High expression of SURF4 promotes migration, invasion and proliferation of gastric cancer cells by inhibiting tight junction proteins

doi:10.12122/j.issn.1673-4254.2025.08.17

Abstract

Abstract:

Objective To study the impact of SURF4 expression level on long-term prognosis of gastric cancer (GC) and biological behaviors of GC cells. Methods SURF4 expression level in GC and its association with long-term patient prognosis were analyzed using publicly available databases and in 155 GC patients with low and high SURF4 expressions detected immunohistochemically. The Cox proportional hazard model and Kaplan-Meier survival curves were used to analyze independent prognostic predictors of GC and the 5-year survival rate of the patients with different SURF4 expression levels. Informatics analyses were conducted to explore the correlation of SURF4 expression level with immune cell infiltration in GC, SURF4-related differential genes and their associated pathways. In cultured GC cell line HGC-27, the effects of SURF4 knockdown and overexpression on proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) were investigated. Results Analysis of GEPIA dataset and immunohistochemical results suggested significant SURF4 overexpression in GC (P<0.05), which was associated with shortened 5-year survival time of the patients (χ²=38.749, P<0.001). The prognosis of GC was closely related to tumor stage T3-4, N2-3, CEA≥5 μg/L and CA19-9≥37 kU/L (P<0.05). SURF4 expression level was negatively correlated with activated B cells, NK cells and CD8⁺ effector memory T cells (P<0.05) and positively correlated with CD4⁺ T cells (P<0.05). GO and KEGG enrichment analysis suggested that SUFR4 may participate in GC carcinogenesis by promoting EMT through the tight junction pathway. In HGC-27 cells, SURF4 overexpression significantly decreased E-cadherin expression, increased N-cadherin expression, inhibited ZO-1 and claudin-1 expressions, and promoted cell proliferation, migration and invasion. Conclusion SURF4 is highly expressed in GC, and its overexpression is associated with a shortened 5-year survival of the patients possibly by enhancing tumor cell proliferation, migration and invasion via inhibiting tight junction proteins and promoting EMT.

Key words: gastric cancer, SURF4 high expression, prognosis, tight junction protein, epithelial-mesenchymal transition

Ziliang WANG, Xiaohua CHEN, Jingjing YANG, Chen YAN, Zhizhi ZHANG, Bingyi HUANG, Meng ZHAO, Song LIU, Sitang GE, Lugen ZUO, Deli CHEN. High expression of SURF4 promotes migration, invasion and proliferation of gastric cancer cells by inhibiting tight junction proteins[J]. Journal of Southern Medical University, 2025, 45(8): 1732-1742.

Figures/Tables 11

Fig.1 Distribution characteristics of SURF4 in different cancers. A: Expression of SURF4 in different human cancers. B: Expression of SURF4 in gastric cancer. *P<0.05. C: Distribution characteristics of SURF4 in gastric cancer and adjacent tissues detected by immunohistochemistry. D: Relative IOD value of SURF4. n=155. *P<0.05 vs adjacent.

Fig.2 Analysis of expression levels of SURF4 in gastric cancer patients with different pathological parameters based on UALCAN database. A: Sample type. B: Tumor grading. C: Cancer staging. D: Age. *P<0.05, **P<0.01, ***P<0.001 vs Normal.

Fig.3 Relationship between SURF4 expression level and immune microenvironment of gastric cancer analyzed using TISIBD data platform. A: Activated B cells. B: CD8+ effector memory T cells. C: NK cells. D: CD4+ thymocytes.

Tab.1 Relationship between SURF4 expression levels and clinicopathological parameters in 155 patients with gastric cancer ［n（%）］

Factors	n	SURF4 expression		χ²	P
Factors	n	Low (n=77)	High (n=78)	χ²	P
Gender				0.919	0.338
Male	114	54 (47.4)	60 (52.6)
Female	41	23 (56.1)	18 (43.9)
Age (year)				1.459	0.227
<60	65	36 (55.4)	29 (44.6)
≥60	90	41 (45.6)	49 (54.4)
CEA (μg/L)				10.874	<0.001
<5	80	50 (62.5)	30 (37.5)
≥5	75	27 (36.0)	48 (64.0)
CA19-9 (kU/L)				8.080	0.004
<37	87	52 (59.8)	35 (40.2)
≥37	68	25 (36.8)	43 (63.2)
Tumor size (cm)				0.156	0.693
<5	87	42 (48.3)	45 (51.7)
≥5	68	35 (51.5)	33 (48.5)
Histological type				1.455	0.228
Adenocarcinoma	112	59 (52.7)	53 (47.3)
Other	43	18 (41.9)	25 (58.1)
T stage				8.836	0.003
1-2	78	48 (61.5)	30 (38.5)
3-4	77	29 (37.7)	48 (62.3)
N stage				5.441	0.020
0-1	70	42 (60.0)	28 (40.0)
2-3	85	35 (41.2)	80 (58.8)

Fig.4 Relationship between SURF4 expression and 5-year survival of the patients after radical gastrectomy for gastric cancer. A: Relationship between SURF4 expression and overall survival. B: Postoperative survival of patients in high expression group and low expression group.

Tab.2 Cox regression analysis of prognostic factors for 5-year survival after radical gastrectomy for gastric cancer

Factor	Univariate analysis		Multivariate analysis
Factor	Log rank χ²	P	HR	95% CI	P
Gender (Male vs female)	2.023	0.155	-	-	-
Age (≥60 years vs <60 years)	2.691	0.101	-	-	-
SURF4 expression (low vs high)	38.749	<0.001	3.106	1.853-5.206	<0.001
CEA (≥5 μg/L vs <5 μg/L)	34.667	<0.001	1.853	1.092-3.146	0.022
CA19-9 (≥37kU/L vs <37kU/L)	35.752	<0.001	1.949	1.125-3.378	0.017
Tumor size (≥5 cm vs <5 cm)	0.044	0.833	-	-	-
Histological type (Adenocarcinoma vs other)	0.013	0.910	-	-	-
T stage (T3-T4 vs T1-T2)	31.071	<0.001	2.774	1.661-4.635	<0.001
N stage (N2-N3 vs N0-N1)	28.779	<0.001	2.641	1.515-4.604	<0.001

Fig.5 Prediction of 5-year survival of patients with gastric cancer after operation based on SURF4 expression level.

Fig.6 Enrichment analysis results of SURF4. A: KEGG analysis. B: GO analysis.

Fig.7 Effect of SURF4 expression level on proliferation of gastric cancer HGC-27 cells. A: Cell proliferation from day 1 to day 5. B: Comparison of cell proliferation on day 5 (n=4). LV: overexpression; Si: SiRNA. *P<0.05 vs Si-Control; #P<0.05 vs LV-Control.

Fig.8 Effect of SURF4 knockdown and overexpression on migration, invasion and EMT of HGC-27 gastric cancer cells. A, D: Results of scratch assay. B, E: Effect of SURF4 knockdown and overexpression on migration ability of HGC-27 cells. C, F: Invasion ability of HGC-27 cells with SURF4 knockdown and overexpression. G-I: Expressions of E-cadherin and N-cadherin protein in HGC-27 cells with SURF4 knockdown and overexpression. *P<0.05 vs Si-Control; #P<0.05 vs LV-Control(n=4).

Fig.9 Effect of SURF4 knockdown and overexpression on tight junction protein expression in HGC-27 cells detected by Western blotting. A-C: Expressions of ZO-1 and Caudin-1 protein in HGC-27 gastric cancer cells. *P<0.05 vs Si-Control; #P<0.05 vs LV-Control (n=4).

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