Dataset Information

Diclofenac and acetaminophen dim the acute phase response but amplify expression of the iron regulator hepcidin in liver cancer cells - PHH

ABSTRACT: Cancer patients frequently suffer from anemia and cancer-related pain, which can be treated by non-opioid analgesics like Diclofenac (DCF) and Acetaminophen (APAP) attenuating inflammatory responses. The key pro-inflammatory cytokine interleukin (IL)-6 triggers expression of acute phase proteins, including the iron regulator hepcidin. We show by quantitative proteomics and dynamic pathway modelling that DCF and APAP enhance the induction of the feedback-inhibitor SOCS3 and reduce IL-6 mediated STAT3 phosphorylation in hepatoma cells. Consequently, expression of acute phase proteins is decreased with the exception of hepcidin. Our mathematical modelling approach reveals that due to an autocrine activation loop of BMP signaling hepcidin expression in hepatoma cells is amplified and this loop is absent in primary hepatocytes. We experimentally validate our model-based prediction that co-inhibition of the BMP receptor is most promising to reduce excessive hepcidin production in hepatoma cells and could be exploited to prevent iron deficiency caused anemia in liver cancer.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte, Liver

SUBMITTER: Marcel Schilling

LAB HEAD: Prof. Dr. Ursula Klingmüller

PROVIDER: PXD054759 | Pride | 2025-11-11

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	20240621_163355_20240621_PK023_Report.csv	Csv
	20240621_163355_20240621_PK023_Report.setup.txt	Txt
	OTEX2_230516_19-341_PK023_04.raw	Raw
	OTEX2_230516_19-341_PK023_05.raw	Raw
	OTEX2_230516_19-341_PK023_06.raw	Raw

Items per page:

1 - 5 of 21

Similar Datasets

Project description:Non-alcoholic fatty liver disease (NAFLD) is gaining evermore importance due to rapidly rising incidence rates especially in western countries. As the disease progresses, it can develop into hepatocellular carcinoma. Related metabolic changes have been extensively studied in the past. However, the molecular mechanisms responsible for the development of fatty liver disease remain uncovered. Here we show that the basal phosphorylation of the MET receptor can be used as an indicator for hepatocyte dysregulation in fatty liver disease. Using primary hepatocytes isolated from a preclinical model fed with high-fat, high-sugar diet (Western diet; WD) or standard diet (SD), we find a strong downregulation of the PI3K-AKT pathway and upregulation of the MAPK pathway in the WD derived hepatocytes. By developing a mathematical model of HGF-induced signal transduction, calibrated with quantitative time-resolved measurements of both PI3K-AKT and MAPK pathways, we resolve molecular mechanisms responsible for these alterations. Thereby, we identify the basal MET phosphorylation rate as main driver for the altered signal transduction in WD hepatocytes that even leads to an increased proliferation behavior of the usually quiescent hepatocytes in the absence of growth factors. The adaptation of the dynamic pathway model of HGF signal transduction to patient-derived hepatocytes reveals a patient-specific variability of basal MET phosphorylation levels, which correlates with the clinical outcome of patients after liver surgery. These findings suggest that the dysregulated basal MET phosphorylation could be exploited to assess the health status of the liver and thereby inform estimation of the risk of a patient to suffer from liver failure after surgery.Non-alcoholic fatty liver disease (NAFLD) is gaining evermore importance due to rapidly rising incidence rates especially in western countries. As the disease progresses, it can develop into hepatocellular carcinoma. Related metabolic changes have been extensively studied in the past. However, the molecular mechanisms responsible for the development of fatty liver disease remain uncovered. Here we show that the basal phosphorylation of the MET receptor can be used as an indicator for hepatocyte dysregulation in fatty liver disease. Using primary hepatocytes isolated from a preclinical model fed with high-fat, high-sugar diet (Western diet; WD) or standard diet (SD), we find a strong downregulation of the PI3K-AKT pathway and upregulation of the MAPK pathway in the WD derived hepatocytes. By developing a mathematical model of HGF-induced signal transduction, calibrated with quantitative time-resolved measurements of both PI3K-AKT and MAPK pathways, we resolve molecular mechanisms responsible for these alterations. Thereby, we identify the basal MET phosphorylation rate as main driver for the altered signal transduction in WD hepatocytes that even leads to an increased proliferation behavior of the usually quiescent hepatocytes in the absence of growth factors. The adaptation of the dynamic pathway model of HGF signal transduction to patient-derived hepatocytes reveals a patient-specific variability of basal MET phosphorylation levels, which correlates with the clinical outcome of patients after liver surgery. These findings suggest that the dysregulated basal MET phosphorylation could be exploited to assess the health status of the liver and thereby inform estimation of the risk of a patient to suffer from liver failure after surgery.

Dataset Information

Diclofenac and acetaminophen dim the acute phase response but amplify expression of the iron regulator hepcidin in liver cancer cells - PHH

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets