scholarly journals Ovulation sources coagulation protease cascade and hepatocyte growth factor to support physiological growth and malignant transformation

2021 ◽  
Author(s):  
Hsuan-Shun Huang ◽  
Pao-Chu Chen ◽  
Sung-Chao Chu ◽  
Ming-Hsun Lee ◽  
Chi-Ya Huang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Malignant Transformation ◽  
Blood Circulation ◽  
Tissue Injury ◽  
Serous Carcinoma ◽  
Transient Event ◽  
Transformation Activity ◽  
Hepatocyte Growth

The fallopian tube fimbrial epithelium (FTE), which is exposed to the follicular fluid (FF) contents of ovulation, is regarded as the main origin of ovarian high-grade serous carcinoma (HGSC). Previously, we found that growth factors in FF, such as IGF2, are responsible for the malignant transformation of FTE. However, ovulation is a monthly transient event, whereas carcinogenesis requires continuous, long-term exposure. Here, we found the transformation activity of FF sustained for more than 30 days after drainage into the peritoneal fluid (PF). Hepatocyte growth factor (HGF), activated through the ovulation injury-tissue factor-thrombin-HGFA-HGF cleavage cascade confers a sustained transformation activity to FTE, HGSC. Physiologically, the high reserve of the coagulation-HGF cascade sources a sustained level of HGF in PF, then to the blood circulation. This HGF axis promotes the growth of the corpus luteum and repair of tissue injury after ovulation.

scholarly journals A Potential Mechanism of Tumor Progression during Systemic Infections Via the Hepatocyte Growth Factor (HGF)/c-Met Signaling Pathway

2020 ◽  
Vol 9 (7) ◽  
pp. 2074 ◽  
Author(s):  
Hironori Tsujimoto ◽  
Hiroyuki Horiguchi ◽  
Yusuke Matsumoto ◽  
Risa Takahata ◽  
Nariyoshi Shinomiya ◽  
...  
Keyword(s):  
Growth Factor ◽  
Liver Metastasis ◽  
Hepatocyte Growth Factor ◽  
Liver Metastases ◽  
Signaling Pathway ◽  
Tumor Cells ◽  
High Serum ◽  
Term Survival ◽  
Hepatocyte Growth

Background: Increasing evidence has demonstrated that postoperative infectious complications (PICs) after digestive surgery are significantly associated with negative long-term outcomes; however, precise mechanisms of how PICs affect the poor long-term survival remain unclear. Here, we focused on the hepatocyte growth factor (HGF)/c-Met signaling pathway as one of those mechanisms. Methods: In the clinical setting, serum HGF levels were measured in the patients with sepsis and those with PICs after undergoing esophagectomy. Using a liver metastasis mouse model with cecal ligation and puncture (CLP), expressions of HGF and the roles of the HGF/c-Met pathway in the progression of tumor cells were examined. Results: Serum HGF levels were very high in the patients with intra-abdominal infection on postoperative days (PODs) 1, 3, and 5; similarly, compared to the patients without PICs, those with PICs had significantly higher serum HGF levels on 1, 3, and 5 days after esophagectomy. The patients with PICs showed poorer overall survival than those without PICs, and the patients with high serum HGF levels on POD 3 showed poorer prognosis than those with low HGF levels. Similarly, at 24 and 72 h after operation, serum levels of HGF in CLP mice were significantly higher than those in sham-operated mice. Intraperitoneal injection of mouse recombinant HGF significantly promoted liver metastases in sham-operated mice on 14 days after surgery. Knocking down c-Met expression on NL17 tumor cells by RNAi technology significantly inhibited the promotion of CLP-induced liver metastases. Conclusions: Infections after surgery increased serum HGF levels in the clinical as well as experimental settings. Induction of high serum HGF levels by CLP promoted liver metastases in a murine liver metastasis model, suggesting the involvement of the HGF/c-Met signaling pathway in tumor promotion mechanisms. Thus, targeting the HGF/c-Met signaling pathway may be a promising approach for malignant tumors, particularly in the patients with PICs.

scholarly journals Long-term effects of hepatocyte growth factor gene therapy in rat myocardial infarct model

Gene Therapy ◽  
2011 ◽  
Vol 19 (8) ◽  
pp. 836-843 ◽  
Author(s):  
Y-N Jin ◽  
M Inubushi ◽  
K Masamoto ◽  
K Odaka ◽  
I Aoki ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Myocardial Infarct ◽  
Long Term Effects ◽  
Factor Gene ◽  
Growth Factor Gene ◽  
Myocardial Infarct Model ◽  
Hepatocyte Growth

The expression of hepatocyte growth factor (HGF) and c-Met in uterine serous carcinoma

