Role of Abelson interactor 2 in progression and prognosis of gastric cancer and its regulatory mechanisms

doi:10.12122/j.issn.1673-4254.2024.09.04

Abstract

Abstract:

Objective To explore the regulatory role of Abelson interactor 2 (ABI2) in progression and prognosis of gastric cancer. Methods TIMER2.0, GEPIA, Kaplan-Meier Plotter and DAVID databases were used to analyze ABI2 expression in pan-cancer and its association with the prognosis of gastric cancer. Gastric cancer and adjacent tissues from 120 patients undergoing radical gastrectomy in our hospital between January, 2016 and October, 2018 were examined for ABI2 expression and its correlation with disease progression and prognosis. MGC-803 cell models of ABI2 knockdown and overexpression were established for observing the changes in cell proliferation, migration, and invasion, and the impact of ABI2 expression modulation on xenograft growth was evaluated in nude mice. Results Database analysis and examination of the clinical samples showed that ABI2 was highly expressed in gastric cancer tissues. Survival analysis suggested that gastric cancer patients with a high expression of ABI2 had a reduced postoperative 5-year survival rate (P<0.0001), and further Cox univariate and multivariate survival analyses indicated that a high ABI2 expression was an independent risk factor affecting the patients survival outcomes (P=0.022, HR=1.887, 95% CI: 1.096-3.249). Enrichment analysis suggested the involvement of ABI2 in Wnt signaling. In MGC-803 cells, ABI2 overexpression promoted cell proliferation and xenograft growth in nude mice, increased the expressions of vimentin and N-cadherin, and lowered E-cadherin expression, while ABI2 knockdown produced the opposite effects. Mechanistic analysis revealed that ABI2 overexpression promoted the expressions of Wnt2 and β-catenin in both MGC-803 cells and the xenografts, and their expressions were significantly lowered by ABI2 knockdown. Conclusion ABI2 is highly expressed in gastric cancer, which affects long-term prognosis of the patients, possible due to its regulatory effect on Wnt signaling to promote proliferation, migration and invasion of gastric cancer cells.

Key words: gastric cancer, ABI2, prognosis, proliferation, migration, invasion, Wnt signaling pathway

Xiaohua CHEN, Hui LU, Ziliang WANG, Lian WANG, Yongsheng XIA, Zhijun GENG, Xiaofeng ZHANG, Xue SONG, Yueyue WANG, Jing LI, Jianguo HU, Lugen ZUO. Role of Abelson interactor 2 in progression and prognosis of gastric cancer and its regulatory mechanisms[J]. Journal of Southern Medical University, 2024, 44(9): 1653-1661.

Figures/Tables 9

Fig.1 ABI2 is highly expressed in gastric cancer. A: Pan-cancer expression analysis. B: Expression of ABI2 in gastric and adjacent tissues. C, D: Immunohistochemical staining of ABI2 in gastric and adjacent tissues. *P<0.05, **P<0.01, ***P<0.001.

Tab.1 Correlation of ABI2 expression level with clinicopathological parameters of gastric cancer patients

Factors		n	ABI2 expression (n, %)		χ²	Ρ
Factors		n	Low (n=60)	High (n=60)	χ²	Ρ
Gender	Male	95	47 (49.47%)	48 (50.53%)	0.051	0.822
Gender	Female	25	13 (52.00%)	12 (48.00%)	0.051	0.822
Age (year)	<60	49	27 (55.10%)	22 (44.90%)	0.862	0.353
Age (year)	≥60	71	33 (46.48%)	38 (53.52%)	0.862	0.353
CEA (μg/L)	<5	57	35 (61.40%)	22 (38.60%)	5.647	0.017
CEA (μg/L)	≥5	63	25 (39.68%)	38 (60.32%)	5.647	0.017
CA19-9 (kU/L)	<37	67	44 (65.67%)	23 (34.33%)	14.903	<0.001
CA19-9 (kU/L)	≥37	53	16 (30.19%)	37 (69.81%)	14.903	<0.001
Tumor size (cm)	<5	64	33 (51.56%)	31 (48.44%)	0.134	0.714
Tumor size (cm)	≥5	56	27 (48.21%)	29 (51.79%)	0.134	0.714
Cancer cell type	Adenocarcinoma	89	46 (51.69%)	43 (48.31%)	0.391	0.532
Cancer cell type	Other	31	14 (45.16%)	17 (54.84%)	0.391	0.532
Pathological grading	G1-G2	66	41 (62.12%)	25 (37.88%)	8.620	0.003
Pathological grading	G3-G4	54	19 (35.19%)	35 (64.81%)	8.620	0.003
T stage	T1-T2	51	33 (64.71%)	18 (35.29%)	7.673	0.006
T stage	T3-T4	69	27 (39.13%)	42 (60.87%)	7.673	0.006
N stage	N0-N1	60	36 (60.00%)	24 (40.00%)	4.800	0.028
N stage	N2-N3	60	24 (40.00%)	36 (60.00%)	4.800	0.028

Fig.2 ABI2 expression level in gastric cancer tissue is positively correlated with peripheral blood levels of CEA and CA19-9.

Fig.3 ABI2 expression level in gastric cancer tissues affects prognosis of the patients. A: ABI2 expression level affects overall survival of gastric cancer patients. B: Kaplan-Meier survival analysis of 5-year survival rate of the patients after radical gastrectomy.

Fig.4 ABI2 expression level in gastric cancer tissue is an independent prognostic factor for gastric cancer patients.

Fig.5 Results of KEGG and GO enrichment analysis. A: KEGG enrichment analysis. B-D: Biological processes, cellular component and molecular function in GO enrichment analysis.

Fig.6 ABI2 overexpression promotes proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of gastric cancer cells in vitro. A, B: Lentiviral transfection efficiency. C, D: Results of CCK-8 assay (presented as A values) from day 1 to day 5. E, F: Expression of EMT markers in MGC803 cells. G, H: Wound-healing assay of the cells. I-L: Migration and invasion of MGC803 cells. Si: siRNA; LV: overexpression. *P<0.05 vs Control (n=3).

Fig.7 ABI2 overexpression promotes proliferation and epithelial-mesenchymal transition of gastric cancer cells in nude mice. A: Representative image of the transplanted tumors. B, C: Transplanted tumor volume from day 5 to day 25. D, E: Expression of EMT markers in the transplanted tumor. *P<0.05 vs Control (n=3).

Fig.8 The effect of ABI2 on malignant biological behaviors of gastric cancer cells is related to the Wnt signaling pathway. A, B: Expression of Wnt2 and β-catenin in MGC803 cells. C, D: Expression of Wnt2 and β-catenin in the transplanted tumors. *P<0.05 vs Control (n=3).

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