Genetic and epigenetic aspects of initiation and progression of hepatocellular carcinoma

Table 1 Genes upregulated in hepatocellular carcinoma; putative oncogenes

Symbol (location)	Biological function	Expression	n	Relevant clinical factors	Functional analyses	Interacting molecules	In vivo	Ref.
AURKA (20q13)	Cell cycle-regulated kinase	IHC	44	OS, RFS, number, stage	Chemoresistance, apoptosis	NF-κB, miRNA-21, PTEN	Yes	40
BIRC7 (20q13.3)	Inhibitor of apoptosis protein family	mRNA, IHC, WB	61	None	Proliferation, migration, invasion, apoptosis	CDK	-	21
Brachyury (6q27)	Embryonic nuclear transcription factor	mRNA, IHC	112	OS, size, stage	Migration, invasion	PTEN, Akt, Snail, EMT	-	22
CCL20 (2q36.3)	Cytokine displaying chemotactic activity for lymphocytes	IHC	62	OS, RFS, AFP, size, mumber, vascular invasion, differentiation	Proliferation, migration	pAKT, β-catenin, EMT	-	45
CCT8 (21q22.11)	Transport and assembly of newly synthesized proteins	IHC	102	OS, grade, size	Proliferation, cell cycle	-	-	30
CTSL (9q21.33)	A lysosomal cysteine proteinase for intracellular protein catabolism	mRNA, IHC, WB	82	OS, RFS, stage, differentiation	Proliferation, tumorigenesis	-	Yes	36
CYTH3 (7p22.1)	Mediator of protein sorting and membrane trafficking	mRNA, IHC	202	OS, size, vascular invasion	Proliferation, migration	-	-	24
DLX4 (17q21.33)	Forebrain and craniofacial development	mRNA, IHC, WB	226	OS, size, differentiation, AFP	-	-	-	27
GOLPH3 (5p13.3)	Peripheral membrane protein of the Golgi stack regulating Golgi trafficking	mRNA, IHC	173	OS, stage	Chemoresistance, apoptosis, angiogenesis, proliferation	NF-κB	Yes	44
GSC (14q32.1)	Autoregulatory transcription factor	mRNA, IHC, WB	112	OS, distant metastasis	Migration, invasion	EMT	-	39
HSF1 (8q24.3)	Heat-shock transcription factor rapidly induced after temperature stress	IHC	67	OS	Proliferation	-	-	34
IL-6 (7p21)	Cytokine that functions in inflammation and the maturation of B cells	mRNA, IHC, WB, ELISA	120	RFS, vascular invasion, number	Stemness	IGFIR, OCT4, NANOG	Yes	43
ISG15 (1p36.33)	Chemotactic activity towards neutrophils	mRNA, IHC	50	OS, differentiation, distant metastasis	Proliferation, migration	Survivin	Yes	33
KPNA2 (17q24.2)	Nuclear transporter of proteins and VJ recombination	mRNA, IHC	314	OS, RFS, size	Proliferation, metastasis	PLAG1	-	29
LGALS3 (14q22.3)	Member of the galectin family of carbohydrate binding proteins	mRNA, IHC, WB	165	OS, microvessel density	Proliferation, migration, invasion, apoptosis	-	-	31
MACC1 (7p21.1)	Regulator of HGF-HGFR pathway	mRNA, IHC, WB	50	OS, grade, stage	Proliferation, apoptosis	HGF, c-MET, PI3K, AKT, Caspase 9	Yes	47
MAGED2 (Xp11.21)	Promotor of the cancer cell adhesion to the vascular epithelium	mRNA, IHC	151	OS	-	-	-	51
MAGED4 (Xp11.22)	Unknown	mRNA, IHC	94	OS, RFS, AFP, vascular invasion, differentiation	-	-	-	50
MCT4 (17q25)	Catalyzing lactic acid and pyruvate transport across plasma membranes.	IHC	318	OS, RFS, AFP, size	Proliferation, migration, invasion	pAKT, HIF-1α	-	26
MRC2 (17q23.2)	Extracellular matrix remodeling by mediating the internalization	IHC	96	OS, number, vascular invasion	Migration, invasion	TGFb	-	25
PDGFRα (4q12)	Cell surface tyrosine kinase receptor for platelet-derived growth factor family	mRNA	57	OS, RFS, vascular invasion, microvessel density	Proliferation, migration, invasion	EMT	Yes	38
PKM2 (15q22)	Pyruvate kinase generating ATP and pyruvate	mRNA, IHC, WB	721	OS, RFS, size, vascular invasion, differentiation	Proliferation, migration, invasion	pAKT, HIF-1α	Yes	46
PLK1 (16p12.2)	Controlling mitotic entry, centrosome maturation, and bipolar spindle formation	IHC	67	Differentiation, capsule invasion	Proliferation, cell cycle, apoptosis	caspase 3/8, Bax, Bcl-2	-	37
PTP4A1 (6q12)	Regulator of cellular processes, including cell proliferation and migration	IHC	167	OS	Migration, invasion	PI3K/AKT/ GSK3β pathway	-	32
SERPINB3 (18q21.3)	Ovalbumin family of serine proteinase inhibitors	mRNA, IHC	67	RFS	-	HIF-2α	-	41
SIRT1 (10q21.3)	Regulating epigenetic gene silencing and suppress recombination of rDNA	mRNA, IHC, WB	99	OS, size, number, stage	Migration, invasion	EMT	Yes	28
		mRNA	-	-	Proliferation, cell cycle	miR29c	-	58
		IHC	248	RFS	Proliferation, cell cycle	p53, AMPK, mTOR	-	59
TPX2 (20q11.2)	Microtubule organization during mitosis	mRNA, IHC	130	OS, RFS, stage, number, differentiation	Migration, invasion	MMP2/9, pAKT	-	35
		mRNA, IHC	86	OS, RFS, vascular invasion, stage	Proliferation		Yes	62
TREM1 (6p21.1)	Receptor belonging to the Ig superfamily that is expressed on myeloid cells	mRNA, IHC, WB	322	OS, RFS, age, AFP	Proliferation, invasion, cell cycle, apoptosis	IL-1β, TNF-α, MCP-1, p65, STAT3, ERK	-	23
UBE2Q1 (1q21.3)	Member of the E2 ubiquitin-conjugating enzyme family	IHC	86	OS, grade	Proliferation, cell cycle	p53, p21	-	42
UBE4B (1p36.3)	Conjugation factor E4 involved in multiubiquitin chain assembly	mRNA, IHC, WB	149	OS, grade, stage	Proliferation, migration, invasion, apoptosis	p53, Bcl-2, caspase 3	-	48
VEGF-B (11q13)	Regulator of angiogenesis	mRNA	48	Number, vascular invasion, capsule invasion, stage	-	-	-	12
YY1AP1 (1q22)	Unknown	Microarray	76	OS	Proliferation, apoptosis, spheroid-formation	EpCAM	Yes	49

