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Magee et al. Egr1 in liver metabolism and cancer

-/-
Therefore, Egr1 plays a critical role in liver regeneration contrast, a recent study using WT and Egr1 mice in
after injury. chronic APAP-induced liver injury has demonstrated
-/-
that Egr1 livers exhibited a more severe hepatotoxicity
EGR1 IN LIVER FIBROSIS AND and fibrotic response compared to WT mice under
[77]
ACETAMINOPHEN-INDUCED APAP overdose . Collectively, these data support
HEPATOTOXICITY Egr1 as an important mediator in APAP-induced
hepatotoxicity and liver fibrosis; however, whether Egr1
could act as an inducer or protector against APAP-
Liver fibrosis is the wound-healing response of the induced liver injury has remained elusive. Additional
liver to chronic injury that entails cell proliferation, studies using cell-type specific Egr1-deficient animals
inflammation, angiogenesis, as well as synthesis and to determine the involvement of Egr1 in acute and
remodeling of extracellular matrix [67-70] . Prolonged chronic APAP-induced liver injury would be highly
tissue injury can lead to excessive accumulation of beneficial for a more clear definition of cell-type
extracellular matrix in the organ, a hallmark of fibrosis. specific role of Egr1 in liver injury and fibrosis.
Egr1 has been shown to induce transcription of growth
factors and stimulate collagen production in human EGR1 AND LIVER CANCER
fibroblasts and fibrosarcoma cells, suggesting the
contribution of Egr1 to fibrogenesis [22,71] . TGF-β1, a key
regulator of fibrogenesis, is an upstream regulator of Egr1 is demonstrated to act as both a tumor suppressor
Egr1 [10] ; however, Egr1 also regulates the expression and a tumor promoter in cancers. The tumorigenic role
of TGF-β1 in response to the hepatitis B virus [72] , which of Egr1 was described in prostate, skin and kidney
[78]
hints to the existence of a possible feedback regulation cancers . By contrast, tumor suppressor activity
between TGF-β1 and Egr1 during fibrogenesis. of Egr1 was reported in fibrosarcoma, glioblastoma,
[79,80]
lung and breast cancers . The role of Egr1 in liver
cancers remains elusive, as studies evaluating the role
Acetaminophen (APAP) is widely used to treat pain of Egr1 in liver cancer development and progression
and reduce fever. APAP is mainly metabolized by have reported contradicting conclusions.
the liver, undergoing glucuronidation, sulfation, or
N-hydroxylation. The sulfate product is the primary, Accumulating studies suggest Egr1 as a tumor
non-toxic metabolite in children; whereas, the suppressor in HCC. Egr1 is commonly downregulated
glucuronide metabolite is the primary, non-toxic in HCC tissues from humans and murine, indicating
metabolite in adults. The hydroxylated product is the that the downregulation of Egr1 is related to HCC
bioactivation of APAP by cytochrome 2E1 (Cyp2E1) development [81] . However, mechanisms responsible
that leads to the toxic, reactive metabolite, N-acetyl- for the downregulation of Egr1 in liver cancer remain
p-benzoquinone imine (NAPQI). The final attempt to unknown. A recent study has described that EGR1
prevent toxicity is to conjugate NAPQI to glutathione [73] . carries mutational intratumoral heterogeneity and
In the event of APAP overdose, the glutathione stores frameshift mutations in colorectal and gastric
are depleted; the reactive metabolite binds to hepatic cancers which have high microsatellite instability [82] .
proteins, leading to hepatic necrosis. In western Thus, it could be interesting to know whether the
countries, acute liver injury due to APAP overdose is same mechanism could exist in liver cancer and
the main cause for drug-induced acute liver failure [74] . contribute to the decrease of EGR1. Aberrant
In addition, long-term application of APAP has been MAPK signaling activation is a key player in driving
linked to the increased hepatic inflammation and liver tumor proliferation [83-85] . Inhibition of P42/44MAPK
fibrosis in patients [75] . in HepG2 cells leads to suppression on cell growth,
proliferation, and survival, accompanied by an
The report of Egr1 function in acute or chronic APAP- induction of Egr1 in tumor cells [86] . Recently, (125)I-UdR
induced hepatotoxicity is contradictory. In an acute radionuclide therapy combined with Egr1-promoter-
APAP-induced liver injury mouse model, both Egr1 based interferon gamma (IFNγ) gene therapy was
mRNA level and transcriptional activity in hepatocytes described to efficiently reduce tumor proliferation
are increased [76] . Inhibition on ERK1/2-mediated Egr1 and promote animal survivals in mice bearing H22
transcriptional activation by caffeic acid (an organic hepatomas [87] . Overexpression of Egr1 decreases the
compound found in coffee, fruit, and herbs) attenuates growth rate and tumorigenicity of the HCC cell line
APAP-induced hepatotoxicity [76] , suggesting that HHCC cells [88] . Furthermore, Egr1 induces apoptosis
inhibiting Egr1 activation is beneficial to protect against in human hepatoma cells (HepG2 and Hep3B) that
APAP-overdose induced acute hepatotoxicity. By can be enhanced by synthetic chenodeoxycholic acid

272 Hepatoma Research ¦ Volume 3 ¦ November 20, 2017