. 2024 May 27;9:128. doi: 10.1038/s41392-024-01828-x

Table 2.

Mechanisms of Notch signaling pathway-mediated tumorigenesis and progression

Cancer	Notch signaling component	Role	Involved biological process	Mechanism	Related molecule	Cell line	Ref.
ESCC	Notch1, Notch3	Oncogene	EMT	TGF-β→active Zeb1→represses Notch3→limiting terminal differentiation; TGF-β→active Notch1→drive EMT→promote SCC tumor initiation	TGF-β, ZEB1	TE11, EN60, EPC2T	³⁴⁶
HCC	Notch1	Oncogene	EMT	Tspan5 ↑ →Activation of Notch signaling→enhance EMT and actin skeleton rearrangement→promote tumor metastasis	Tspan5	HL7702, BEL7402, Hep3B, HUH7, MHCC97H, MHCC97L, PLC, QGY7701, SK-Hep1	³⁴⁵
SCLC	Notch2, HES1	Oncogene	EMT	ZLDI-8→inhibit the Notch signaling→inhibit migration, invasion and EMT phenotype of drug-resistant lung cancer	ZLDI-8	A549 cells, resistance A549/Taxol cells	³⁵⁴
Glioblastoma	RBPJ	Oncogene	EMT, chemoresistance	RBPJ ↓ →blocks EMT activators→reduce cellular invasion and resistance	ZEB1	GBM1, BTSC407/407p, JHH520/JHH	³⁵³
HNSCC	Notch4, HEY1	Oncogene	EMT	Notch4-HEY1 pathway ↑ →promote EMT→induce proliferation and cisplatin resistance	E-cadherin, Vimentin, Fibronectin, TWIST1, and SOX2	SKN3, Cal27, SCC61, and SCC090	³⁴⁷
ACC	HEY1, Notch1	Oncogene	EMT	Notch1-HEY1 pathway ↑ →drive self-renewal and EMT→increase proliferation, invasion and metastasis	MMPs	The SACC-LM cell line	³⁴⁸
NSCLC	Notch1, DLL4	Oncogene	Angiogenesis	ZLDI-8→suppress Notch1-HIF1α-VEGF signaling pathway→inhibit angiogenesis and vasculogenic mimicry	ZLDI-8, HIF1α, VEGF	The HUVECs, resistance A549/Taxol cells	³⁷⁷
CLL	DLL4, Notch1	Oncogene	Angiogenesis	DLL4→active Notch signaling→cell migration and angiogenesis↑	CXCR4	OP9-DLL1 and -DLL4 cells, Mouse OP9 BM stromal cells	³⁶³
Breast cancer	JAG1, DLL4, Notch1	Oncogene	Angiogenesis	linc-OIP5 ↓ → and JAG1 ↓ →disrupted DLL4/Notch/NRP1 signaling→suppress proliferation, migration, and tube formation	Linc-OIP5, YAP1, NRP1	MCF-10 cells, MDA-MB-231 cells, MCF-7 cells, HUVECs	³⁷¹
Breast cancer	JAG1	Oncogene	Angiogenesis	JAG1 ↑ → MALAT1-miR-1405p-JAG1/VEGFA pathway ↑ →microenvironment angiogenesis↑	MALAT1, miR-140-5p, VEGFA	MCF-10A, T47D, MCF-7, MDA-MB-231 (231), MDA-MB-231 Bone (231B), HUVEC	³⁷⁰
Glioma	Notch1	Oncogene	Angiogenesis	DGC-secreted FMOD→activate integrin-dependent Notch1 signaling→promote angiogenesis	FMOD	GSCs MGG4, MGG6, and MGG8, DBT-Luc cells, ST1 endothelial cells, B.End3 cell line, The U251/U87/LN229 cell line	³⁷⁶
Glioma	DLL4, Notch1, NICD	Oncogene	Angiogenesis	Fibulin-3→active Notch signaling→DLL4 ↑ →promotes glioma angiogenesis	Fibulin-3	CNS1, GSCs GBM8 and GBM34, HBMECs	³⁶⁴
Melanoma	Notch1, N1ICD	Oncogene	Angiogenesis	Notch1 ↑ →CD133 ↑ →mitogen-activated protein kinase activation ↑ →melanoma growth, angiogenesis, and lung metastasis↑	CD133, p-p38	CD133 + , CD133- or unsorted B16F10-Luc cells	³⁷⁵
