High YEATS2 expression promotes epithelial-mesenchymal transition in gastric cancer cells by activating the Wnt/β-catenin signaling pathway

doi:10.12122/j.issn.1673-4254.2025.11.14

Abstract

Abstract:

Objective To investigate YEATS2 expression in gastric cancer (GC), its prognostic value, and its regulatory role in epithelial-mesenchymal transition (EMT) of GC cells. Methods YEATS2 expression in GC was analyzed using publicly available databases. Paired GC and adjacent tissues were collected from 100 patients undergoing radical surgery for immunohistochemical detection of YEATS2 expression, and its correlations with the patients' clinicopathological parameters and Ki67 expression were analyzed. The prognostic value of YEATS2 was assessed using Kaplan-Meier analysis, Cox regression and ROC curves, and its regulatory mechanisms were analyzed using KEGG enrichment analysis. In cultured GC cell lines (HGC-27 and AGS), the effect of YEATS2 knockdown and overexpression on migration, invasion and EMT of the cells were examined with scratching assay, Transwell assay and Western blotting. Results YEATS2 was significantly overexpressed in GC tissues with a positive correlation with Ki67 (P<0.05). High YEATS2 expression was associated with elevated CEA (≥5 μg/L), CA19-9 (≥37 kU/L), T3-4 stage, and N2-3 stage (all P<0.05). Patients with high YEATS2 expression had significantly reduced 5-year survival (P<0.001); ROC analysis showed that YEATS2 expression levels had a sensitivity of 80.00% and a specificity of 66.67% for predicting patient survival (P<0.05). Cox regression identified high YEATS2 as an independent risk factor for poor postoperative 5-year survival outcome of GC patients (HR: 1.675, 95%CI: 1.013-2.771; P=0.045). KEGG enrichment analysis suggested involvement of YEATS2 in EMT in GC and Wnt/β-catenin signaling. In cultured GC cells, YEATS2 overexpression significantly promoted cell migration and invasion, upregulated the expressions of vimentin, N-cadherin, Wnt and active β-catenin, and downregulated E-cadherin expression, and these changes were obviously suppressed by treatment with XAV-939 (a Wnt/β-catenin inhibitor). Conclusion High YEATS2 expression activates Wnt/β-catenin signaling to promote EMT in GC and is correlated with poor prognosis of GC patients.

Key words: Gastric cancer, YEATS2, prognosis, epithelial-mesenchymal transition, Wnt/β-catenin

Xuening JIANG, Qingqing HUANG, Ying XU, Shunyin² WANG, Xiaofeng² ZHANG, Lian¹ WANG, Yueyue² WANG, Lugen ZUO. High YEATS2 expression promotes epithelial-mesenchymal transition in gastric cancer cells by activating the Wnt/β-catenin signaling pathway[J]. Journal of Southern Medical University, 2025, 45(11): 2416-2426.

Figures/Tables 10

Fig.1 Expression and correlation analysis of YEATS2 and Ki67 in gastric cancer. A: Expression of YEATS2 in different human tumors. B: Expression of YEATS2 in gastric cancer. C: Immunohistochemical staining of YEATS2 and Ki67. D,E: Relative IOD values of YEATS2 and Ki67. F: Correlation between YEATS2 and Ki67 in gastric cancer tissues. *P<0.05,***P<0.001 vs adjacent tissue.

Fig.2 High YEATS2 expression is significantly associated with tumor grading and staging in gastric cancer patients. A: Correlation between YEATS2 TPM and tumor grading in gastric cancer. B: Correlation between YEATS2 TPM and tumor staging in gastric cancer. ***P<0.001 vs adjacent tissue.

