RNA-centered mechanisms sustaining self-renewal in hepatocellular carcinoma stem cells: Effector dosage, protein output and regulatory deployment

Table 1 RNA-centered mechanisms linked to hepatocellular carcinoma cancer stem cell self-renewal or stem-like phenotypes

RNA regulator/machinery	Class	Primary operation	Proximal target or molecular partner	Convergent pathway/functional output	Functional evidence captured in manuscript	Evidence level	Ref.
Effector dosage/availability
miR-338-3p	miRNA	Dosage/threshold control	SOX4 repression	SOX4-linked stemness	Sphere/stemness and functional phenotypes	Supportive	[45]
miR-2117	miRNA	Dosage/threshold control	SOX2 repression	SOX2-linked CSC expansion and chemoresistance	CSC expansion/chemoresistance assays	Supportive	[46]
circ_0000972	circRNA	Transcript-level competition	miR-96-5p/PFN1 axis	Stemness suppression	Stemness phenotypes; not primary deployment evidence	Supportive	[42]
METTL3-SOCS3	m6A writer axis	Dosage/RNA fate	SOCS3 mRNA; JAK2-STAT3 signaling	STAT3 pathway output	Stemness/tumorigenicity assays	Supportive	[35]
SOCS2-AS1	LncRNA	Dosage/ceRNA-like control	miR-454-3p/CPEB1	Stemness suppression axis	CSC phenotype assays	Supportive	[28]
DIO3OS	LncRNA	Transcript availability/export	NONO-mediated ZEB1 mRNA export	ZEB1 protein availability	RNA export and CSC phenotype assays	Supportive	[18]
DUBR	LncRNA	Dosage feedback architecture	miR-520d-5p/CIP2A/E2F1	NOTCH1-associated stemness	Mechanistic feedback and CSC phenotypes	Supportive	[33]
IGF2BP1	m6A reader/RBP	Transcript persistence	MGAT5 mRNA stability	MGAT5-linked CSC phenotype	m6A-dependent binding and stemness assays	Supportive	[27]
RALYL	RNA-binding protein	Transcript persistence	TGF-β2 mRNA stability	PI3K-AKT-STAT3 signaling	Transcript-stability mechanism and CSC phenotypes	Core	[6]
LINC01013	LncRNA	Dosage/ceRNA-like control	miR-6795-5p/FMNL3	CSC features	CSC phenotype assays	Supportive	[29]
MALAT1	LncRNA	Dosage/ceRNA-like control	miR-375/YAP1	YAP1-linked CSC expansion	CSC phenotype assays	Supportive	[30]
miR-192-5p	miRNA	Metabolic threshold control	GLUT1, PFKFB3, c-MYC	Glycolytic permissiveness	Metabolic and stem-like phenotype assays	Supportive	[24]
miR-5188	miRNA	Dosage/pathway threshold control	FOXO1 repression	β-catenin nuclear accumulation; HBV/HBX-linked context	Target-and-rescue logic; pathway mechanism	Core	[7]
miR-613	miRNA	Dosage/threshold control	SOX9 repression	Stemness suppression	CSC expansion assays	Supportive	[47]
miR-26b-5p	miRNA	Marker-associated dosage control	HSPA8 in malignant EpCAM-positive cells	EpCAM-positive malignant compartment	Malignant vs non-malignant EpCAM-positive comparison	Supportive	[21]
miR-365	miRNA	Dosage/threshold control	RAC1 repression	CSC phenotype suppression	CSC phenotype assays	Supportive	[48]
THOR	LncRNA	Dosage/pathway output	β-catenin-associated regulation	Wnt-β-catenin-linked CSC expansion	CSC expansion assays	Supportive	[31]
miR-302a/d	miRNA	Dosage/pathway threshold control	E2F7/AKT-β-catenin signaling	CSC context signaling	Sphere/tumorigenicity-related assays	Supportive	[23]
miR-200b-ZEB1	miRNA circuit	CSC-state composition	ZEB1 circuit	Marker-defined CSC state redistribution	Marker-state and stemness assays	Supportive	[20]