IHC: Immunohistochemistry; WB: Western blotting; OS: Overall survival; RFS: Recurrence free survival; AFP: Alpha-fetoprotein; PIVKA: Protein induced by vitamin K antagonists.

Table 2 Genes suppressed in hepatocellular carcinoma; putative tumor suppressors

Symbol (location)	Biological function	Expression	n	Relevant clinical factors	Functional analyses	Interacting molecules	In vivo	Ref.
ARNT2 (15q24)	Partner for several sensor proteins of the bHLH-PAS family	IHC	195	OS, RFS, age, size, number, vascular invasion, AFP, differentiation, stage	Proliferation, invasion, migration	-	Yes	79
BTG1 (12q22)	Regulates cell growth and differentiation	mRNA, IHC	151	OS, RFS, PIVKA-II, size, differentiation, vascular invasion, stage, extra-hepatic recurrence	-	-	-	80
CDH3 (16q22.1)	Calcium-dependent cell-cell adhesion glycoprotein	IHC	69	Stage	Proliferation	-	-	71
EBP1 (12q13.2)	RNA-binding protein involved in cell growth regulation	IHC, WB	103	OS, grade, size	Growth, cell cycle	-	-	74
FBLN5 (14q32.1)	Secreted extracellular matrix protein	mRNA, IHC	86	OS, number, vascular invasion, grade, stage	Migration, invasion	MMP7	-	76
Fbxw7 (4q31.3)	Ubiquitin-mediated degradation of cyclin E	IHC	60	OS, size, vascular invasion, grade, stage	Growth, apoptosis	YAP	Yes	77
GPx3 (5q23)	Detoxification of hydrogen peroxide	mRNA, IHC, ELISA	113	OS, RFS, size, number, vascular invasion, stage	Proliferation, invasion	Erk, NFκB, SIP1	Yes	75
IGFBP-1 (7p12.3)	Mediator of the IGFs	IHC	90	OS, differentiation, cirrhosis, vascular invasion, stage	Invasion	MMP9	-	73
LGALS4 (19q13.2)	Modulating cell-cell and cell-matrix interactions	mRNA, IHC, ELISA	201	Size, differentiation, vascular invasion, stage	Migration, invasion	-	-	72
TIPE1 (19p13.3)	Unknown	IHC	50	OS, grade	Growth, apoptosis	Nec-1, Rac-1	Yes	78

IHC: Immunohistochemistry; WB: Western blotting; OS: Overall survival; RFS: Recurrence free survival; AFP: Alpha-fetoprotein; PIVKA: Protein induced by vitamin K antagonists.