2011 ◽  
Vol 121 (1) ◽  
pp. 218-223 ◽  
Author(s):  
Erin A. Bishop ◽  
Ernst R. Lengyel ◽  
S. Diane Yamada ◽  
Anthony Montag ◽  
Sarah M. Temkin
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Serous Carcinoma ◽  
Uterine Serous Carcinoma ◽  
Hepatocyte Growth

scholarly journals Progress of Gene Therapy in Cardiovascular Disease

Hypertension ◽  
2020 ◽  
Vol 76 (4) ◽  
pp. 1038-1044
Author(s):  
Munehisa Shimamura ◽  
Hironori Nakagami ◽  
Fumihiro Sanada ◽  
Ryuichi Morishita
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Dna Vaccine ◽  
Critical Limb Ischemia ◽  
Dna Vaccines ◽  
Limb Ischemia ◽  
Hepatocyte Growth

Gene therapy has been extensively studied in peripheral and cardiac ischemia, heart and vein graft failure, and dyslipidemia, but most clinical trials failed to show their efficacies despite good outcomes in preclinical studies. So far, 2 gene therapies for dyslipidemia and one for critical limb ischemia in peripheral artery disease have been approved. In critical limb ischemia, gene therapy using proangiogenic factors has emerged as a novel therapeutic modality for promoting angiogenesis. Initial researches mainly focused on vascular endothelial growth factor, fibroblast growth factor, or hepatocyte growth factor. After the favorable results of basic research, several phase I and II clinical trials of these proangiogenic factors have shown promising results. However, only a phase III clinical trial of the intramuscular injection of hepatocyte growth factor plasmid DNA has shown successful outcomes, and it was recently approved in Japan for treating patients with critical limb ischemia who have ulcers and for whom no alternative therapeutic options are available. DNA vaccine is another promising modality of gene therapy. An antitumor vaccine suppressing angiogenesis through the inhibition of proangiogenic factors and an antihypertensive vaccine inhibiting the renin–angiotensin system are representative DNA vaccines. The advantage of DNA vaccine is its long-term effectiveness with a few vaccinations; however, the benefits and risks, such as adverse T-cell reaction against self-antigen or long-term side effects, of DNA vaccines should be carefully evaluated. In this review, we discuss the recent advances in proangiogenic gene therapy for critical limb ischemia and DNA vaccine for hypertension.

scholarly journals Hepatocyte Growth Factor Activator: A Proteinase Linking Tissue Injury with Repair

2018 ◽  
Vol 19 (11) ◽  
pp. 3435 ◽  
Author(s):  
Tsuyoshi Fukushima ◽  
Shuichiro Uchiyama ◽  
Hiroyuki Tanaka ◽  
Hiroaki Kataoka
Keyword(s):  
Stem Cells ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Tissue Injury ◽  
Current Knowledge ◽  
Coagulation Factor ◽  
Factor Xii ◽  
Proteolytic Activation ◽  
Hepatocyte Growth

Hepatocyte growth factor (HGF) promotes pleiotropic signaling through its specific receptor tyrosine kinase, MET. As such, it has important roles in the regeneration of injured tissues. Since HGF is produced mainly by mesenchymal cells and MET is expressed in most epithelial, endothelial and somatic stem cells, HGF functions as a typical paracrine growth factor. HGF is secreted as an inactive precursor (proHGF) and requires proteolytic activation to initiate HGF-induced MET signaling. HGF activator (HGFAC) is a serum activator of proHGF and produces robust HGF activities in injured tissues. HGFAC is a coagulation factor XII-like serine endopeptidase that circulates in the plasma as a zymogen (proHGFAC). Thrombin, kallikrein-related peptidase (KLK)-4 or KLK-5 efficiently activates proHGFAC. The activated HGFAC cleaves proHGF at Arg494-Val495, resulting in the formation of the active disulfide-linked heterodimer HGF. Macrophage stimulating protein, a ligand of RON, is also activated by HGFAC in vivo. Although HGFAC functions primarily at the site of damaged tissue, a recent report has suggested that activated HGFAC relays a signal to stem cells in non-injured tissues via proHGF activation in the stem cell niche. This review focuses on current knowledge regarding HGFAC-mediated proHGF activation and its roles in tissue regeneration and repair.

scholarly journals Ovulation sources coagulation protease cascade and hepatocyte growth factor to support physiological growth and malignant transformation

Neoplasia ◽  
2021 ◽  
Vol 23 (11) ◽  
pp. 1123-1136
Author(s):  
Hsuan-Shun Huang ◽  
Pao-Chu Chen ◽  
Sung-Chao Chu ◽  
Ming-Hsun Lee ◽  
Chi-Ya Huang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Malignant Transformation ◽  
Hepatocyte Growth

scholarly journals Acute Hepatocyte Growth Factor Treatment Induces Long-Term Neuroprotection and Stroke Recovery via Mechanisms Involving Neural Precursor Cell Proliferation and Differentiation

2010 ◽  
Vol 31 (5) ◽  
pp. 1251-1262 ◽  
Author(s):  
Thorsten R Doeppner ◽  
Britta Kaltwasser ◽  
Ayman ElAli ◽  
Anil Zechariah ◽  
Dirk M Hermann ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Neuronal Cell ◽  
Matrix Metalloproteases ◽  
Neural Precursor ◽  
Long Term Effects ◽  
Neurologic Recovery ◽  
Hepatocyte Growth

