Table 2.

Metastasis suppressors interacting with MDM2

Gene	Roles in liver cancer metastasis	Binding to MDM2	Functional association with MDM2	References
E-cadherin	Reduced E-cadherin expression is associated with high tumor grade, vascular invasion, intrahepatic metastasis, disease progression, and poor outcomes.	Endogenous binding	MDM2 promotes E-cadherin degradation in breast cancer cell lines.	[68–72]
NME2	NME2 expression is increased in HCC.	Endogenous binding	MDM2 suppresses the ability of NME2 to negatively regulate cell motility in renal cell carcinoma and lung cancer cell lines.	[77–79]
TAp63	Role of TAp63 in HCC metastasis is not explored.	Endogenous binding	MDM2 suppresses TAp63 activity by inhibiting its nuclear localization in MEFs and osteosarcoma cell lines. Conversely, MDM2 increases TAp63 levels and its transcriptional activity in osteosarcoma and monkey kidney fibroblast-like cell lines.	[91,92,94]
FOXO family	Direct association of FOXO proteins with HCC metastasis remains unknown.	Endogenous binding	MDM2 degrades FOXO1, 3, and 4 in MEFs, breast cancer, and lung cancer cell lines.	[110–112]
MTBP	MTBP inhibits HCC migration and metastasis in ACTN4-dependent and -independent manners. Controversially, MTBP may increase HCC metastasis by stabilizing MDM2.	Exogenous	The roles of MTBP in cancer metastasis, the underlying mechanisms, and functional association between MDM2 and MTBP remain to be further investigated.	[114–117,122]

MDM2: murine double minute 2; FOXO: forkhead box O; NME2: non-metastatic cells 2; MTBP: MDM2 binding protein; HCC: hepatocellular carcinoma