miR-217	miRNA	Dosage/threshold control	DKK1-dependent Wnt regulation	Wnt-linked stem-like traits	Stem-like phenotype assays	Supportive	[43]
miR-500a-3p	miRNA	Dosage/threshold control	SOCS2, SOCS4, PTPN11	STAT3 signaling	Functional CSC assay and target-rescue logic	Core	[17]
MSI2	RNA-binding protein	RBP-linked dosage control; proximal mechanism unresolved	LIN28A downstream component	CSC self-renewal and tumorigenicity	Functional evidence; direct mRNA stabilization unresolved	Supportive	[26]
miR-452	miRNA	Dosage/threshold control	Sox7 repression	Wnt-β-catenin activation	Stem-like phenotype assays	Supportive	[44]
miR-589-5p	miRNA	Marker-associated dosage control	MAP3K8 in CD90-positive cells	CD90-positive compartment dependency	Marker-defined compartment evidence	Supportive	[22]
miR-491	miRNA	Supportive threshold logic	GIT-1/NF-κB/EMT	CSC-like properties	CSC-like phenotype assays	Supportive	[49]
ICR	LncRNA	Transcript persistence/RNA-RNA duplex control	ICAM-1 mRNA stability	ICAM-1 + CSC state; PVTT-associated phenotype	Sphere assays, in vivo ICR inhibition, clinical PVTT correlation	Supportive	[25]
miR-25	miRNA	Supportive threshold logic/apoptotic resistance	PTEN-PI3K-AKT-Bad	Apoptotic resistance in CSC context	Treatment/phenotype-linked evidence	Supportive	[50]
miR-1246	miRNA	Dosage/pathway threshold control	AXIN2 and GSK3β repression	β-catenin destruction machinery	Functional CSC evidence and pathway mechanism	Core	[3]
miR-4461	miRNA	Dosage/threshold control	SIRT1 repression	CSC expansion and chemoresistance	CSC expansion/chemoresistance assays	Supportive	[51]
Protein output/translational competence
YTHDF1	m6A reader	Protein output	m6A-modified NOTCH1 mRNA	NOTCH1 output	Patient-derived organoids, conditional mouse systems, mechanistic rescue	Core	[4]
METTL16	RNA methyltransferase/ribosome biogenesis regulator	Protein output/translational competence	rRNA maturation; ribosome biogenesis; eIF3a	Functional CSC frequency; de novo HCC initiation	Genetic loss and functional CSC assays	Core	[9]
ADAR1	RNA-editing enzyme	Protein output/recoding	GLI1 R701G editing	Hedgehog activity; mitophagy; oxidative phosphorylation	Mechanistic editing evidence plus tumor initiation	Core	[10]
SNHG3	LncRNA	m6A/RBP-linked RNA fate	miR-502-3p; YTHDF3/METTL3; ITGA6	ITGA6-linked CSC self-renewal	Self-renewal phenotypes and molecular axis	Supportive	[37]
ALKBH5-SOX4	RNA demethylase axis	RNA modification/pathway output	SOX4 demethylation; SHH signaling	Hedgehog/SHH activity	CSC phenotype and mechanism assays	Supportive	[36]
METTL3-FZD10	m6A writer axis	Protein output/receptor-level signaling	FZD10 expression	β-catenin and YAP1 signaling	Mechanistic pathway and functional assays	Core	[5]
TRMT6-TRMT61A	tRNA m1A methyltransferase complex	Protein output/tRNA modification	Selected tRNAs; PPARδ translation	Cholesterol synthesis; Hedgehog activation	tRNA modification and CSC-associated output	Core	[38]
CPEB1	RNA-binding protein	Translational accessibility	SIRT1 3′ untranslated region; poly(A)-tail regulation	SIRT1 protein output	Translation-focused mechanism and tumorigenicity phenotypes	Supportive	[32]
EIF5A2	Translation-associated factor	Protein output/translational machinery	c-MYC-miR-29b circuit	CD133-positive HCC stem-like cells	Marker-enriched evidence; weaker than direct translation models	Supportive	[39]
