Aberrant expression of alternative isoforms of transcription factors in hepatocellular carcinoma

Table 1 Transcription factors and their isoforms deregulated in hepatocarcinogenesis

TF	No. of isoforms expressed in the liver	Types of isoforms	Regulated processes (canonical isoform)	Upstream signaling pathways	Target genes expressed in the liver	Isoforms that presumably promote hepatocarcinogenesis	Isoforms that exhibit tumor-suppressive effects	Ref.
C/EBPβ	3	TA, DN	Metabolism POS: apoptosis, inflammatory response NEG: proliferation	TNF	UP(LAP1): cytochrome p450 genes UP(LIP): GADD45B DOWN (LAP1): CCNA, CCNE, CDK2, PCNA DOWN (LIP): CLU, NUMB	C/EBPβ-LIP	C/EBPβ-LAP1, C/EBPβ-LAP2	[59,65,74,76,77, 78,139]
ERα	4	DN	POS: proliferation	Estrogen signaling	UP: CCND1, HNRNPH2, MYC, RET, WWC1	ERα-36, ERα-46, ER-αΔ5	ERα-66	[41,43,44,47,139,140]
HIF1α	3	DN	NEG: apoptosis, inflammatory response	PI3K/Akt, mTOR	UP: VEGFA	HIF1α1.1	HIF1α516, HIF1α736	[125,131,133,134,139]
HNF4α	9-12	TA	POS: angiogenesis	AMPK, Hippo, TGFβ	UP: CDH1, CDKN1A, HNF1a, PERP DOWN: BMP7, HMGA2, MYC, SNAI1, SNAI2	HNF4α7-α9	HNF4α1-α3	[28,29,37,139,141,142]
KLF6	3	TA, DN	POS: differentiation, morphogenesis, apoptosis	TGFβ	UP(wtKLF6): ССND1, CDH1, CDK4 UP(SV2): CDKN1A DOWN(wtKLF6): MDM2 DOWN(SV1): CDKN1A	SV1	wtKLF6, SV2	[105,108-114,143]
p73	3	TA, DN	NEG: proliferation, invasion, metastases	p53, Hippo, mTOR	UP: BCL2 family genes, caspases, CD95, TNF-R, TRAIL-R	ΔN-p73, ΔEx2p73, ΔEx2/3p73	TA-p73	[87-91,139,144]
PGC1α	3	TA, DN	POS: proliferation, differentiation, apoptosis	AMPK, Insulin signaling	UP: GLUT4, PDK4, PEPCK, PPARA, PPARG	PGC1α1-a, LPGC1α, NT-Pgc 1α-a* (*promote replication and assembly of in HBV and HCV)		[49,52,54-56,139]
TCF4 (TCF7L2)	17	TA	POS: apoptosis	Wnt, Hippo	UP: AXIN2, CCND1, IRS1, JUN, MMP7, WISP1	TCF-4J, TCF-4C	TCF-4B, TCF-4K	[98-102,139,145]
WT1	4	DN	NEG: cell cycle progression		UP: BCL2 family genes, cFLIP DOWN: FADD, HNF4A, NF-κB	WT1(+/) 17АА(+)KTS	WT1(-)KTS	[119-122,146]
ZIP (ZGPAT)	2	DN	POS: gluconeogenesis		DOWN: CDC25A, EGFR, FGF5, FGF14, PDGFB, PTEN, RGS3, TBPL1, VCAM1	sZIP	ZIP(fl)	[135-137]

C/EBP: CCAAT enhancer binding protein; TF: Transcription factor; TA: Isoforms with differential transactivation properties; DN: Dominant-negative; POS: Positive regulation; NEG: Negative regulation; UP: Up regulation; DOWN: Down regulation.