CRC	NICD	Oncogene	Stem-like properties	Lipids→recruit Numb→MDM2 degrade Numb→activate Notch signaling→promote stem-like cell features	Lipids, Numb, MDM2	HCT116, HT29	³⁸⁷
CRC	JAG2, Notch1, Notch2	Oncogene	Stem-like properties	tRF/miR-1280 ↑ →inhibit Notch signaling→suppress CSC phenotypes→suppress CRC growth and metastasis	tRF, miR-1280	HCT116, HCT15, HT29, Panc-1, 293 T cells	³⁸⁸
Liver cancer	Notch1	Oncogene	Stem-like properties	iNOS/NO→activate TACE/ADAM17→activate Notch1 signaling→aggressive cancer phenotype	iNOS/NO, TACE/ADAM17	HLE, MHCC-97H, PLC/PRF/5, HepG2	³⁹³
LUAD	Notch	Oncogene	Stem-like properties	HIF1ɑ-regulated miR-1275→ activate Wnt/beta-catenin and Notch signaling→enhance the stemness of LUAD→promote tumorigenicity, recurrence, and metastasis	HIF1ɑ, miR-1275	EBAS-2B, L78, H460, A549, GLC-82, SPC-A1, PC9, H1299, H1975, H2228, A549-luc, H1299-luc	³⁹⁷
Breast cancer	Notch1, Notch3, Notch4, Hey1	Oncogene	Stem-like properties	Syndecan-1→regulate IL-6/STAT3, Notch and EGFR signaling pathways→modulate CSC phenotype	Syndecan-1	SUM-149, SKBR3	³⁹⁹
Glioma	Notch1	Oncogene	Glioma stem cells stemness	Notch1 ↑ →lncRNA TUG1 ↑ →sponging miR-145 and recruiting polycomb→maintain stemness features	lncRNA TUG1, miR-145	1228-GSC, 222-GSC	³⁸⁹
Breast cancer	NICD, Hey2	Oncogene	Stem-like properties, chemoresistance	HIF2α ↑ →activate Wnt and Notch pathways→ promote stem phenotype conversion and induce resistance	HIF2α	MCF7, MDA-MB-231	³⁹⁸
PDAC	Notch3, Notch4	Oncogene	Stem-like properties	KLF10 ↓ →activate Notch signaling→promote stem cell phenotype and tumorigenesis	KLF10	BCRC 60284, BCRC 60139	⁴⁰³
GC	Notch1	Oncogene	Glycolysis, chemoresistance	Pyrimidine biosynthesis→augmente Notch signaling→critical glycolytic enzymes ↑ →enhance aerobic glycolysis→confer chemoresistance	c-Myc and PKM2	AGS, HGC-27	⁴³⁴
Lung cancer	Notch1	Oncogene	Glycolysis	Notch1/TAZ axis→inhibit cytotoxic T cell activity, promote aerobic glycolysis and immune escape	TAZ	A549, PC9	⁴¹⁶
T-ALL	Notch1	Oncogene	Metabolic reprogramming	Notch1 signaling ↓ →inhibition of glutaminolysis→induce a metabolic shutdown	PTEN	(HEK) 293 T, HPB-ALL, DND41	⁴²⁸
OC	NICD	Tumor suppressor	Glycolysis	miR-101 and miR-26a ↑ → imposed glucose restriction on T cells→EZH2 ↓ →inhibit the Notch pathway→inhibit T cell survival→poor antitumor immunity	miR-101 and miR-26a, EZH2	HEK293T	⁴¹⁹
CRC	Notch1	Oncogene	Tumor microenvironment	Notch1 ↑ →promote TGF-β-mediated neutrophil infiltration recruitment→drive metastasis	TGF-β	villinCre^ER; Kras^G12D/+; Trp53^fl/fl Rosa26^N1icd/+ organoids; villinCreER; Apc^fl/fl; Kras^G12D/+; Trp53^fl/fl TgfbrI^fl/fl organoids	⁴⁴²
HCC	HEY1	Oncogene	Hypoxia	Hypoxia→HIF-1 ↑ → HEY1 ↑ → PINK1 ↓ →reduced oxidative stress, increased HCC growth	HIF-1, PINK1	HeLa, PLC/PRF/5, HepG2, Hep3B	⁴⁶¹
