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Lin et al. Hepatoma Res 2018;4:26 I http://dx.doi.org/10.20517/2394-5079.2018.27 Page 3 of 8

[21]
heterodimerizes with HIF1β and binds core hypoxia-response element [HRE, 5′-(A/G)CGTG-3′] . Many
HIF target genes play important roles in HCC proliferation, metabolism, angiogenesis, invasion and
[6]
metastasis .
Activation of Wnt/β-catenin pathway, PI3K/AKT pathway and SNAIL1 are involved in the epithelial
mesenchymal transition (EMT), increasing HCC invasion and metastasis [22,23] . As reported, β-catenin can
[24]
reinforce the transcriptional activity of HIF1α and consequently facilitate hypoxia-induced EMT . And
regulation of BCL9 expression by HIF1α may explain the crosstalk between Wnt/β-catenin signaling and
[25]
hypoxia signaling pathways . Besides, HIF1α activation can be regulated by PI3K/Akt pathway, and the
activation of PI3K/Akt/HIF1α pathway mediates hypoxia-induced EMT and drug resistance [26,27] . HIF1α
[28]
also promotes EMT through increasing SNAIL1 transcription in HCC cells under hypoxia . Angiogenic
factors like VEGF, bone morphogenetic protein 4 (BMP4) and stem cell factor (SCF) can enhance HCC
[29]
[30]
angiogenesis . VEGF has been well characterized as a direct target of HIF systems , promoting
endothelial cell proliferation and migration especially in areas of hypoxia [31,32] . Additionally, hypoxia-induced
[33]
[34]
BMP4 expression is regulated by HIF1α and SCF expression is HIF2α-dependent to promote HCC
angiogenesis and metastasis. Many glycolysis-related genes can be transcriptionally activated by HIF1α,
such as phosphoglycerate kinase 1 (PGK1), hexokinase-2 (HK2), glyceraldehyde-3-phosphate dehydrogenase
(GAPDH) and phosphofructokinase (PFK) [6,16] . It indicates that there is an increased glycolysis in the
progression of hypoxia HCC to adapt to oxygen deficiency. HIF1α induces growth factors, including TGF-α
[35]
and IGF-2, to promote cell proliferation and survival . TGF-α/EGFR can be activated by HIF2α and
[31]
contribute to sorafenib resistance in HCC cells . Besides, HIF1α regulates the expression of MMPs to
[36]
induce extracellular matrix degradation and tumor metastasis . NKG2D is critical in directing NK cell
[37]
responses against tumors. Yamada et al. show that hypoxia promotes downregulation of the NKG2D
ligand MICA by tumor cells via a HIF1α-dependent mechanism. Under hypoxia and in the presence of
+
TGF-β, CD4 T cells upregulate Foxp3 through direct binding of HIF1 to Foxp3 promoter region, inducing
[38]
Treg formation and immune tolerance . Taken together, HIF system regulates hypoxic responses of HCC
through diverse signaling pathways, and contributes to HCC progression and malignant process.

HIFs-independent pathways
HMGB1 signaling pathways
[39]
HMGB1 is a chromatin-binding nuclear damage associated molecular pattern . Its release under hypoxic
condition can induce an inflammatory response to promote invasion and metastasis in HCC cells. Under
hypoxic, HMGB1 activates TLR4 and RAGE signaling pathways to induce caspase-1 activation. Caspase-1
subsequently mediates the cleavage and release of a series of pro-inflammatory cytokines (IL-1β and IL-
18), which in turn promote cancer invasion and metastasis [18,40] . Moreover, recent studies suggest that
HMGB1 can also translocate from the nucleus to the cytosol under hypoxia, and then bind to mtDNA
[39]
released from damaged mitochondria . Subsequent activation of TLR9 signaling pathway promotes HCC
proliferation [18,39] , indicating a novel mechanism of the involvement of HMBG1 in HCC progression under
hypoxia.

Hippo-YAP pathways
The Hippo pathway is a classical regulator of organ size and regeneration, and YAP is an important
transcriptional co-factor locating at the downstream of Hippo pathway [41,42] . The activation of YAP promotes
[43]
survival, chemoresistance, metastasis, and the other malignant properties of HCC . It has been reported
in recent studies that hypoxia induces nuclear translocation and activation of YAP in a HIF-independent
way, and the subsequent activation of target genes promotes cell survival, resistance to SN38 and sorafenib
in HCC [17,43] . Meanwhile, statins (the inhibitors of hydroxymethylglutaryl-CoA reductase) can suppress YAP
[43]
target genes and overcome hypoxia-induced resistance to sorafenib . Moreover, YAP could also contribute
[44]
to liver tumorigenesis by inducing HIF1α-dependent aerobic glycolysis . HMGB1 is relevant in this process
[44]
by binding to GA-binding protein alpha (GABPα) to promote the expression of YAP .