ABI2在胃癌进展和预后中的作用及其调控机制

doi:10.12122/j.issn.1673-4254.2024.09.04

南方医科大学学报 ›› 2024, Vol. 44 ›› Issue (9): 1653-1661.doi: 10.12122/j.issn.1673-4254.2024.09.04

ABI2在胃癌进展和预后中的作用及其调控机制

陈孝华¹(), 鲁辉¹, 王子良¹, 王炼¹, 夏勇生¹, 耿志军²^,⁴, 张小凤²^,⁴, 宋雪²^,⁴, 王月月³^,⁴, 李静³^,⁴, 胡建国³^,⁴, 左芦根¹^,⁴()

^1.蚌埠医科大学第一附属医院，胃肠外科，安徽蚌埠 233004
^2.蚌埠医科大学第一附属医院，中心实验室，安徽蚌埠 233004
^3.蚌埠医科大学第一附属医院，检验科，安徽蚌埠 233004
^4.炎症相关性疾病基础与转化研究安徽省重点实验室，安徽蚌埠 233004

收稿日期:2024-04-22 出版日期:2024-09-20 发布日期:2024-09-30
通讯作者: 左芦根 E-mail:chenxiaohua9116@163.com;zuolugen@126.com
作者简介:陈孝华，硕士，E-mail: chenxiaohua9116@163.com
基金资助:
安徽省卫生健康科研项目(AHWJ2022a019);蚌埠医学院第一附属医院杰出青年基金(2019byyfyjq01);安徽省高校优秀青年人才支持计划重点项目(gxyqZD2022066)

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

Xiaohua CHEN¹(), Hui LU¹, Ziliang WANG¹, Lian WANG¹, Yongsheng XIA¹, Zhijun GENG²^,⁴, Xiaofeng ZHANG²^,⁴, Xue SONG²^,⁴, Yueyue WANG³^,⁴, Jing LI³^,⁴, Jianguo HU³^,⁴, Lugen ZUO¹^,⁴()

^1.Department of Gastrointestinal Surgery,
^2.Central Laboratory,
^3.Department of Laboratory Medicine, First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, China
^4.Anhui Provincial Laboratory of Basic and Translational Research of Inflammation-Related Diseases, Bengbu 233004, China

Received:2024-04-22 Online:2024-09-20 Published:2024-09-30
Contact: Lugen ZUO E-mail:chenxiaohua9116@163.com;zuolugen@126.com

摘要/Abstract

摘要：

目的探讨Abelson相互作用因子2（ABI2）在胃癌进展和预后中的作用及机制。方法通过TIMER2.0和GEPIA数据库分析ABI2在泛癌和胃癌中的表达，采用Kaplan-Meier Plotter数据库分析ABI2表达水平与胃癌预后的关系，通过DAVID数据库预测ABI2在生物系统中的功能。纳入在我院于2016年1月~2018年10月接受胃癌根治术治疗的120例胃癌患者，检测胃癌及癌旁组织中ABI2的表达水平，分析其与疾病进展的联系，并通过Cox单因素和多因素分析影响患者预后的危险因素。构建胃癌细胞系（MGC-803）ABI2干扰及过表达模型并构建裸鼠移植瘤模型，联合CCK-8、划痕、Transwell和免疫印迹实验分析ABI2对胃癌细胞增殖、迁移和侵袭的影响。结合体内外研究分析ABI2影响胃癌细胞恶性生物学行为的可能分子机理。结果生信分析和本院胃癌组织检测结果表明ABI2在胃癌组织中高表达（P<0.05）。Kaplan-Meier Plotter数据库分析表明ABI2低表达患者的术后生存率优于高表达患者（P<0.0001）。本院患者的生存分析结果显示，胃癌组织中ABI2高表达患者术后5年生存率降低（P<0.0001），Cox单因素和多因素生存分析进一步表明，ABI2高表达是影响胃癌患者预后的独立危险因素（P=0.022，HR=1.887，95% CI：1.096~3.249）。富集分析提示，ABI2的作用可能与Wnt信号通路相关。上调ABI2促进裸鼠移植瘤和胃癌细胞的增殖能力（P<0.05），并增加Vimentin和N-cadherin的表达，同时降低E-cadherin的表达（P<0.05）；下调ABI2则相反（P<0.05）。机制分析发现上调ABI2促进移植瘤组织和胃癌细胞中Wnt2和β-catenin的表达（P<0.05），下调ABI2则相反（P<0.05）。结论 ABI2在胃癌中表达升高并影响疾病远期预后，其可能与调控Wnt信号通路进而促进胃癌细胞增殖、迁移和侵袭能力有关。

关键词: 胃癌, ABI2, 预后, 增殖, 迁移, 侵袭, Wnt信号通路

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

陈孝华, 鲁辉, 王子良, 王炼, 夏勇生, 耿志军, 张小凤, 宋雪, 王月月, 李静, 胡建国, 左芦根. ABI2在胃癌进展和预后中的作用及其调控机制[J]. 南方医科大学学报, 2024, 44(9): 1653-1661.

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.

图/表 9

图1 ABI2在胃癌组织中表达水平升高

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.

表1 胃癌组织中ABI2的表达量与胃癌患者临床及病理参数间的关系

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

图2 胃癌组织中ABI2表达水平与外周血CEA和CA19-9水平呈正相关

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

图3 胃癌组织中ABI2表达水平影响胃癌患者预后

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.

图4 胃癌组织中ABI2表达水平是胃癌患者的独立预后因素

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

图5 ABI2的KEGG和GO富集分析结果

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.

图6 ABI2在体外实验中促进胃癌细胞增殖、迁移、侵袭和上皮间充质转化

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).

图7 ABI2在体内实验中促进胃癌细胞增殖和上皮间充质转化

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).

图8 ABI2对胃癌细胞恶性生物学行为的影响可能与Wnt通路相关

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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ABI2在胃癌进展和预后中的作用及其调控机制

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

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