Background:
ErbB2 is a prominent member of the epidermal growth factor receptor superfamily, a
group of transmembrane receptors that mainly attract attention as oncogenic drivers
and therapeutic targets in cancer. Besides transmembrane signaling, ErbB2 may also
translocate into the nucleus and mediate distinct nuclear signaling effects, including
DNA repair and cell cycle arrest.
Methods:
The immunohistochemical pattern of ErbB2 staining was analyzed in 334 liver biopsy
samples from patients with hepatic dysfunction.
Results:
We found a cytoplasmic and nuclear ErbB2 expression in hepatocytes from different
disease conditions, with the strongest expression being detected in alcoholic steatohepatitis.
These ErbB2 overexpressing hepatocytes revealed peculiar metabolic and hormonal changes:
enhanced lipid turnover (increase of fatty acid synthase and acyl-CoA-dehydrogenase),
downregulation of estrogen receptor, cell cycle alterations (increase of p21 and heat
shock protein 27), and an increase of phospho-Stat3, a downstream effector of nuclear
ErbB2 signaling. Notably, ballooned hepatocytes, often interpreted as degenerative
cells, exhibited a particularly strong ErbB2 expression and appeared to be highly
metabolically active as described above. Of note, an increased ErbB2 expression as
well as metabolic alterations and signs of cell cycle deregulation similar to that
described in human steatohepatitis specimens were detected when HepG2 cells were subjected
to 48-hour ethanol treatment.
Discussion:
These novel observations on hepatocellular ErbB2 expression with evidence of nuclear
receptor signaling and metabolic alterations imply a so far unknown mechanism in hepatocytes
upon cellular stress events, particularly ethanol exposure. This molecular reprogramming
might improve cellular survival, have a significant effect on disease course with
therapeutic implications and play a role in progression to hepatocellular carcinoma
and thus opens a wide field of future research on the role of hepatocellular ErbB2
expression.
Corresponding author: Döring, Paula
E-Mail:
paula.doering@uni-greifswald.de
