Page 125 - Read Online

greatly contributes to tumor development through inhibition human HCC. [32-35]
of p53 activity. MDM2 is also a transcriptional target of p53,
hence forming autoregulatory negative feedback loop. MDM2 directly binds to HIF-1α, and overexpression of MDM2
[11]
results in accumulation of HIF-1α in hypoxic cells and increase
Increasing evidence, however, indicates that MDM2 also has in hypoxia-induced VEGF transcription. [36,37] Conversely,
p53-independent functions toward malignant progression MDM2 is shown to degrade HIF-1α under hypoxic conditions,
when overexpressed. Approximately 10% of human cancers which is inhibited by phosphorylation of MDM2 at serine
have both MDM2 overexpression and mutant p53. Mice 166 by AKT. [38,39] Thus, the roles of MDM2 in regulating HIF-
[12]
carrying a MDM2 transgene develop a higher percentage 1α function need to be further investigated. Although both
of sarcomas regardless of p53 status, as compared with MDM2 and HIF-1α play roles in HCC progression, there is
p53-null mice. Ectopic expression of MDM2 in mammary no existing study that directly shows MDM2 enhancing liver
[13]
epithelial cells of mice, as well as in mouse embryonic cancer metastasis through upregulation of HIF-1α.
fibroblasts (MEFs), increases aneuploidy and chromosome/
chromatid breaks regardless of p53 status. [14,15] MDM2 Slug
interacts with different proteins and alters their activities, Slug (also known as Snail family zinc finger 2: Snail2) is a
leading to malignant progression independent of p53. member of the Snail family of transcription factors that induce
[11]
Specifically, MDM2 inhibits Nijmegen breakage syndrome EMT crucial for embryogenesis and cancer metastasis by
1, leading to inhibition of double-strand break repair. repressing E-cadherin. Slug is upregulated in many cancer
[40]
[16]
MDM2 also promotes p21 degradation. [17,18] Additionally, types, including HCC, and its overexpression is associated
MDM2 promotes cell cycle progression through activation with invasion and metastasis of HCC. [41-43]
of S-phase, via interaction with the retinoblastoma tumor
suppressor protein and the transcriptional factor E2F. [19,20] MDM2 is shown to stabilize Slug mRNA in a p53-independent
MDM2 furthermore enhances doxorubicin resistance in manner, while knockdown of Slug nullifies invasion of
acute lymphoblastic leukemia cells through its binding to the HCT116 p53-null colon cancer cells induced by MDM2
[44]
Sp1-binding site in the p65 promoter. MDM2 is shown to overexpression. However, direct evidence demonstrating
[21]
bind to Sp1 and inhibit Sp1-dependent transcription. Thus, that MDM2’s involvement in promoting HCC metastasis via
[22]
numerous MDM2 binding partners and effectors contribute upregulation of Slug has not yet been demonstrated.
to its p53-independent functions. [23]
Matrix metalloproteinase-9
MDM2 overexpression is clinically correlated with metastasis Matrix metalloproteinase 9 (MMP-9), is a type IV collagenase
of multiple cancer types including liver cancer, [24-27] but the which is a group of zinc-containing endopeptidases to degrade
underlying mechanisms remain unclear. In this review, structural proteins of extracellular matrix, thus playing a
[45]
we focus on p53-independent roles of MDM2 in cancer pivotal role in the metastatic process. Overexpression
metastasis, specifically in liver cancer. We categorize of MMP-9 is well correlated with invasion, metastasis, and
effectors of MDM2 into metastasis promoters [Table 1] and poor prognosis in liver cancer. [46-49] Correlation between the
suppressors [Table 2]. expression of MMP-9 and MDM2 is shown in benzopyrene-
induced lung cancer in rats, where both protein expression
METASTASIS PROMOTERS is higher in stage III and IV lung cancer tissues as compared
[50]
with stage I and II tissues. Also, in human breast cancer,
Hypoxia-inducible factor-1-alpha MDM2 expression is positively correlated with that of
Hypoxia-inducible factor-1-alpha (HIF-1α) and HIF-1β MMP-9, and is also negatively correlated with disease-free
are a class of transcription factors that play a key role in survival. Moreover, knockdown of MDM2 in pancreatic
[51]
regulating cellular response against hypoxia. While HIF- carcinoma SW1990HM cells results in reduced MMP-9
[28]
1β is constitutively expressed, expression of HIF-1α is protein expression, and MDM2 promotes invasion of both
[52]
dependent on oxygen tension. In normoxic conditions, MCF7 and MDA-MB-231 cell lines by increasing the MMP-9
it is rapidly degraded, whereas in hypoxic states, HIF-1α promoter activity. Although there is definite clinical and
[51]
heterodimerizes with HIF-1β on hypoxia response elements functional correlation between MMP-9 and MDM2, it remains
in the promoter regions of numerous downstream target unclear whether MDM2 induces invasion and metastasis in
genes, thus promoting tumor invasion, angiogenesis, and liver cancer through upregulation of MMP-9.
[29]
metastasis. For example, HIF-1α transactivates Snail1 and
vascular endothelial growth factor (VEGF) that accelerate Hu antigen R
epithelial-mesenchymal transition (EMT), a crucial biologic Hu antigen R (HuR, also known as ELAV-like protein 1) was first
process for epithelial tumors to gain metastatic potential, identified in drosophila as a member of the embryonic lethal
and angiogenesis, respectively, thereby enhancing invasion abnormal vision (ELAV) family RNA-binding proteins. [53,54] HuR
[30]
and metastasis. HIF-1α is overexpressed in multiple types binds to AU-rich elements in the 3’ untranslated region of
of human cancer including HCC. [31,32] Overexpression of HIF- target mRNAs and stabilizes them, resulting in regulation
1α is correlated with vascular invasion and poor survival in of cell proliferation, survival, immune response, and

Hepatoma Research | Volume 2 | May 6, 2016 116