Lung cancer	Notch1	Tumor suppressor	Tumor microenvironment	Apoptotic lung cancer cells→trigger Notch1 signaling→WISP-1 production ↑ →preventing the migration and invasion	WISP-1	344SQ, A549, HCT116	⁴⁴⁴
Glioma	Notch1	Oncogene	Tumor immune microenvironment	NKAP ↑ →Notch1 ↑ →active Notch1-dependent immune-suppressive tumor microenvironment→promote glioma growth and invasion	NKAP, SDF-1, M-CSF	U251, U87, Gl261	⁴⁴⁷
Glioma	DLL1	Oncogene	Hypoxia	hypoxia→Notch signaling ↓ →HES1 and Hey1 ↓ →promote neuroendocrine differentiation	NSE, β3-tubulin	LNCaP, PC-3, Du145	⁴⁵⁸
CRC	Notch2, RBPJ	Oncogene	Chemoresistance	miR195-5p→Notch2 and RBPJ ↓ →reduced CRC cell sternness and chemoresistance	miR195-5p	SW480, SW620, HT-29, HCT-160	⁴⁸⁶
PC	Notch2	Oncogene	Chemoresistance	Midkine–Notch2 interaction→activated Notch signaling→increase chemoresistance	Midkine	PaCa 5061, 5072, and 5156; L3.6pl (19), BxPC-3, PANC-1 cells	⁴⁷²
PC	N1ICD	Oncogene	Chemoresistance	LINC00261 → N1DARP→inhibit USP10-Notch1 oncogenic signaling →inhibit chemoresistance	LINC00261, N1DARP, USP10	Aspc1, Bxpc3, Capan1, MiaPaCa2, Panc1, Sw1990, and Patu8988; HPNE; MDA-MB-231 and MCF-10A; A549 and BEAS-2B; HCT116 and NCM460	⁴⁷⁶
PC	Notch1	Oncogene	Chemoresistance	GAS41 → H2A.Z.2→Notch1 ↑ →GEM resistance	GAS41, H2A.Z.2	PANC-1, BXPC3, Capan-1, MiaPaCa-2, SW1990	⁴⁷⁵
LUAD	Notch1	Oncogene	Chemoresistance	Notch1/AP-1/miR-451/MDR-1 signaling axis→influence chemoresistance of LUAD	AP-1, miR-451, MDR-1	SPC-A1 and H1299	⁴⁸⁰
Breast cancer	Notch1	Oncogene	Chemoresistance	Exosomal miR-378a3p and miR-378d → EZH2/STAT3 signaling→activate WNT and Notch stemness pathways→induce drug resistance	miR-378a3p, miR-378d, EZH2, STAT3	CAL51, MDA-MB231, MCF-7	⁴⁸³
TNBC	Notch1	Oncogene	Chemoresistance	Notch1→MVP→activate AKT pathway→promote EMT→promote chemoresistance	MVP	MDA-MB-231, BT549, MCF-7, T47D, SKBR-3, HCC1937, ZR751	⁴⁸⁴
Skin tumor	Notch1	Tumor suppressor	N/A	Notch1 ↓ →Gli2 ↑ →basal-cell carcinoma-like tumors ↑ ; Notch1 ↓ →beta-catenin ↑ →skin carcinogenesis	Gli2, beta-catenin	Primary keratinocytes	⁴⁹⁶
Skin tumor	Notch1	Tumor suppressor	Tumor microenvironment	Notch1 ↓ →epidermal differentiation/barrier formation defects→skin carcinogenesis	N/A	N/A	⁴⁹⁸
Multifocal epithelial tumor	CSL/RBP-Jκ	Tumor suppressor	N/A	CSL/RBP-Jκ ↓ →c-Jun and c-Fos ↑ →promote tumor cell proliferation	c-Jun, c-Fos	Dermal fibroblasts	⁴⁹⁹
SCC	Notch1	Tumor suppressor	N/A	Notch1 ↑ →ROCK1/2 and MRCK α kinases ↓ →suppress SCC	p53, ROCK1/2, MRCK α kinases	SCC011, SCC012, SCC022, SCC028	⁵⁰⁰
SCLC	Notch	Tumor suppressor	N/A	Notch ↑ →hASH1 ↓ →cell cycle arrest	hASH1, p21, p27kip1, ERK1, ERK2, raf/MEK/MAPK	DMS53, NCI-H209, Low passage 293, NCI-H209/ΔRaf-1:ER cells	⁵⁰²
Forebrain tumor subtypes	Notch1, Notch2, RBPJ	Tumor suppressor	N/A	Notch1/Notch2/RBPJ ↓ →accelerate glioma	p53, Trp53	Platinum-E cells	⁵⁰³
