Page 50 - Read Online

Page 2 of 8 Lin et al. Hepatoma Res 2018;4:26 I http://dx.doi.org/10.20517/2394-5079.2018.27

[6]
Hypoxia is a common phenomenon in the intratumor regions of HCC patients . Abnormal
[6,7]
microvasculature and unrestrained proliferation of HCC cells lead to oxygen deficiency . Hypoxia is
involved in multiple biological process of HCC and promotes tumor aggressiveness, chemoresistance and
[8,9]
immunotherapy resistance . Consequently, the hypoxic microenvironment has been regarded as promising
target for HCC treatments. Under hypoxia, hypoxia-induced factors (HIFs) would be stabilized to trigger
the transactivation of a series of hypoxia-response genes which promote the malignance of HCC. Thus,
[8]
the transcription factors HIFs have been regarded as master regulators of hypoxic microenvironment .
In contrast, several lines of evidence also implicated the HIF-independent hypoxia responses [10-14] . Taken
together, the mechanisms in HCC progression under hypoxia are complicated and sophisticated. This
review will summarize current research advances in hypoxia-mediated molecular mechanism, how hypoxia
participates in the progression of HCC and the current intervetion strategies targeting intratumor hypoxia
of HCC.

HYPOXIA PLAYS CRITICAL ROLES IN THE PROGRESSION AND MALIGNANCE OF HCC
Due to the rapid-growing nature of HCC, increased numbers of cells consume increased amount of oxygen,
[15]
and hypoxia exists in regions of the tumor that are far away from blood vessels . Through various signaling
pathways, hypoxia further triggers a series of HCC transformation, mediating its angiogenesis, metastasis,
[6]
metabolism deregulation and drug resistance . Hypoxia is a major cause of hypervasculature of HCC by
[15]
inducing angiogenic factors to stimulate angiogenesis and support tumor growth . In addition, a variety
of genes would be transactivated under hypoxia by HIFs or the other transcriptional factor and involved
in multiple steps of HCC metastasis including epithelial-mesenchymal transition (EMT), invasion of the
[5]
extracellular matrix, intravasation, extravasation, and secondary growth of the metastases . Besides,
[16]
hypoxia-regulated glycolysis module also contributes to HCC progression . Recent study also indicates
that hypoxia promotes the differentiation and expansion of immune-suppressive stromal cells, and remodels
[9]
the metabolic landscape to support immune privilege . Therefore, hypoxia can reduce the effectiveness
of cancer immunotherapy. Thus, hypoxia microenvironment is highly relevant in HCC development and
extensively involved in the process of HCC progression.

MOLECULAR PATHWAYS INVOLVED IN HYPOXIC HCC MALIGNANCE
The complicated and sophisticated pathways underlying hypoxia have been extensively investigated, and
HIFs are identified to play pivotal roles under hypoxia, which has attracted most attention in this field for
[6,8]
the last decades . Yet recently, the findings on the HIFs-independent regulation of tumor angiogenesis
and chemoresistance under hypoxic conditions have challenged this notion and raised the possibility that
the other important signaling pathways may also participate and promote the progression and malignance
[17]
of HCC [10-14] . Accumulating evidence shows that Yes associate-Protein (YAP) , matrix metalloproteinases
(MMPs), high mobility group box 1 (HMGB1) and glucose metabolism enzymes are involved in hypoxia-
[18]
mediated effects in HCC . The above key molecules would be activated as sensors of intratumoral oxygen
tension, and trigger the subsequent activation of hypoxia-mediated process, thus may also be regarded as
potential targets for HCC therapy.

HIFs-dependent pathways
HIF system is composed of α-subunits and β-subunits. Under normoxia, HIF1α is maintained at very low
basal activities due to constitutive degradation. Prolyl hydroxylation of HIF1α by prolyl hydroxylase domain-
containing proteins (PHD1, PHD2 and PHD3) induces its ubiquitination and proteasomal degradation by
[6]
an E3 ligase , von Hippel-Lindau tumor suppressor protein (pVHL). Besides, asparaginyl hydroxylation
of HIF1α by factor inhibiting HIF (FIH) interferes its interaction with transcriptional coactivators,
CREB-binding protein (CBP) and p300 [19,20] . Under hypoxia, lacking sufficient oxygen, hydroxylation and
proteasomal degradation of HIF1α are impaired. HIF1α is stabilized and then translocates into nucleus,