Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma

Chronic liver injury leads to fibrosis and cirrhosis. Cirrhosis, the end stage of chronic liver disease, is a leading cause of death worldwide and increases the risk of developing hepatocellular carcinoma. Currently, there is a lack of effective antifibrotic therapies to treat fibrosis and cirrhosis. Development of antifibrotic therapies requires an in-depth understanding of the cellular and molecular mechanisms involved in inflammation and fibrosis after hepatic injury. Two growth factor signaling pathways that regulate liver fibrosis are transforming growth factor-β (TGFβ) and platelet-derived growth factor (PDGF). However, their specific contributions to fibrogenesis are not well understood. Using a genetic model of liver fibrosis, we investigated whether the canonical TGFβ signaling pathway was necessary for fibrogenesis. PDGF-C transgenic ( PDGF-C Tg) mice were intercrossed with mice that lack Smad3, and molecular and histological fibrosis was analyzed. PDGF-C Tg mice that also lacked Smad3 had less fibrosis and improved liver lobule architecture. Loss of Smad3 also reduced expression of collagen genes, which were induced by PDGF-C, but not the expression of genes frequently associated with hepatic stellate cell (HSC) activation. In vitro HSCs isolated from Smad3-null mice proliferated more slowly than cells from wild-type mice. Taken together, these findings indicate that PDGF-C activates TGFβ/Smad3 signaling pathways to regulate HSC proliferation, collagen production and ultimately fibrosis. In summary, these results suggest that inhibition of both PDGF and TGFβ signaling pathways may be required to effectively attenuate fibrogenesis in patients with chronic liver disease.

Download Full-text

Inhibition of platelet-derived growth factor C and their receptors additionally increases doxorubicin effects in triple-negative breast cancer cells

European Journal of Pharmacology ◽

10.1016/j.ejphar.2021.173868 ◽

2021 ◽

Vol 895 ◽

pp. 173868

Author(s):

Sangmin Kim ◽

Daeun You ◽

Yisun Jeong ◽

Sun Young Yoon ◽

Sung A. Kim ◽

...

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative ◽

Platelet Derived Growth Factor ◽

Factor C

Download Full-text

On-line hemodiafiltration modulates atherosclerosis signaling in peripheral lymphomonocytes of hemodialysis patients

Journal of Nephrology ◽

10.1007/s40620-020-00958-z ◽

2021 ◽

Author(s):

Simona Simone ◽

Annarita Chieti ◽

Paola Pontrelli ◽

Federica Rascio ◽

Giuseppe Castellano ◽

...

Keyword(s):

Growth Factor ◽

Gene Networks ◽

Mononuclear Cells ◽

Expression Profiles ◽

Hemodialysis Patients ◽

Monoamine Oxidase A ◽

Platelet Derived Growth Factor ◽

Peripheral Blood Mononuclear ◽

On Line ◽

Factor C

Abstract Background Hemodialysis patients present a dramatic increase in cardiovascular morbidity/mortality. Circulating immune cells, activated by both uremic milieu and dialysis, play a key role in the pathogenesis of dialysis-related vascular disease. The aim of our study was to identify, through a high-throughput approach, differences in gene expression profiles in the peripheral blood mononuclear cells (PBMCs) of patients treated with on-line hemodiafiltration and bicarbonate hemodialysis. Methods The transcriptomic profile was investigated in PBMCs isolated from eight patients on on-line hemodiafiltration and eight patients on bicarbonate hemodialysis by microarray analysis. The results were evaluated by statistical and functional pathway analysis and validated by real time PCR (qPCR) in an independent cohort of patients (on-line hemodiafiltration N = 20, bicarbonate hemodialysis n = 20). Results Eight hundred and forty-seven genes were differentially expressed in patients treated with on-line hemodiafiltration and bicarbonate hemodialysis. Thirty-seven functional gene networks were identified and atherosclerosis signaling was the top canonical pathway regulated by on-line hemodiafiltration. Among the genes of this pathway, on-line hemodiafiltration was associated with a reduced expression of Platelet-derived growth factor A chain (PDGF A), Clusterin, Monoamine Oxidase A, Interleukin-6 (IL-6) and Vascular Endothelial Growth Factor C (VEGF-)C and with an increase of Apolipoprotein E. qPCR confirmed the microarray results. Platelet derived growth factor AA (PDGF-AA), IL-6 and VEGF-C serum levels were significantly lower in the on-line hemodiafiltration group. Finally, 10 patients previously on bicarbonate hemodialysis were switched to on-line hemodiafiltration and PBMCs were harvested after 6 months. The qPCR results from this perspective group confirmed the modulation of atherosclerotic genes observed in the cross-sectional analysis. Conclusions Our data suggest that type of dialysis (on-line hemodiafiltration versus bicarbonate hemodialysis) may modulate the expression of several genes involved in the pathogenesis of atherosclerotic disease.