Tab.1 Relationship between YEATS2 expression level and parameters of malignant progression in gastric cancer tissues (n=50)

Factor		n	YEATS2 expression		χ²	P
Factor		n	Low (n=50)	High (n=50)	χ²	P
Gender	Female	19	6 (31.58%)	13 (68.42%)	3.184	0.074
Gender	Male	81	44 (54.32%)	37 (45.68%)	3.184	0.074
Age (year)	˂60	35	18 (51.43%)	17 (48.57%)	0.044	0.834
Age (year)	≥60	65	32 (49.23%)	33 (50.77%)	0.044	0.834
Cancer cell type	Adenocarcinoma	79	42 (53.16%)	37 (46.84%)	1.507	0.220
Cancer cell type	Other	21	8 (38.10%)	13 (61.90%)	1.507	0.220
CEA (μg/L)	˂5	35	24 (68.57%)	11 (31.43%)	7.429	0.006
CEA (μg/L)	≥5	65	26 (40.00%)	39 (60.00%)	7.429	0.006
CA19-9 (kU/L)	˂37	44	27 (61.36%)	17 (38.64%)	4.058	0.044
CA19-9 (kU/L)	≥37	56	23 (41.07%)	33 (58.93%)	4.058	0.044
Tumor size (cm)	˂5	49	27 (55.10%)	22 (44.90%)	1.000	0.317
Tumor size (cm)	≥5	51	23 (45.10%)	28 (54.90%)	1.000	0.317
T stage	T1-T2	36	25 (69.44%)	11 (30.56%)	8.507	0.004
T stage	T3-T4	64	25 (39.06%)	39 (60.94%)	8.507	0.004
N stage	N0-N1	43	27 (62.79%)	16 (37.21%)	4.937	0.026
N stage	N2-N3	57	23 (40.35%)	34 (59.65%)	4.937	0.026

Fig.3 Effect of YEATS2 on prognosis of patients with gastric cancer. A: Kaplan-Meier analysis. B: Survival curves. C: Predictive value of YEATS2 for 5-year survival after radical gastrectomy.

Tab.2 Analysis of risk factors affecting 5-year survival rate of gastric cancer patients after radical gastrectomy

Factor	Univariate analysis		Multivariate analysis
Factor	Log-rank χ²	P	HR	95% CI	P
Gender (male vs female)	<0.001	0.989
Age (˂60 years vs ≥60 years )	0.014	0.907
Cancer cell type (adenocarcinoma vs other)	0.539	0.463
CEA (˂5 μg/L vs ≥5 μg/L)	24.128	<0.001	2.760	1.480-5.147	0.001
CA19-9 (˂37kU/L vs ≥37 kU/L)	30.316	<0.001	2.600	1.480-4.569	<0.001
Tumor size (˂5 cm vs ≥5 cm)	1.041	0.308
T stage (T1-T2 vs T3-T4)	15.477	<0.001	2.015	1.129-3.593	0.018
N stage (N0-N1 vs N2-N3)	25.115	<0.001	2.238	1.275-3.928	0.005
YEATS2 expression (high vs low)	13.939	<0.001	1.675	1.013-2.771	0.045

Fig.4 KEGG and GO enrichment analysis of YEATS2. A: KEGG enrichment analysis results. B: GO enrichment analysis results.

Fig.5 YEATS2 promotes migration of gastric cancer cells. A-D: Validation of YEATS2 knockdown and overexpression in gastric cancer cells. E, F: High expression of YEATS2 promotes HGC-27 cell migration. G, H: High expression of YEATS2 promotes AGS cell migration. n=3, *P<0.05 vs shNC or vs Vector.

Fig.6 YEATS2 promotes migration and invasion of gastric cancer cells. A-D: High expression of YEATS2 promotes HGC-27 cell migration and invasion. E-H: High expression of YEATS2 promotes AGS cell migration and invasion. n=3, *P<0.05 vs shNC or vs Vector.

Fig.7 YEATS2 promotes EMT process in gastric cancer cells. A, B : Expressions of key EMT-related proteins in HGC27 cells. C, D: Expressions of key EMT-related proteins in AGS cells. n=3, *P<0.05 vs shNC or vs Vector.

Fig.8 Elevated expression of YEATS2 in gastric cancer cells activates the Wnt/β-catenin signaling pathway. A, B: Expressions of Wnt, active β-catenin and c-myc in HGC-27 cells. C, D: Expressions of Wnt, active β-catenin and c-myc in AGS cells. E: Expressions of key EMT-related proteins in HGC27 cells. F: Expressions of key EMT-related proteins in AGS cells. n=3, *P<0.05 vs shNC or vs Vector or vs OE-YEATS2.

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