Differentiation-inducing therapy: A potential therapeutic strategy that targets liver cancer stem cells

Table 1 Molecules and agents with differentiation-inducing effects in hepatocellular carcinoma

Agent/molecule	Target/mechanism	Key effects on HCC	Ref.
HNF-4α (gene delivery)	Master hepatocyte transcription factor	Induces differentiation, reduces stemness (CD133, CD90), abolishes tumorigenicity, inhibits metastasis	[16]
HNF-3γ (gene delivery)	HNF	Promotes differentiation, sensitizes to sorafenib via OATP1B1/1B3	[18]
miR-148a mimic	IKKα/NUMB/Notch inhibitor	Induces hepatocytic differentiation, suppresses tumor growth, reduces fibrosis	[23]
ATRA	Nuclear receptor	Induces differentiation of tumor-initiating cells, reverses EMT, potentiates cisplatin, eradicates LCSCs	[3,27]
Sophocarpine	AKT/GSK-3β/β-catenin, TGF-β/EMT	Reduces LCSCs ratio, inhibits sphere formation, reverses malignant phenotype	[13]
ICG-001	CBP/β-catenin interaction	Eliminates drug-resistant, upregulates let-7a (in pancreatic cancer)	[21]
P-T3H2 peptide	TRIB3-HNF-4α interaction	Stabilizes HNF-4α, restores hepatic functions, induces senescence	[15]
5-azacytidine	CpG demethylation	Inhibiting HCC cell tumorigenicity	[25]
Trichostatin A	Histone deacetylase inhibitor	Cell growth inhibition and the mature hepatic gene expression	[28]
Oxygen species	Activation of Akt/IKK signaling pathway	Trans-differentiation into endothelial	[31]
Small molecule cocktail	TGF-β, GSK-3β, G9a, ATRA	Induces differentiation via Akt/mTOR/HIF1α, suppresses Snail	[34]

HCC: Hepatocellular carcinoma; HNF: Hepatocyte nuclear factor; IKKα: Inhibitor of kappa kinase α; NUMB: NUMB endocytic adaptor protein; ATRA: All-trans retinoic acid; EMT: Epithelial-mesenchymal transition; LCSCs: Liver cancer stem cells; AKT: Protein kinase B; GSK-3β: Glycogen synthase kinase-3 beta; TGF-β: Transforming growth factor β; CBP: CREB-binding protein; TRIB3: Tribbles homolog 3; mTOR: Mammalian target of rapamycin; HIF1α: Hypoxia-inducible factor 1 alpha.