normal liver attractor. Biologically, HNF4α, C/EBPα, and Foxa2
are liver-enriched transcription factors which regulate the synergis-
tic transcriptional activation of hepatocyte specific genes
[47, 69]. These liver-enriched transcription factors have mutual
activations which form positive feedback loop and maintain normal
liver tissue state [47, 69].Experiments also show that fibroblasts can
be induced to functional hepatocyte-like cells by overexpressing
these liver-specific transcription factors [32].The activated
HNF4α-C/EBPα-Foxa2loop also maintains normal liver attractor
by affecting the status of other functional modules, such as sup-
pressing hepatocyte cell cycle and related metabolism [70, 71],
suppressing inflammation [70], inducing differentiation of
hepatocyte [47].
The model reveals that two positive feedback loops, RTKs/Ras,
Akt, ERK,β-catenin/Myc, HIF and TNF-α, IL-1, IL-6/NF-κB
(Kuppfer cell), are responsible for the establishment and mainte-
nance of HCC attractor. Biologically, RTKs/Ras, Akt, ERK,
β-catenin /Myc, HIF is a conserved growth-related positive feedback
loop. Receptor tyrosine kinases (RTKs) are the high-affinity cell
surface receptors including EGFR, VEGFR etc. Once activated,
RTKS will lead to downstream activation of a number of common
signaling molecules [72]. The activation of signaling pathways will
change the gene expression profiles, the changes in gene expression
in turn activate the RTKs ligands, in this way forms a positive
feedback loop to support cell proliferation [73, 74].TNF-α, IL-1,
IL-6/NF-κB (Kuppfer cell) is an inflammation-related positive feed-
back loop [75], pro-inflammatory stimuli, TNF and IL-1β,will
activate the IκB kinase (IKK), resulting in IκB phosphorylation and
leading to the nuclear entry of freed NF-κB dimmers in Kuppfer cell.
Activated Kupffer cells produce a panel of inflammatory cytokines
and growth factors including IL-1, IL-6, TNF-α, thus forming anTable 5
(continued)Gene name Model result
GSK3β Gain-of-function
β-catenin Loss-of-function
Myc Loss-of-function
P53 Loss-of-function
TGF-β Loss-of-function
P21 –
Twenty-four proteins in endogenous network were predicted to have a higher probabil-
ity as loss-of-function in normal liver. Seven proteins in endogenous network were
predicted to have a higher probability as gain-of-function in normal liver. This approach
cannot predict the probable mutation of the reminding six genes (–)234 Gaowei Wang et al.