TGF-β1 Up-Regulates the Expression of PDGF-β Receptor mRNA and Induces a Delayed PI3K-, AKT-, and p70<sup>S6K</sup>-Dependent Proliferative Response in Activated Hepatic Stellate Cells

Shah, Ruchi; Reyes‐Gordillo, Karina; Arellanes‐Robledo, Jaime; Lechuga, Carmen G.; Hernández‐Nazará, Zamira H.; Cotty, Adam; Rojkind, Marcos; Lakshman, Raj

doi:10.1111/acer.12167

Cited by 57 publications

(37 citation statements)

References 39 publications

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“…This was suggested by the fact that PDGF inhibitor, Crenolanib, reversed PEDF reduction caused by TGF-β. Our findings are consistent with prior results, were TGF-β1 was found to enhance PDGFR-β expression in hepatic stellate cells (32). Further analysis showed that PDGFR-β induction by TGF-β1 required PI3K, JNK1/2, p38 and to a lesser degree Erk1/2.…”

Section: Discussionsupporting

confidence: 94%

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Melanoma Cells Block PEDF Production in Fibroblasts to Induce the Tumor-Promoting Phenotype of Cancer-Associated Fibroblasts

et al. 2016

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Summary Loss of pigment epithelium-derived factor (PEDF, SERPINF1) in cancer cells is associated with poor prognosis and metastasis, but the contribution of stromal PEDF to cancer evolution is poorly understood. Therefore, we investigated the role of fibroblast-derived PEDF in melanoma progression. We demonstrate that normal dermal fibroblasts expressing high PEDF levels attenuated melanoma growth and angiogenesis in vivo, whereas PEDF-depleted fibroblasts exerted tumor-promoting effects. Accordingly, mice with global PEDF knockout were more susceptible to melanoma metastasis. We also demonstrate that normal fibroblasts in close contact with PEDF-null melanoma cells lost PEDF expression and tumor suppressive properties. Further mechanistic investigations underlying the crosstalk between tumor and stromal cells revealed that melanoma cells produced PDGF-BB and TGF-β, which blocked PEDF production in fibroblasts. Notably, cancer-associated fibroblasts (CAF) isolated from patient-derived tumors expressed markedly low levels of PEDF. Treatment of patient CAF and TGF-β-treated normal fibroblasts with exogenous PEDF decreased the expression of CAF markers and restored PEDF expression. Finally, expression profiling of PEDF-depleted fibroblasts revealed induction of interleukin-8, SERPINB2, hyaluronan synthase-2, and other genes associated with tumor promotion and metastasis. Collectively, our results demonstrate that PEDF maintains tumor-suppressive functions in fibroblasts to prevent CAF conversion, and illustrate the mechanisms by which melanoma cells silence stromal PEDF to promote malignancy.

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Section: Discussionsupporting

confidence: 94%

“…TGF-β is known to up-regulate PDGF receptors in hepatic cells (32). Similarly, PDGFR-β was significantly higher in primary fibroblasts treated with TGF-β (Fig.…”

Section: Resultsmentioning

confidence: 99%

Melanoma Cells Block PEDF Production in Fibroblasts to Induce the Tumor-Promoting Phenotype of Cancer-Associated Fibroblasts

et al. 2016

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“…Consistent with our findings, a recent report showed that Raptor knock out mice were more susceptible to DEN-induced hepatic fibrosis and HCC [31]. Although the TGF-β1-mTORC1 axis plays essential roles for fibrogenesis in HSC [32, 33], we showed the presence of negative feedback regulation from mTORC1 to TGF-β1 signaling in this study (Supplementary Figure 6B). Activating this feedback regulation by BCAA could reduce the pro-fibrosis signaling in both HSC and hepatocytes that was observed in vitro and in vivo in this study.…”

Section: Discussionsupporting

confidence: 92%

Branched-chain amino acids prevent hepatic fibrosis and development of hepatocellular carcinoma in a non-alcoholic steatohepatitis mouse model

et al. 2017

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Oral supplementation with branched-chain amino acids (BCAA; leucine, isoleucine, and valine) in patients with liver cirrhosis potentially suppresses the incidence of hepatocellular carcinoma (HCC) and improves event-free survival. However, the detailed mechanisms of BCAA action have not been fully elucidated. BCAA were administered to atherogenic and high-fat (Ath+HF) diet-induced nonalcoholic steatohepatitis (NASH) model mice. Liver histology, tumor incidence, and gene expression profiles were evaluated. Ath+HF diet mice developed hepatic tumors at a high frequency at 68 weeks. BCAA supplementation significantly improved hepatic steatosis, inflammation, fibrosis, and tumors in Ath+HF mice at 68 weeks. GeneChip analysis demonstrated the significant resolution of pro-fibrotic gene expression by BCAA supplementation. The anti-fibrotic effect of BCAA was confirmed further using platelet-derived growth factor C transgenic mice, which develop hepatic fibrosis and tumors. In vitro, BCAA restored the transforming growth factor (TGF)-β1-stimulated expression of pro-fibrotic genes in hepatic stellate cells (HSC). In hepatocytes, BCAA restored TGF-β1-induced apoptosis, lipogenesis, and Wnt/β-Catenin signaling, and inhibited the transformation of WB-F344 rat liver epithelial stem-like cells. BCAA repressed the promoter activity of TGFβ1R1 by inhibiting the expression of the transcription factor NFY and histone acetyltransferase p300. Interestingly, the inhibitory effect of BCAA on TGF-β1 signaling was mTORC1 activity-dependent, suggesting the presence of negative feedback regulation from mTORC1 to TGF-β1 signaling. Thus, BCAA induce an anti-fibrotic effect in HSC, prevent apoptosis in hepatocytes, and decrease the incidence of HCC; therefore, BCAA supplementation would be beneficial for patients with advanced liver fibrosis with a high risk of HCC.

