocyte growth factor supply makes extensive hepatectomy possible in cirrhotic rats

Involvement of Oxidative Stress in Tumor Cytotoxic Activity of Hepatocyte Growth Factor/Scatter Factor

A functional domain in the heavy chain of scatter factor/hepatocyte growth factor binds the c-Met receptor and induces cell dissociation but not mitogenesis.

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