Systems Biology (Methods in Molecular Biology)

inflammation-related positive feedback loop [76]. The two activated

positive feedback loops maintain HCC attractor by affecting the

status of other functional modules, such as activating cell prolifera-

tion and growth [73, 74], activating angiogenesis [74], inhibiting

cell apoptosis [73], inducing dedifferentiation [71].

One straightforward predication is that HCC may be induced to

normal liver by inhibiting the proliferative-related feedback loops

RTKs/Ras, Akt, ERK, β-catenin/Myc, HIF and inflammation-

related feedback loops TNF-α, IL-1/NF-κB (Kuppfer cell)/TNF-α,

IL-1, IL-6, and simultaneously activating differentiated liver-specific

related loop, HNF4α/C/EBPα/Foxa2 (Fig.3).The implication of

this strategy means that we may induce HCC to normal liver by

Fig. 3Maintenance of normal liver and HCC by distinct positive feedback loops. (a) Liver-specific positive
feedback loop HNF4α–C/EBPα–Foxa2 is responsible for the maintenance of normal liver attractor. (b)
proliferation related positive feedback loops, RTKs–Ras, Akt, ERK,β-catenin–Myc, HIF and inflammation
related positive feedback TNF-α, IL-1, IL-6–NF-κB (in Kupffer cell), are responsible for the maintenance of
HCC attractor. HCC may be cured or relieved by inhibiting proliferation and inflammation, and simultaneously
inducing liver differentiation

Endogenous Molecular-Cellular Network Cancer Theory 235