Hepatocyte growth factor inhibits growth of hepatocellular carcinoma cells.

Shiota, Goshi; Rhoads, David B.; Wang, Yichen; Nakamura, Toshikazu; Schmidt, Emmett V.

doi:10.1073/pnas.89.1.373

Cited by 240 publications

(168 citation statements)

References 25 publications

(25 reference statements)

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“…It has been reported that HGF inhibits the growth of various hepatoma cell lines in vitro 39 and in vivo. 40 Shiota et al demonstrated that no liver tumors occurred in HGF transgenic mice for more than 18 months. 15 In contrast, Sakata et al recently reported that more than half of the HGF transgenic mice studied above 17 months of age developed benign and/or malignant tumors.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…Recent efforts to find substances that inhibit the activation of c-Met are thus expected to lead to suppression of the malignant transformation of cells. However, HGF has an opposing effect on the regulation of cell proliferation in accordance with cell type: it promotes the proliferation of some tumor cells, but suppresses that of others (3,4). This opposing effect is considered to depend on differences in the downstream pathways of c-Met (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

“…However, HGF has an opposing effect on the regulation of cell proliferation in accordance with cell type: it promotes the proliferation of some tumor cells, but suppresses that of others (3,4). This opposing effect is considered to depend on differences in the downstream pathways of c-Met (3)(4)(5). Thus, elucidation of the pathways responsible for the effect is expected to lead to new drugs for the suppression of tumor growth.…”

Section: Introductionmentioning

confidence: 99%

ERK-Dependent Downregulation of Skp2 Reduces Myc Activity with HGF, Leading to Inhibition of Cell Proliferation through a Decrease in Id1 Expression

Bian²,

Takizawa³

et al. 2013

Molecular Cancer Research

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Hepatocyte growth factor (HGF) has an inhibitory effect on human HepG2 hepatoma cell proliferation. Previously, it was shown that HGF treatment downregulated Id1 and upregulated p16 INK4a in an ERK-dependent manner, leading to the inhibition of cellular proliferation. Here, new insight suggests that Skp2, an SCF complex component and potential prognosticator in cancer, is downregulated by injection of HGF into established HepG2 xenograft tumors. The downregulation was evident at both the mRNA and protein level and in an ERK-dependent manner. Critically, high expression of Skp2 restored HGF-inhibited cell proliferation, indicating that the inhibitory effect of HGF required the downregulation of Skp2. However, downregulation was not involved in the HGFinduced upregulation of a CDK inhibitor, p27 Kip1 , a known SCF-Skp2 target. Instead, data revealed that Skp2 regulated Myc activity, which has oncogenic potential in the generation of hepatocellular carcinoma. Elevated expression of Skp2 or a mutant that is unable to associate with the SCF complex was capable of activating Myc, suggesting that Skp2 does not act on Myc as a component of the SCF complex, and thus functions as an activator of Myc independent of its role in ubiquitination. Furthermore, Skp2 regulated Id1 expression by regulating Myc activity, and the regulation of Skp2 is involved in the activity of p16 promoter through regulation of Id1 expression. Overall, these mechanistic findings provide the first evidence that ERK-dependent downregulation of Skp2 reduced Myc activity, leading to HGF-induced inhibition of cell proliferation through decreased Id1 expression.

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“…[8][9][10] However, studies using human HCC cell lines in vitro show that HGF-SF inhibits cells growth. 11,12 Similarly, in animal studies in which HCC is induced using diethylnitrosamine, infusion of HGF resulted in decreased cell proliferation by up to 50%. 13 HGF-SF has also been reported to induce proapoptotic genes in human HCC cells in culture.…”

mentioning

confidence: 99%

Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of hepatocellular carcinoma

et al. 2002

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Hepatocyte growth factor inhibits growth of hepatocellular carcinoma cells.

Cited by 240 publications

References 25 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

ERK-Dependent Downregulation of Skp2 Reduces Myc Activity with HGF, Leading to Inhibition of Cell Proliferation through a Decrease in Id1 Expression

Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of hepatocellular carcinoma

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