Cervical cancer	Notch1	Tumor suppressor	N/A	Notch1 ↑ →SST, SSTR1 and SSTR2 ↑ →inhibit cervical cancer	SST, SSTR1 and SSTR2	HeLa, HeLa-GFP, HeLa-ICN1	²⁵⁷
K-ras–induced PDAC	Notch1	Tumor suppressor	N/A	Notch1 ↓ →increase tumor incidence and progression	K-ras	Primary pancreatic ductal cells	⁵⁰⁴
B-ALL	HES1	Tumor suppressor	N/A	HES1 ↑ → PARP1 ↑ →cell apoptosis	PARP1, bHLH	JM1, Nalm6, 697, SupT1, Molt4, HEK-293	⁵⁰⁵

ESCC esophageal squamous cell carcinoma, HCC hepatocellular carcinoma, SCLC small cell lung cancer, HNSCC head and neck squamous cell carcinoma, ACC adenoid cystic carcinoma, NSCLC non-small cell lung cancer, CLL chronic lymphocytic leukemia, CRC colorectal cancer, LUAD lung adenocarcinoma, PDAC pancreatic ductal adenocarcinoma, GC gastric cancer, T-ALL T cell acute lymphoblastic leukemia, B-ALL B cell acute lymphoblastic leukemia, OC ovarian cancer, PC pancreatic cancer, TNBC triple-negative breast cancer, EMT epithelial-mesenchymal transition, TGF-β transforming growth factor beta, Zeb1 zinc finger E-box-binding homeobox 1, SCC squamous cell carcinoma, Tspan5 tetraspanin-5, MCAM melanoma cell adhesion molecule, RBPJ recombining binding protein suppressor of hairless, HEY1 hairy and enhancer of split 1, HIF1α hypoxia-inducible factor 1-alpha, VEGF vascular endothelial growth factor, DLL4 delta-like ligand 4, JAG1 Jagged-1, linc-OIP5 long intergenic non-protein coding RNA OIP5-AS1, MALAT1 metastasis-associated lung adenocarcinoma transcript 1, miR microRNA, FMOD fibromodulin, DGC discoidin domain-containing receptor 1, CD133 cluster of differentiation 133, MDM2 mouse double minute 2, tRF transfer RNA-derived fragment, CSC cancer stem cell, iNOS inducible nitric oxide synthase, NO nitric oxide, TACE tumor necrosis factor-alpha converting enzyme, ADAM17 a disintegrin and metalloprotease 17, IL-6 interleukin 6, STAT3 signal transducer and activator of transcription 3, EGFR epidermal growth factor receptor, lncRNA TUG1 long non-coding RNA taurine upregulated gene 1, KLF10 Krüppel-like factor 10, USP24 ubiquitin-specific protease 24, PLK1 polo-like kinase 1, GSI gamma-secretase inhibitor, AKT protein kinase B, mTOR mammalian target of rapamycin, EZH2 enhancer of Zeste homolog 2, PINK1 PTEN-induced putative kinase 1, WISP-1 Wnt-induced signaling protein 1, NKAP NF-kappa-B-activating protein, HES1 hairy and enhancer of split 1, Hey1 Hes-related family bHLH transcription factor with YRPW motif 1, RBPJ recombining binding protein suppressor of hairless, N1ICD Notch1 intracellular domain, GAS41 growth arrest-specific 41, H2A.Z.2 histone H2A.Z.2, GEM gemcitabine, MVP major vault protein, SST somatostatin, SSTR somatostatin receptor, PARP1 poly ADP-ribose polymerase1, bHLH basic-helix-loop-helix