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“…GDF-15 leads to the extracellular matrix (ECM) accumulation in the mechanism: (1) directly increasing the synthesis of ECM components as procollagen 1a, (2) inhibition of tissue collagenases expression, (3) increasing synthesis of ECM-degrading enzyme inhibitors (as plasminogen activator inhibitor type 1, tissue inhibitors of metalloproteinases) 18–20…”

Section: Discussionmentioning

confidence: 99%

Growth Differentiation Factor 15 Predicts Chronic Liver Disease Severity

Lee

Kim

et al. 2017

Gut and Liver

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Background/AimsGrowth differentiation factor 15 (GDF-15) belongs to the transforming growth factor-β superfamily. GDF-15 is emerging as a biomarker for several diseases. The aim of this study was to determine the clinical performances of GDF-15 for the prediction of liver fibrosis and severity in chronic liver disease.MethodsThe serum GDF-15 levels were examined via enzyme immunoassay in 145 patients with chronic liver disease and 101 healthy individuals. The patients with chronic liver disease consisted of 54 patients with chronic hepatitis, 44 patients with compensated liver cirrhosis, and 47 patients with decompensated liver cirrhosis.ResultsOf the patients with chronic liver diseases, the decompensated liver cirrhosis patients had an increased serum GDF-15 (3,483 ng/L) level compared with the patients with compensated liver cirrhosis (1,861 ng/L) and chronic hepatitis (1,232 ng/L). The overall diagnostic accuracies of GDF-15, as determined by the area under the receiver operating characteristic curves, were as follows: chronic hepatitis=0.656 (>574 ng/L, sensitivity, 53.7%; specificity, 79.2%), compensated liver cirrhosis=0.886 (>760 ng/L, sensitivity, 75.6%; specificity, 92.1%), and decompensated liver cirrhosis=0.984 (>869 ng/L, sensitivity, 97.9%; specificity, 94.1%).ConclusionsThis investigation represents the first study to demonstrate the availability of GDF-15 in chronic liver disease. GDF-15 comprised a useful biomarker for the prediction of liver fibrosis and severity in chronic liver disease.

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TGF-β1 Up-Regulates the Expression of PDGF-β Receptor mRNA and Induces a Delayed PI3K-, AKT-, and p70^S6K-Dependent Proliferative Response in Activated Hepatic Stellate Cells

Abstract: We conclude that liver injury up-regulates TGF-β1 that inhibits parenchymal cell proliferation, but stimulates HSC proliferation leading to the production of ECM and type I collagen resulting in fibrosis.

Cited by 57 publications

References 39 publications

Melanoma Cells Block PEDF Production in Fibroblasts to Induce the Tumor-Promoting Phenotype of Cancer-Associated Fibroblasts

Melanoma Cells Block PEDF Production in Fibroblasts to Induce the Tumor-Promoting Phenotype of Cancer-Associated Fibroblasts

Branched-chain amino acids prevent hepatic fibrosis and development of hepatocellular carcinoma in a non-alcoholic steatohepatitis mouse model

Growth Differentiation Factor 15 Predicts Chronic Liver Disease Severity

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TGF-β1 Up-Regulates the Expression of PDGF-β Receptor mRNA and Induces a Delayed PI3K-, AKT-, and p70S6K-Dependent Proliferative Response in Activated Hepatic Stellate Cells

Abstract: We conclude that liver injury up-regulates TGF-β1 that inhibits parenchymal cell proliferation, but stimulates HSC proliferation leading to the production of ECM and type I collagen resulting in fibrosis.

Cited by 57 publications

References 39 publications

Melanoma Cells Block PEDF Production in Fibroblasts to Induce the Tumor-Promoting Phenotype of Cancer-Associated Fibroblasts

Melanoma Cells Block PEDF Production in Fibroblasts to Induce the Tumor-Promoting Phenotype of Cancer-Associated Fibroblasts

Branched-chain amino acids prevent hepatic fibrosis and development of hepatocellular carcinoma in a non-alcoholic steatohepatitis mouse model

Growth Differentiation Factor 15 Predicts Chronic Liver Disease Severity

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TGF-β1 Up-Regulates the Expression of PDGF-β Receptor mRNA and Induces a Delayed PI3K-, AKT-, and p70^S6K-Dependent Proliferative Response in Activated Hepatic Stellate Cells