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[55]
differentiation. Elevated expression of HuR is reported in functioning as a metastasis suppressor. [81-86] On the other
many types of cancer. [56,57] Specifically, HuR is upregulated hand, isoforms of p63 lacking N-terminal domain show
in HCC, and its expression is positively correlated with oncogenic function and are overexpressed in multiple
advanced stages of HCC, as well as poor outcomes in HCC cancer types. [85,87,88] Mice with deletion of the p63 gene
[58]
patients. HuR promotes proliferation and differentiation of spontaneously develop tumors, while compound knockout
[59]
hepatocytes, as well as HCC transformation. Importantly, mice for p53 and p63 show high frequency of metastasis as
MDM2 neddylates HuR, protects it from degradation, and compared with p53 or p63 knockout mice. [89,90]
induces its nuclear localization in mouse liver progenitor,
[60]
colon cancer, and HCC cell lines. Although all the cell TAp63 weakly binds to MDM2, and MDM2 is shown to
[91]
lines contain wild-type p53, neddylation of HuR by MDM2 attenuate apoptotic function of TAp63 by inhibiting its
is likely to be p53-independent, which needs to be clarified nuclear localization. However, it is unknown whether or
[92]
in the future. Importantly, it also remains unknown whether not MDM2 inhibits metastasis suppressor function of TAp63.
neddylated HuR by MDM2 enhances HCC metastasis. Conversely, it is also reported that MDM2 competes with
TAp63 for binding to p53 R175H mutant to restore p63 activity,
[93]
METASTASIS SUPPRESSORS and overexpression of MDM2 increases the steady-state
level of intracellular TAp63 and enhances its transcriptional
E-cadherin activity. Thus, the functional relationship of MDM2 with
[94]
E-cadherin is a single transmembrane glycoprotein involved TAp63 is controversial.
in Ca -mediated cell adhesion, mobility, and proliferation of
2+
epithelial cells and functions as a metastasis suppressor. [61,62] Forkhead box O family
Reduced expression of E-cadherin is correlated with high Forkhead box O (FOXO) proteins (FOXO1, 3, 4, and 6) are
potential of invasion and metastasis, as well as poor members of the forkhead family of transcription factors.
[95]
prognosis, in many cancer types including breast, gastric, FOXO proteins have been implicated in suppression of
[64]
[63]
lung, colorectal, and pancreatic cancer. Also in HCC, tumor progression in multiple cancer types. [96-100] Expression
[66]
[65]
[67]
reduced E-cadherin expression is associated with high tumor of FOXO proteins is negatively correlated with migration,
grade, vascular invasion, intrahepatic metastasis, disease invasion, and metastasis of renal cell carcinoma, [101] lung
progression, and poor outcomes. [68-71] cancer, [102] prostate cancer, [103] and urothelial cancer. [104]
Importantly, FOXO3 inhibits EMT by suppressing activities
MDM2 is found to directly interact with E-cadherin and of β-catenin in prostate cancer [103] and Twist1 in urothelial
[72]
facilitate its degradation in a p53-independent manner. cancer, [104] while FOXO4 functions as a metastasis-suppressor
Expression of MDM2 and E-cadherin is inversely correlated through counteracting the PI3K/AKT signal pathway in
in breast cancer having lymph node metastasis. However, prostate cancer [105] and inhibiting EMT in lung cancer. [106]
[72]
it remains unclear whether or not MDM2 promotes HCC
metastasis by degrading E-cadherin. Although reduced expression of FOXO proteins is correlated
with hepatocarcinogenesis and poor survival of HCC patients,
Non-metastatic cells 2 direct association of FOXO proteins with HCC metastasis
[107-109]
Non-metastatic cells 2 (NME2, also known as NDPK-B, remains unknown. MDM2 functions as an E3 ubiquitin
NM23B, NM23-H2) belongs to the nonmetastatic family ligase for FOXO1, FOXO3, and FOXO4 to promote their
[110-112]
and functions as a metastasis suppressor. Reduced NME2 degradation. However, it remains unsolved whether
[73]
expression is associated with increased metastatic potential degradation of FOXO proteins by MDM2 accelerates cancer
of oral squamous cell carcinoma, lung, ovarian, colon, and metastasis.
breast cancer. [74-76] However, NME2 expression is found to be
increased in HCC. [77,78] MDM2 binding protein
MDM2 binding protein (MTBP) was originally identified as a
MDM2 interacts with NME2 in H1299 lung cancer and protein that binds to MDM2. [113] Although these two proteins
HEK293 embryonic kidney cell lines and also suppresses the interact exogenously, their endogenous interactions have not
ability of NME2 to negatively regulate cell motility in renal cell yet been demonstrated. Overexpression of MTBP is shown
carcinoma (UOK117 and its derivative 1.27) and H1299 cell to suppress cell migration and metastasis of osteosarcoma
lines. However, the role of NME2 in metastasis suppression and HCC in alpha-actinin 4 (ACTN4)-dependent and
[79]
of HCC and its functional association with MDM2 in HCC -independent manners. [114-116] Also, in MTBP knockout mice,
remain to be investigated. MTBP haploinsufficiency increases metastasis of tumors
induced in the p53 heterozygous background. [117] Clinically,
TAp63 reduced MTBP expression is associated with reduced patient
TAp63, along with TAp73, are tumor suppressor proteins survival with head and neck carcinoma, as well as capsular/
that belong to the p53 family with high homology in the vascular invasion and lymph node metastasis in HCC. [116,118]
DNA binding domain and recognize the same p53 responsive On the other hand, increased MTBP expression is observed
elements. TAp63 suppresses migration and metastasis in B-cell lymphoma and triple negative breast cancer where
[80]
in many human cancer types including liver cancer, thus it contributes to tumor progression through its interaction
117 Hepatoma Research | Volume 2 | May 6, 2016