E74-like E26 transformation-specific transcription factor 3 in gastric cancer: Functions, mechanisms, and clinical translation - unresolved issues

Table 1 Summary of E74-like E26 transformation-specific transcription factor 3 functions across different tumor types[9-12,19,21,24-28,30-35,37,40-52]

Tumor type	Functional role	Key findings
Gastric cancer[21]	Pro-tumorigenic	ELF3 is significantly overexpressed, an independent risk factor for poor overall survival; directly binds CDH1 promoter to inhibit E-cadherin, inducing EMT; directly binds CXCL11 promoter to inhibit expression, impairing CTL recruitment, mediating immune evasion
Gastric cancer[39]	Potentially tumor-suppressive	FZD5 inhibits ZEB1 expression and prevents EMT through PKC-ELF3 axis; FZD5 and ELF3 associated with longer survival
Gastric cancer[26]	Regulatory relationship	ELF3 directly represses lncRNA UBE2CP3; UBE2CP3 promotes gastric cancer metastasis via miR-138-5p/ITGA2 axis
Gastric cancer[27]	Regulatory relationship	ELF3-AS1 promotes gastric cancer progression by binding hnRNPK and regulating CCL20 expression
Gastric cancer[24,25]	Regulatory relationship	ELF3 mRNA is highly expressed in gastric cancer, correlates with expression of transcription factors such as HNF4A and GATA6
Colorectal cancer[9]	Pro-tumorigenic	Drives β-catenin transactivation, promotes proliferation and invasion; high expression is associated with poor prognosis
Colorectal cancer[41]	Pro-tumorigenic	High mRNA and protein expression associated with increased recurrence rate and shortened relapse-free survival in stage II patients; an independent poor prognostic factor
Colorectal cancer[11]	Therapeutic targeting	In KRAS (G13D)-mutant colorectal cancer, ELF3 core transcription factor of HER2-ELF3-KRAS axis, drives progression and confers cetuximab resistance by upregulating KRAS; small molecule YK1 disrupts ELF3-MED23 interaction, restores drug sensitivity
Hepatocellular carcinoma[10]	Pro-tumorigenic	Increased expression associated with poor prognosis; promotes proliferation, migration, invasion; binds miR-141-3p promoter to inhibit its expression, protecting ZEB1 from silencing and inducing EMT
Non-small cell lung cancer[28]	Pro-tumorigenic	mRNA and protein upregulated, associated with overall survival; ELF3 silencing inhibits proliferation and metastasis; activates PI3K/Akt and ERK pathways
Non-small cell lung cancer[42]	Regulatory relationship	miR-320a-3p directly binds ELF3 mRNA 3'UTR, downregulates ELF3 expression, inhibits proliferation, migration, invasion via PI3K/Akt pathway
Lung adenocarcinoma[37]	Pro-tumorigenic (lineage-specific)	Focal amplification at 1q32.1, gene dosage and promoter hypomethylation affect locus; oncogene in lung adenocarcinoma but not in lung squamous cell carcinoma; required for tumor growth
Endometrial cancer[30]	Pro-tumorigenic	ELF3 knockdown inhibits proliferation and colony formation, promotes E-cadherin expression, inhibits N-cadherin and vimentin, reduces EMT; ELF3 promotes EMT and tumor development by binding TPM1 promoter and inhibiting its transcription
Papillary thyroid cancer[31]	Pro-tumorigenic	Core gene in EMT-related gene expression program GEP3, drives tumor invasion and angiogenesis; ELF3 knockdown inhibits EMT and angiogenesis, reduces cell migration and invasion
Biliary tract cancer[32]	Tumor-suppressive	Directly inhibits ZEB2, upregulates CGN maintaining cell junctions; regulates ALOX5 and CXCL16 affecting immune response; conditioned medium from ELF3-overexpressing cells significantly enhances NK cell and CD8+ T cell migration
Ovarian cancer[33]	Tumor-suppressive	Downregulated expression associated with shortened survival; overexpression inhibits proliferation and anchorage-dependent growth; increases epithelial markers, decreases mesenchymal markers
Ovarian cancer[43]	Pro-tumorigenic (context-specific)	Highly expressed under hypoxic conditions; acts as a transcription factor for IGF1, promotes IGF1 and VEGF secretion, enhances endothelial cell proliferation, migration, and angiogenesis
Bladder urothelial carcinoma[34]	Tumor-suppressive	Downstream component of WNT7B/FZD5 signaling, transcriptionally regulates NOTCH1, exerts tumor-suppressive effects
Bladder cancer[44]	Transcriptional regulator	Single-cell analysis identified anti-apoptotic tumor subpopulation; ELF3 together with CEBPB, EGR1, EZH2 acts as a key transcriptional regulator, interacts with immune and stromal cells via FGF, CXCL, VEGF signaling pathways to promote tumor progression
Bladder cancer[45]	Functional alteration	ELF3 mutation (14%) leads to truncated protein, altering regulatory interactions and upregulating neighboring gene PIK3C2B expression
Breast cancer[35]	Tumor-suppressive	Transcriptional repressor of estrogen receptor α; inhibits receptor dimerization and DNA binding activity by interacting with its DNA-binding domain, suppressing estrogen-dependent cell proliferation
Breast cancer[46]	Pro-tumorigenic	In luminal B and HER2 subtypes, high mRNA expression is associated with worse relapse-free survival; ELF3 knockdown inhibits proliferation, colony formation, and anchorage-independent growth
Breast cancer[47,48]	Upregulated expression	Copy number gain at 1q32 is associated with ELF3 overexpression; among differentially expressed cancer driver genes in triple-negative breast cancer
Pancreatic cancer[49]	Pro-tumorigenic	Negatively regulated by miR-1224-5p; overexpression is associated with poor prognosis and advanced clinical stage; negatively correlated with immune cell infiltration
Pancreatic cancer[50]	Pro-metastatic	Netrin-1-ELF3 positive feedback loop promotes liver metastasis via hepatic stellate cell activation and retinoid signaling
Esophageal squamous cell carcinoma[51]	Downstream target	LINC00886 recruits SIRT7 to reduce H3K18 acetylation level at ELF3 promoter, inhibiting ELF3 expression; ELF3 promotes ZEB1/ZEB2 expression by binding miR-144 promoter, facilitating EMT
Esophageal small cell carcinoma[19]	Increased regulatory activity	ELF3 regulatory activity elevated in extracellular matrix fibroblasts (eCAFs)
Neuroendocrine carcinoma[52]	Pro-tumorigenic	One of super-enhancer-associated transcription factors; ELF3 knockdown leads to reduced cell viability
Prostate cancer[12]	Pro-tumorigenic	Overexpressed in primary and metastatic tumors; induced by IL-1β/NF-κB, interacts with NF-κB subunits p65/p50, enhancing their nuclear translocation and transcriptional activity

EMT: Epithelial-mesenchymal transition; ELF3: E74-like E26 transformation-specific transcription factor 3.