Abstract
Background and AimsEndoplasmic reticulum (ER) stress is induced in many forms of chronic liver disease and may promote the development of hepatocellular carcinoma. The activator protein 1 (AP-1) complex is a transcription factor that promotes hepatic carcinogenesis in response to cellular stress. The aim of this study was to determine the role of ER stress in the regulation of the hepatic AP-1 complex.MethodsHuman hepatocellular carcinoma (HepG2) cells and C57BL/6J mice were subjected to pharmacologic ER stress and the expression of AP-1-associated genes and proteins was assessed. To determine the role of MAPK signaling in ER stress-induced AP-1 activation, ER stress was induced in JNK- and ERK-inhibited HepG2 cells.ResultsInduction of ER stress promoted the activation of both Jun- and Fos-related genes and proteins of the AP-1 complex in HepG2 cells and murine liver. Inhibition of ERK phosphorylation in HepG2 cells completely prevented ER stress-induced activation of the fos-related components of AP-1 whereas activation of Jun-related components was only partially attenuated. Conversely, inhibition of JNK phosphorylation in HepG2 cells reduced ER stress-induced activation of Jun-related components but did not prevent activation of fos-related components.ConclusionsER stress activates the hepatic AP-1 complex via MAPK-dependent signaling pathways. ER stress-induced activation of Fos-related components is dependent primarily on ERK activation whereas ER stress-induced activation of Jun-related components is dependent primarily on JNK activation, although there is interplay between these regulatory pathways. These data implicate a novel signaling pathway by which sustained ER stress, as observed in many chronic liver diseases, may promote hepatic carcinogenesis.
Highlights
The incidence of hepatocellular carcinoma (HCC) has more than doubled over the past 20 years attributable in large part to the high rate of new hepatitis C virus infection 30 to 40 years ago [1,2]
We examined the effect of Endoplasmic reticulum (ER) stress on the expression of the fos-related genes (CFOS and fos-related antigen 1 (FRA1)), and jun-related genes (CJUN and JUND) of the activator protein 1 (AP-1) complex
We sought to determine whether ER stress activates the AP-1 complex in vivo
Summary
The incidence of hepatocellular carcinoma (HCC) has more than doubled over the past 20 years attributable in large part to the high rate of new hepatitis C virus infection 30 to 40 years ago [1,2]. It is becoming increasingly evident that patients with cirrhosis secondary to nonalcoholic fatty liver disease (NAFLD) are at high risk for developing HCC. Recent observations suggest that NAFLD is a risk factor for HCC even in the absence of cirrhosis [3,4]. Significant progress is being made toward curing chronic hepatitis C, the prevalence of NAFLD is rapidly escalating in the United States. Endoplasmic reticulum (ER) stress is induced in many forms of chronic liver disease and may promote the development of hepatocellular carcinoma. The activator protein 1 (AP-1) complex is a transcription factor that promotes hepatic carcinogenesis in response to cellular stress. The aim of this study was to determine the role of ER stress in the regulation of the hepatic AP-1 complex
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