Hepatocyte growth factor (HGF) is an interesting candidate for acute stroke treatment as shown by continuous infusion or gene delivery protocols. However, little is known about HGF-mediated long-term effects. The present study therefore analyzed long-term effects of an acute intrastriatal HGF treatment (5 μg) after a 45-minute stroke, with regard to brain injury and neurologic recovery. Hepatocyte growth factor induced long-term neuroprotection as assessed by infarct volume and neuronal cell death analysis for as long as 4 weeks after stroke, which was associated with sustained neurologic recovery as evidenced by corner-turn and tight-rope tests. Analyzing underlying mechanisms of HGF-induced sustained neuroprotection, enhanced cell proliferation followed by increased neuronal differentiation of neural precursor cells (NPCs) was observed in the ischemic striatum of HGF-treated mice, which persisted for up to 4 weeks. In line with this, HGF promoted neurosphere formation as well as proliferation of NPC and decreased caspase-3-dependent hypoxic injury in vitro. Preservation of blood—brain barrier integrity 24 hours after stroke was furthermore noticed in animals receiving HGF, which was associated with the inhibition of matrix metalloproteases (MMP)-2 and MMP-9 at 4 and 24 hours, respectively. We suggest that sustained recruitment of proliferating cells together with improved neurovascular remodeling provides an explanation for HGF-induced long-term neuroprotection.

scholarly journals Hepatocyte growth factor regulates neovascularization in developing fat pads

2014 ◽  
Vol 306 (2) ◽  
pp. E189-E196 ◽  
Author(s):  
Heather M. White ◽  
Anthony J. Acton ◽  
Malgorzata M. Kamocka ◽  
Robert V. Considine
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Fat Pad ◽  
Clonal Line ◽  
Important Regulator ◽  
Vascular Structures ◽  
Hepatocyte Growth ◽  
Fat Pads ◽  
Over Time

In this study, we used lentiviral-delivered shRNA to generate a clonal line of 3T3-F442A preadipocytes with stable silencing of hepatocyte growth factor (HGF) expression and examined the long-term consequence of this modification on fat pad development. HGF mRNA expression was reduced 94%, and HGF secretion 79% ( P < 0.01), compared with preadipocytes treated with nontargeting shRNA. Fat pads derived from HGF knockdown preadipocytes were significantly smaller ( P < 0.01) than control pads beginning at 3 days postinjection (0.022 ± 0.003 vs. 0.037 ± 0.004 g), and further decreased in size at day 7 (0.015 ± 0.004 vs. 0.037 ± 0.003 g) and day 14 (0.008 ± 0.002 vs. 0.045 ± 0.007 g). Expression of the endothelial cell genes TIE1 and PECAM1 increased over time in control fat pads (1.6 ± 0.4 vs. 11.4 ± 1.7 relative units at day 3 and 14, respectively; P < 0.05) but not in HGF knockdown fat pads (1.1 ± 0.5 vs. 5.9 ± 2.2 relative units at day 3 and 14). Contiguous vascular structures were observed in control fat pads but were much less developed in HGF knockdown fat pads. Differentiation of preadipocytes to mature adipocytes was significantly attenuated in HGF knockdown fat pads. Fat pads derived from preadipocytes with knockdown of the HGF receptor c-MET were smaller than control pads at day 3 postinjection (0.034 ± 0.002 vs. 0.049 ± 0.004 g; P < 0.05), and remained the same size through day 14. c-MET knockdown fat pads developed a robust vasculature, and preadipocytes differentiated to mature adipocytes. Overall these data suggest that preadipocyte-secreted HGF is an important regulator of neovascularization in developing fat pads.

scholarly journals Hepatocyte growth factor stimulates neutrophil degranulation but not respiratory burst

1993 ◽  
Vol 2 (2) ◽  
pp. 129-133 ◽  
Author(s):  
I. C. Kowanko ◽  
A. Ferrante ◽  
T. Nakamura
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Respiratory Burst ◽  
Tissue Injury ◽  
Cell Types ◽  
Neutrophil Function ◽  
Enzyme Release ◽  
Neutrophil Degranulation ◽  
Different Cell Types ◽  
Hepatocyte Growth

Neutrophil function is regulated in part by cytokines with growth factor activities for different cell types. Hepatocyte growth factor (HGF) is a cytokine produced during injury to the liver and other organs. Neutrophils are numerous in such tissue injury sites and may be influenced by HGF. In the present study the effect of HGF on neutrophils was investigated. The data show that HGF at 1–10 ng/ml increased lysosomal enzyme release from both specific and azurophilic granules of cytochalasin-B treated neutrophils. The release of specific granule contents in response to N-formyl-methionyl-leucylphenylalanine was also increased by HGF. In contrast there were no significant effects of HGF on neutrophil respiratory burst, adherence or locomotion. It is concluded that HGF modulates neutrophil granule exocytosis.

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