Page 313 - Read Online

Page 4 of 15 Chen et al. Hepatoma Res 2018;4:29 I http://dx.doi.org/10.20517/2394-5079.2018.18

activates expression of matrix metalloproteinase 10, which further stimulates migration of HCC cells .
[46]
In summary, these evidences showed that inflammation contributes to cancer by supplying important and
various molecules to the tumor microenvironment.

Signaling pathways
PI3K/AKT/mTOR pathway
In 1993, Kisen et al. observed the existence of autophagy in pre-cancerous hepatocytes induced by chemical
[47]
carcinogens in rats, and proposed a new target that could potentially be used to treat HCC. Autophagy has
the dual role of promoting and inhibiting the evolution of liver cancer [48,49] . Autophagy often occurs in the
reduction from the pre-cancer stage to the occurrence of cancer and the reduction of autophagy can lessen
tumor cell autophagic death, so it plays a facilitating role in the growth of the tumor. However, before the
formation of blood vessels, the tumor cells are in a state of low nutrition and hypoxia, which stimulate
autophagy through the PI3K/AKt/mTOR pathway. Enhanced autophagy can provide nutrients to the hungry
tumor cells by removing damaged proteins, organelles and macromolecules, thereby inhibiting apoptosis
of tumor cell. The PI3K/AKt/mTOR pathway is of great importance to the development, progression and
treatment of HCC. It has been reported that TNF-α and IL-6 induced VEGF expression and angiogenesis
can be significantly inhibited by rapamycin, indicating that mTOR plays an important role in inflammation-
induced angiogenesis . Inflammatory factors such as TNF-α, IL-6, IL-1β and other secretions are also
[50]
regulated by mTOR signaling pathway . In the case of sustained activation of the mTORC1 pathway, the
[51]
expression of pro-inflammatory cytokines such as IL-6, TNF-α are decreased and the expression of the anti-
inflammatory cytokine IL-10 is increased .
[52]

The role of PI3K/AKt/mTOR pathway in HCC can be summarized as follows: (1) promoting the formation of
tumor blood vessels: PI3K/AKt/mTOR pathway participates in the formation of blood vessels in tumor mainly
through two ways: PI3K/AKt signaling pathway can activate the cyclooxygenase 2 (COX-2), which is a key
enzyme that catalyzes the synthesis of prostaglandin-like substances, thereby promoting the angiogenesis of liver
cancer . Hypoxia and growth factors can induce the expression of hypoxia inducible factor 1α (HIF-1α) ,
[53]
[54]
the downstream blood vessels endothelial growth factor (VEGF) transcription . The PI3K/AKt pathway
[55]
activation can up-regulate the expression of HIF-1α and VEGF, thus making endothelial cell migrate to form
new blood vessels; (2) promoting tumor invasion and metastasis: Johnson and Tee have shown that PI3K/
[56]
AKt/mTOR activation can make the downstream molecules p70s6k phosphorylated to make actin filament
remodel and to enhance the ability of tumor cells to move, thus increasing the invasion and metastasis
of cancer cells. Activation of Akt increases the transcriptional activity of NF-κB and the motor function
of tumor cells, which facilitates invasion of cancer cells . The PI3K/AKt/mTOR pathway can up-regulate
[57]
the expression of matrix metalloproteinase 2 (MMP-2) mRNA and protein, and degrade the extracellular
matrix (ECM) to promote tumor cell metastasis ; (3) promoting cell cycle progression: studies show that
[58]
the PI3K/AKt/mTOR signaling pathway can transmit mitotic signals to p70s6k, and p70s6k can up-regulate
major cell cycle proteins such as cyclin and CDK4 , while increasing the expression of CDK4 accelerates
[59]
the cell cycle progression, thereby promoting cell proliferation and differentiation which both result in
liver cancer . Unfortunately, the EVOLVE-1 randomized clinical trial showed that the MTOR inhibitor,
[60]
everolimus, did not improve overall survival in patients with advanced HCC whose disease progressed
during or after receiving sorafenib or who were intolerant of sorafenib . The molecular classification and
[61]
predictive biomarkers may be necessary for further studies.

WNT/β-catenin pathway
WNT signaling pathway plays a role in organogenesis, regeneration and differentiation, and maintaining the
homeostasis of tissues and organs. In liver tissue, hepatocytes, hepatic stellate cells and Kupffer cells could
express this pathway . There is growing evidence that WNT signaling pathway is involved in the development
[62]
of HCC. The sequencing studies of HCC tissues have identified the frequently activating mutations of