Regulatory deployment/Locus access/RBP redistribution
SNORA49	snoRNA	Regulatory deployment	HNRNPU-ZC3H18 complex; SOX9 promoter access	SOX9/self-renewal transcription	Functional CSC renewal assays; mechanistic complex/Locus evidence	Core	[19]
SNORD88B	snoRNA	Regulatory deployment	WRN nucleolar retention; XRCC5-dependent STK4 repression	Hippo attenuation	Liver cancer-initiating cell self-renewal assays	Core	[11]
circIPO11	circRNA	Regulatory deployment/Locus access	TOP1 recruitment to GLI1 promoter	Hedgehog/GLI1 output	Limiting dilution, patient-derived cells, genetic knockout model	Core	[1]
LINC00324	LncRNA	Regulatory deployment/TF association	PU.1 association; FasL expression	CSC-like properties	Functional evidence less extensive than core locus-access models	Supportive	[40]
circZKSCAN1	circRNA	Regulatory deployment/RBP redistribution	FMRP sequestration; CCAR1 mRNA interaction	β-catenin-dependent transcription	RBP competition and stemness assays	Core	[14]
HAND2-AS1	LncRNA	Regulatory deployment/Locus access	INO80 recruitment to BMPR1A promoter	BMP signaling	Functional and locus-access evidence	Core	[12]
Lnc-DILC	LncRNA	Regulatory deployment/promoter control	Promoter-associated IL-6 transcription	IL-6-STAT3 circuit	Mechanistic promoter and CSC context evidence	Supportive	[16]
LncCAMTA1	LncRNA	Regulatory deployment/Locus-linked repression	CAMTA1 promoter association	CSC-like properties	Locus-linked and CSC-like phenotype evidence	Supportive	[41]
Boundary mechanisms
SNORA74A	snoRNA	Protein persistence/proximity-mediated dosage control	DCAF13-E2F2 interaction; K48-linked E2F2 ubiquitination	NOTCH3 signaling; liver CSC self-renewal	Genetic deletion, self-renewal and hepatocarcinogenesis assays; ASO intervention	Core	[13]
circRAPGEF1	circRNA with m6A-dependent stabilization	Regulatory deployment/RBP redistribution	IGF2BP3 redistribution away from ASS1 mRNA	Aspartate accumulation; S6K-CAD pathway	Mechanistic RNA-RBP competition plus CSC phenotypes	Core	[34]
Lnc-β-Catm	LncRNA	Protein persistence/proximity control	EZH2-β-catenin proximity	β-catenin stabilization	Mechanistic proximity and CSC phenotypes	Core	[15]
DDX3	RNA helicase	RNA-helicase-associated, epigenetically mediated control of tumor-suppressive miRNA networks	Tumor-suppressive miRNA repression	CSC phenotypes	Upstream machinery evidence; boundary to miRNA section	Supportive	[52]

Note: Evidence level follows the hierarchy defined in the CONCEPTUAL AND EVIDENTIARY FRAMEWORK section and uses two categories only. “Core” indicates a cancer stem cell-relevant functional assay combined with at least one higher-stringency feature, such as limiting dilution, serial propagation, genetic depletion or in vivo ablation, patient-derived functional models or mechanistic rescue. “Supportive” indicates evidence based mainly on marker-enriched fractions, sphere formation, bulk tumorigenicity, treatment response or incomplete mechanistic rescue. Cross-operation placement is recorded in the “Primary operation” column and is not an evidence level. CSC: Cancer stem cell; EMT: Epithelial-mesenchymal transition; NF-κB: Nuclear Factor-κB; HCC: Hepatocellular carcinoma; IL-6: Interleukin-6.