Association Of Hepatocyte Growth Factor Research Articles

Association of hepatocyte growth factor gene polymorphisms with primary angle closure glaucoma from Lahore, Pakistan.

To determine the association of hepatocyte growth factor gene single nucleotide polymorphismsrs 5745718 and rs17427817 with primary angle closure glaucoma.. This case-control study was conducted at the Department of Biotechnology, Lahore College for Women University, Lahore, Pakistan, from August 2016 to September 2017. In this study seventy sporadic cases of primary angle closure glaucoma and sixty healthy controls were enrolled from different hospitals of the Lahore, Punjab. Blood samples were obtained from all the subjects. Genomic deoxyribonucleic acid was extracted by non-organic method. Two single nucleotide polymorphism (SNPs) rs5745718 and rs17427817 in Hepatocytes Growth Factor (HFG) gene were genotyped in patients and ethnically same healthy controls by using polymerase chain reaction restriction fragment length polymorphism (RFLP) assay. Data was analysed using SPSS (version20). Of the 130 subjects, 70(54%) were cases and 60(46%) controls. The mean age of the cases was 54±17 years (range: 13-85 years). The differences in genotype distribution were statistically significant for rs 5745718 (p=0.005 and p=0.009), while results were not significant for rs 17427817 (p=0.06 and p=0.09) between the cases and the controls. AC alleles were found to be protective while CC alleles were a risk factor for primary angle closure glaucoma in rs5745718 single nucleotide polymorphism.

Abstract P369: Hepatocyte Growth Factor is Positively Associated With Progression of Atherosclerosis: the Multi-Ethnic Study of Atherosclerosis

Introduction: Hepatocyte growth factor (HGF) is released in response to endothelial injury, and higher levels of circulating HGF are associated with atherosclerosis. However, the association of HGF with atherosclerosis progression is unknown. Hypothesis: Circulating HGF is positively associated with atherosclerosis progression, measured as progression of 1) carotid artery plaque and 2) coronary artery calcium (CAC). Methods: The Multi-Ethnic Study of Atherosclerosis is a large, population-based cohort study of adults aged 45-84 and free of clinical cardiovascular disease. Participants had HGF measured in serum at baseline (2000-02), and were followed for progression of carotid plaque and CAC through 2012. We defined CAC and carotid plaque progression as dichotomous variables (progression, no progression). Carotid plaque progression is an increase in the number of carotid plaques. We used the Hokanson method to define CAC progression as an increase of ≥ 2.5 mm 3 in the square root-transformed calcium volume score. Relative risk regression quantified the association between HGF and carotid plaque progression. Cox regression models using inverse-probability-of-attrition weights estimated the association of HGF with progression of CAC. All effect estimates are adjusted for potential confounding variables. Results: The cohort included 6714 Americans with HGF measurements: 2593 non-Hispanic white, 797 Chinese, 1848 black, and 1476 Hispanic Americans. In 3363 participants with measurements for both carotid plaque and HGF, each standard deviation (259 pg/ml) increase in HGF was associated with a 4% greater risk (95% CI: 1.01-1.07) of carotid plaque progression (n=1875), which did not differ by race/ethnicity (interaction p = 0.3). Out of 6714 participants with measurements for both CAC and HGF, 2994 had CAC progression during follow-up. The association of HGF with CAC progression differed by race/ethnicity (interaction p = 0.01). Each standard deviation increase of HGF was associated with a 10% greater risk of CAC progression in non-Hispanic white (95% CI: 1.05-1.16) and black Americans (95% CI: 1.03-1.17), while HGF was not associated with CAC progression in Chinese (p = 0.5) nor Hispanic (p = 0.7) American participants. Conclusions: Circulating HGF was associated with a modestly increased risk of atherosclerosis progression in this large and diverse population, with the strongest associations between HGF and CAC progression in non-Hispanic white and black Americans. Our results suggest that HGF may have utility as a marker of atherosclerosis progression in some populations.

Expression of c-MET in Invasive Meningioma.

Background:Meningiomas show high recurrence rates even after curative tumor removal. The invasiveness of meningiomas may contribute to their high recurrence rates. Recently, c-MET and hepatocyte growth factor (HGF) have been reported to be involved in cancer invasion.Methods:We examined the immunohistochemical expression of c-MET and HGF in 100 cases of patients with meningiomas who have undergone complete tumor removal.Results:c-MET-High and HGFHigh were found in 17% and 13% of meningiomas, respectively. Brain invasion was observed in 17.6% of c-MET-High meningiomas, but in only 2.4% of c-MET-Low meningiomas (p=.033). Bone/soft tissue invasion was observed in 23.5% of c-MET-High meningiomas and in 9.6% of c-MET-Low meningiomas (p=.119). HGF-High did not show statistical association with brain invasion or bone/soft tissue invasion. c-MET-High demonstrated shorter recurrence-free survival (RFS, 93.5±8.2 months vs 96.1±1.9 months); however, this difference was not statistically significant (p=.139). There was no association of HGF-High with RFS.Conclusions:This study demonstrates that c- MET-High is associated with brain invasion of meningiomas, and that c-MET expression may be a useful predictive marker for meningioma recurrence. Patients with invasive meningiomas with high expressions of c-MET may be good candidates for targeted therapy using c-MET inhibitors.