Download Full-text

JNK signaling activated by Platelet-Derived Growth Factor D (PDGF-D) stimulates secretion of Vascular Endothelial Growth Factor-C (VEGF-C) by cancer-associated fibroblasts to promote lymphangiogenesis and early metastatization in cholangiocarcinoma

Digestive and Liver Disease ◽

10.1016/j.dld.2015.01.052 ◽

2015 ◽

Vol 47 ◽

pp. e22-e23 ◽

Cited By ~ 2

Author(s):

M. Cadamuro ◽

M. Vismara ◽

S. Brivio ◽

A. Furlanetto ◽

M. Strazzabosco ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Platelet Derived Growth Factor ◽

Vascular Endothelial ◽

Cancer Associated Fibroblasts ◽

Jnk Signaling ◽

Factor C ◽

Endothelial Growth Factor

Download Full-text

Platelet-Derived Growth Factor C in Alcoholics

Alcohol and Alcoholism ◽

10.1093/alcalc/agz094 ◽

2020 ◽

Vol 55 (2) ◽

pp. 157-163 ◽

Cited By ~ 1

Author(s):

C Martín-González ◽

L González-Navarrete ◽

I Ribot-Hernández ◽

V Vera-Delgado ◽

J Alvisa-Negrín ◽

...

Keyword(s):

Multivariate Analysis ◽

Platelet Count ◽

Growth Factor ◽

Serum Levels ◽

Muscle Disease ◽

Platelet Derived Growth Factor ◽

Laboratory Evaluation ◽

Prothrombin Activity ◽

Factor C ◽

Factor Α

Abstract Aims Platelet-derived growth factor (PDGF) promotes liver collagen deposition, acting on hepatic stellate cells. Despite this, low serum PDGF levels were reported in chronic hepatitis C or B infection, although some studies yield the opposite result. Since PDGF may be related not only to fibrosis but also with vascular, neuronal or muscle disease, it is important to analyze its behavior in alcoholics. Methods In total, 17 controls and 62 alcoholic patients consecutively admitted to the hospitalization unit of the Internal Medicine Service were included. We determined serum levels of PDGF C, routine laboratory evaluation, tumor necrosis factor-α, interleukin (IL)-6 and IL-8 and malondialdehyde (MDA) levels. We analyzed the relationships between PDGF and liver function, ethanol intake and inflammatory reaction by both univariate and multivariate analysis to discern which variables PDGF levels depend on. Results Serum PDGF levels were significantly lower among patients (675 ± 466 pg/ml) than among controls (1074 ± 337 pg/ml; Z = 3.70; P < 0.001), and even lower among cirrhotics (549 ± 412 among cirrhotics vs 778 ± 487 among non-cirrhotics; Z = 2.33; P = 0.02). PDGF levels showed a direct correlation with prothrombin activity (ρ = 0.50; P < 0.001), platelet count (ρ = 0.44; P < 0.001) and inverse ones with bilirubin (ρ = −0.39; P = 0.002), IL-6 (ρ = −0.33; P = 0.016), IL-8 (ρ = −0.47; P < 0.001), and MDA levels (ρ = −0.44; P < 0.001). By multivariate analysis, only prothrombin activity and platelet count were independently related to PDGF. Conclusion PDGF-C levels are decreased in alcoholics, especially among cirrhotics. Multivariate analysis discloses that only prothrombin activity and platelet count are independently related to PDGF-C levels.

Download Full-text