Activation of nuclear protooncogenes and alpha‐fetoprotein gene in rat liver during the acute inflammatory reaction

Abstract

ABSTRACT— Nuclear protooncogene and alpha‐fetoprotein gene expression is stimulated in hepatocytes during liver regeneration and by various growth factors in vitro. Metabolic adaptation of hepatocytes has been implicated in such gene reprogrammation. We examine here whether induction of an acute inflammation, a physiological situation of important metabolic adjustments, also triggers activation of nuclear oncogenes and of the AFP gene in rat liver. C‐fos, c‐jun and c‐myc mRNA accumulated on Northern blots between 4–12 h of inflammation and the steady‐state level of two small alpha‐fetoprotein transcripts characteristic of the adult liver increased at 4 h and 24 h of inflammation. In situ hybridization showed accumulation of the mRNA of the four genes studied in all hepatocytes, without any zonal lobular heterogeneity. 3H‐histoautoradiography and mitotic counts indicated an inhibition of DNA synthesis and mitosis, prolonged for at least 48 h after inflammation. Thus acute inflammation triggers the activation of nuclear protooncogenes and alpha‐fetoprotein gene in hepatocytes, but this activation is not followed by passage into the replicative cycle.

Liver gene expression analysis reveals endoplasmic reticulum stress and metabolic dysfunction in SCD1-deficient mice fed a very low-fat diet

“…This observation is supported by the elevated expression of macrophage recruitment and liver inflammation genes such as cellular adhesion molecules (Icam1, Vcam1), matrix metalloproteases (Mmp12, Mmp13, Mmp14, Adamts1), macrophage cell surface glycoproteins (Cd14, Cd38, Cd68, Emr1), cytokines (Ccl2, Ccl6, Cxcl2, Cxcl4, Cxcl10, Cxcl16, Tgfb1), and cytokine receptors (Cxcr4, Csf1r, Ccr1, Ccrl1, Ccrl2, Ifngr1, Tlr2) ( Table 6 and Supplementary Tables S2 and S4). We also observed increased expression of the protooncogenes Myc, Jun, and Fos, as well as a dramatic induction of Afp (alpha-fetoprotein) and Lcn2 (lipocalin 2), all of which have been shown to increase in response to inflammation (Table 6) (7,72). This inflammatory response is further indicated by the decreased expression of many hepatic-negative acute-phase mRNAs, including Prlr (prolactin receptor), Dio1 (type I iodothyronine deiodinase), and major urinary proteins Mup1, Mup3, and Mup5 (14,25,75).…”

Influence of aflatoxin B1 on mRNA levels of acute-phase proteins and oncoproteins in albino rat liver

“…AFB 1 induced significant increase in the level of mRNA for c-jun (more than for c-fos), and the highest values were observed 72 hours after AFB 1 treatment (3.7 fold compared to controls). Uncoupling of c-fos and c-jun induction has already been reported after acute inflammation (16). Our earlier study showed that hepatectomy (30%-40%) caused quickly regeneration of the liver accompanied by activation of the genes for CPI, Hp and inhibition of Al gene transcription 24 hours after hepatectomy.…”

“…We obtained the increase of AFP mRNA at 1 st hour after acute poisoning by AFB 1 . Bernuau et al, (16) observed biphasic accumulation of the two AFP mRNA transcripts, the first at 4 th hour and second at 24 th hour after acute inflammation. Better understanding of the role of AFB 1 in modulating liver gene expression, such as oncogenes, tumor suppressor genes, repair genes and APPs genes, should provide better insight regarding mechanisms of AFB 1 induced carcinogenesis.…”

“…AFP gene is normally repressed in adult quiescent hepatocytes. This gene is also an example of a gene activated in the early prereplicative phase of hepatocyte proliferation during liver regeneration or in the hepatocellular carcinoma (16). AFB 1, besides cancerogenic, has also toxic effects on the live.…”

Alpha-Fetoprotein (AFP) and Inflammation: Is AFP an Acute and/or Chronic Phase Reactant?

“…This activation (without DNA synthesis) of a set of genes is referred to as an "immediate early gene response" which includes the nuclear proto-oncogenes c-fos, c-jun, c-myc, and the AFP gene. A later activation occurs in the p53 gene, cKRAS and d-HRAS genes [19]. AFP synthesis is normally repressed in adult liver cells, but is re-activated in the early phases of hepatocyte regeneration following partial hepatectomy [20][21][22].…”