Table 3 Genes epigenetically suppressed in hepatocellular carcinoma through promoter hypermethylation

Symbol (location)	Biological function	Expression	n	Relevant clinical factors	Functional analyses	Interacting molecules	In vivo	Ref.
CLDN3 (7q11.23)	Integral membrane protein and a component of tight junction strands	mRNA, IHC	114	OS	Motility, invasion, tumor formation	Wnt, EMT, β-catenin	Yes	99
DENND2D (1p13.3)	Membrane trafficking protein regulating Rab GTPases	mRNA, IHC	92	OS, RFS	-	-	-	100
DPT (1q12-q23)	Cell-matrix interactions and matrix assembly	mRNA, IHC, WB	202	OS, RFS, AFP, vascular invasion, differentiation	Migration, metastasis	RhoA, FAK, c-SRC, α3β1 integrin	Yes	98
DPYSL3 (5q32)	Cell-adhesion factor involved in the metastatic process of tumor cells	mRNA, IHC	151	OS, RFS, AFP, PIVKAII, gender, vascular invasion, serosal invasion	Migration, invasion	VEGF, FAK	-	105
EFEMP1 (2p16)	Extracellular matrix glycoproteins	mRNA	48	OS, liver damage, AFP	-	-	-	103
FBLN1 (22q13)	Secreted fibrillar extracellular matrix protein	mRNA, IHC, WB	48	number, size, stage	-	-	-	96
MEG3 (14q32)	Unknown	mRNA	72	OS, RFS, tumor size and Edmondson grade	Proliferation, apoptosis	p53, UHRF1	Yes	102
MT1G (16q13)	Preserve the homeostasis of metals	mRNA	48	none	-	-	-	11
PDSS2 (6q16.3-21)	Synthesis of coenzyme Q10	mRNA, IHC	151	OS, RFS, AFP, vascular invasion, differentiation, serosal invasion, stage	-	HNF4a, CDX2	-	101
RELN (7q22)	Secreted extracellular matrix protein	mRNA	48	RFS	-	-	-	104
TIF1γ (7p22.1)	Unknown	IHC, WB	204	OS, RFS, stage	Invasion, metastasis	TGF-β/Smad	-	97
TUSC1 (9p21.2)	Unknown	mRNA, IHC	94	OS, stage	-	-	-	106

IHC: Immunohistochemistry; WB: Western blotting; OS: Overall survival; RFS: Recurrence free survival; AFP: Alpha-fetoprotein; PIVKA: Protein induced by vitamin K antagonists.

Table 4 Dysregulated microRNAs in hepatocellular carcinoma

microRNA	Sample	n	Relevant clinical factors	Functional analyses	Interacting molecules	In vivo	Ref.
miR-9	Tissue	200	OS, vascular invasion, stage	-	-	-	122
miR-21	Tissue	109	RFS, cirrhosis, stage	Growth	AP-1	Yes	129
miR-106b	Tissue	104	OS, size, vascular invasion	-	-	-	125
miR-122, miR-29	Serum	20	Liver damage	-	-	-	127
miR-128-2	Tissue, serum	182	OS, liver damage	-	-	-	132
miR-130a	Tissue	102	OS, gender, HBsAg status, size, stage	-	-	-	124
miR-130b	Tissue	97	OS, RFS, HBsAg status, AFP, size, grade, stage	-	-	-	126
miR-138	Tissue	180	OS, stage, vascular invasion, stage	-	cyclin D3	-	130
miR-148a	Tissue	297	OS, size	Proliferation, migration, invasion	ACVR1, BMP, Wnt	Yes	131
miR-224	Tissue	130	OS, RFS, AFP, stage, grade	-	pAKT	-	128
miR-331-3p	Tissue	108	OS, RFS, size, number, vascular invasion	Proliferation, migration, metastasis	PHLPP, AKT, EMT	Yes	123

miR: MicroRNA; OS: Overall survival; RFS: Recurrence free survival; HBsAg: Hepatitis B surface antigen; AFP: Alpha-fetoprotein.