Inhibitory effect of c‐Met mutants on the formation of branching tubules by a porcine aortic endothelial cell line

The association of hepatocyte growth factor (HGF) with its high-affinity receptor (c-Met) has been shown to induce mitogenesis, motogenesis and morphogenesis in a variety of cell types. Various point mutations in c-Met have been identified in hereditary and sporadic papillary renal carcinomas as well as in other carcinomas. In the present study, we examined the effects of c-Met point mutations on the morphology of a porcine aortic endothelial (PAE) cell line. When cultured in three-dimensional collagen gel, PAE cells formed branching tubule structures, and HGF treatment caused breakdown of the structures and induced a scattered morphology. The exogenous expression of c-Met point mutants inhibited the formation of tubules. HGF treatment induced the formation of tubules by PAE cells expressing some c-Met mutants, but it induced the scattering of PAE cells expressing other c-Met mutants. The presence of a low concentration of a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor cancelled the inhibitory effect of the c-Met point mutations on the formation of tubules. These results suggest that c-Met point mutations affect the extracellular signal-regulated kinase (ERK) signaling required for the formation of tubules by PAE cells, and HGF binding changes the conformation of c-Met mutants, leading to the different signals required for formation of tubules and cell scattering.

Hepatocyte growth factor activates several transduction pathways in rat pancreatic acini

The receptor of hepatocyte growth factor (HGF), c-met induces different physiological responses in several cell types. Little is known about the role of HGF in exocrine pancreas. However, abnormal HGF signaling has been strongly implicated in pancreatic tumorigenesis and association of HGF with pancreatitis has been demonstrated. We have studied the presence of c-met and activation of their intracellular pathways associated in rat pancreatic acini in comparison with cholecystokinin (CCK) and epidermal growth factor (EGF). C-met expression in rat exocrine pancreas was identified by immunohistochemistry and immunoprecipitation followed by Western analysis. Tyrosine phosphorylation of c-met is strongly stimulated as well as kinase pathways leading to ERK1/2 cascade. HGF, but not CCK or EGF, selectively caused a consistent increase in the amount of p85 regulatory subunit of PI3-K present in anti-phosphotyrosine immunoprecipitates. Downstream of PI3-K, HGF increased Ser473 phosphorylation of Akt selectively, as CCK or EGF did not affect it. HGF selectively stimulated tyrosine phosphorylation of phosphatase PTP1D. HGF failed to promote the well-known CCK effects in pancreatic acini such as amylase secretion and intracellular calcium mobilization. Although HGF shares activation of ERK1/2 with CCK, we demonstrate that it promotes the selective activation of intracellular pathways not regulated by CCK or EGF. Our results suggest that HGF is an in vivo stimulus of pancreatic acini and provide novel insight into the transduction pathways and effects of c-met/HGF in normal pancreatic acinar cells.

HGF-mediated chemotaxis and tubulogenesis require activation of the phosphatidylinositol 3-kinase

The association of hepatocyte growth factor (HGF) with its high-affinity receptor, c-met, has been shown to induce mitogenesis, motogenesis, and morphogenesis in renal epithelial cells (L. G. Cantley, E. J. G. Barros, M. Gandhi, M. Rauchman, and S. K. Nigam. Am. J. Physiol. 267 (Renal Fluid Electrolyte Physiol. 36): F271-F280, 1994), suggesting that HGF may be critical to the orchestration of both renal development and regeneration following injury. Although signal transduction pathways activated by c-met include the phosphatidylinositol 3-kinase (PI-3-kinase), phospholipase C gamma, ras, and others, the activation of PI-3-kinase has been the most striking in vivo. We therefore investigated whether the pathways that mediate phenotypic changes in inner medullary collecting duct cells are altered by inhibition of PI-3-kinase with the fungal metabolite, wortmannin. In these cells, the mean inhibitory concentration for in vitro wortmannin inhibition of PI-3-kinase was approximately 0.2 nM. At this low concentration, motogenesis (quantified by chemotaxis) and morphogenesis (by branching-process formation within collagen matrix) were inhibited in a striking and parallel fashion, while mitogenesis was inhibited to a lesser degree. These experiments suggest that activation of PI-3-kinase is critical for c-met-mediated chemotaxis and tubulogenesis.