GPSM2在胃癌组织中高表达并通过促进肿瘤细胞的增殖影响患者预后

doi:10.12122/j.issn.1673-4254.2025.02.03

南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (2): 229-238.doi: 10.12122/j.issn.1673-4254.2025.02.03

• • 上一篇

GPSM2在胃癌组织中高表达并通过促进肿瘤细胞的增殖影响患者预后

宋雪¹(), 陈悦²^,⁴, 张敏²^,⁵, 张诺²^,⁵, 左芦根⁵^,⁶, 李静⁴^,⁶, 耿志军¹, 张小凤¹, 王月月⁴, 王炼⁵, 胡建国⁴()

^1.蚌埠医科大学第一附属医院，中心实验室，安徽蚌埠 233000
^3.蚌埠医科大学第一附属医院，康复科，安徽蚌埠 233000
^4.蚌埠医科大学第一附属医院，检验科，安徽蚌埠 233000
^5.蚌埠医科大学第一附属医院，胃肠外科，安徽蚌埠 233000
^6.蚌埠医科大学第一附属医院，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 233000
^2.蚌埠医科大学检验医学院，安徽蚌埠 233000

收稿日期:2024-08-12 出版日期:2025-02-20 发布日期:2025-03-03
通讯作者: 胡建国 E-mail:songxue0214@bbmc.edu.cn;jghu9200@bbmc.edu.cn
作者简介:宋雪，博士，副研究员，E-mail: songxue0214@bbmc.edu.cn
基金资助:
安徽高校自然科学研究项目(2023AH040289);蚌埠医学院第一附属医院优秀青年基金(2019byyfyyq08);安徽省临床医学研究转化专项(202427b10020094)

GPSM2 is highly expressed in gastric cancer to affect patient prognosis by promoting tumor cell proliferation

Xue SONG¹(), Yue CHEN²^,⁴, Min ZHANG²^,⁵, Nuo ZHANG²^,⁵, Lugen ZUO⁵^,⁶, Jing LI⁴^,⁶, Zhijun GENG¹, Xiaofeng ZHANG¹, Yueyue WANG⁴, Lian WANG⁵, Jianguo HU⁴()

^1.Central Laboratory, First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
^3.Department of Rehabilitation Medicine, First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
^4.Department of Laboratory Medicine, First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
^5.Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
^6.Anhui Provincial Key Laboratory of Basic and Translational Research of Inflammation?Related Diseases, First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
^2.College of Laboratory Medicine, Bengbu Medical University, Bengbu 233000, China

Received:2024-08-12 Online:2025-02-20 Published:2025-03-03
Contact: Jianguo HU E-mail:songxue0214@bbmc.edu.cn;jghu9200@bbmc.edu.cn

摘要/Abstract

摘要：

目的探究G蛋白信号调节因子2（GPSM2）表达水平与胃癌患者临床进展的关系，并进一步分析其功能途径和作用机制。方法基于基因表达谱交互式分析（GEPIA）数据库和收治于本院的109例胃癌患者，分析GPSM2在肿瘤中的表达水平；公共数据库分析GPSM2对胃癌患者术后生存率的影响；生物信息学富集分析GPSM2在胃癌中的功能学途径及作用机制；体外培养MGC803细胞，敲低或过表达GPSM2，利用CCK-8实验、细胞克隆形成实验、流式细胞术和免疫印迹实验分析GPSM2对细胞增殖、迁移的影响及其作用机制，在体通过观察裸鼠移植瘤的大小分析GPSM2对肿瘤生长的影响。结果 GEPIA数据库分析发现，在胃癌组织中GPSM2的表达高于正常组织；免疫组化染色发现，GPSM2在胃癌组织中的表达量升高（P<0.01）；临床数据分析显示，当GPSM2高表达时，T_3~4期、N_2~3期、术前外周血癌胚抗原（CEA）≥5 μg/L和糖类抗原（CA19-9）≥37 kU/L的胃癌患者明显增多（P<0.05）；单因素与Cox多因素联合分析证明，GPSM2蛋白表达量增加是影响胃癌患者术后5年生存率的独立危险因素（P<0.05）。基因本体论（GO）分析其生物学功能发现，GPSM2在胃癌中可能参与调控细胞周期（P<0.05）。体外细胞克隆形成实验和CCK-8实验发现GPSM2可加快MGC803细胞生长速度（P<0.05）；通过免疫印迹与流式细胞技术发现，当GPSM2基因过表达时，将促进MGC803细胞从G1期向S期的转变（P<0.05），同时相关蛋白的表达也有所增加；裸鼠成瘤实验证明GPSM2促进移植瘤的生长；京都基因和基因组百科全书（KEGG）通路富集显示GPSM2可能通过调控p53信号通路发挥生物学功能（P<0.05）；体内和体外免疫印迹实验结果表明，提升GPSM2的表达水平能抑制p53信号通路活性（P<0.05）。结论 GPSM2在胃癌组织中呈现高表达，促进胃癌细胞增殖及G1/S期的转变，影响患者术后生存率，其作用机制可能与抑制p53信号通路有关。

关键词: 胃癌, G蛋白信号调节因子2, 预后, 细胞周期, p53

Abstract:

Objective To explore the association between GPSM2 expression level and gastric cancer progression and analyze the functional pathways and action mechanism of GPSM2. Methods We analyzed GPSM2 expression levels in gastric cancer tumors based on data from the GEPIA database and the clinical data of 109 patients. Public databases enrichment analysis were used to assess the impact of GPSM2 expression level on survival outcomes and the functional pathways and action mechanism of GPSM2. We further observed the effects of GPSM2 knockdown and overexpression on proliferation, migration and apoptosis of MGC803 cells using CCK-8 assay, colony formation assay, flow cytometry and immunoblotting and on the growth of MGC803 cell xenografts in nude mice. Results Bioinformatic analysis and immunohistochemical staining of the clinical specimens both revealed high GPSM2 expressions in gastric cancer (P<0.01). A high GPSM2 expression was significantly correlated with T3-4 stages, N2-3 stages, a carcinoembryonic antigen (CEA) level ≥5 μg/L, and a carbohydrate antigen (CA) 19-9 level ≥37 kU/L (P<0.05). Cox regression analysis identified high GPSM2 expression as an independent risk factor affecting 5-year survival of the patients (P<0.05). Gene ontology (GO) analysis suggested that GPSM2 was involved in cell cycle regulation. In MGC803 cells, GPSM2 overexpression significantly promoted cell proliferation and G1/S transition and xenograft growth in nude mice. KEGG pathway enrichment analysis indicated that GPSM2 executed its biological functions by regulating the p53 signaling pathway, which was confirmed by the results of immunoblotting experiments showing suppression of p53 signaling pathway activity in GPSM2-over expressing MGC803 cells. Conclusion GPSM2 is highly expressed in gastric cancer to affect patient prognosis by promoting tumor cell proliferation and G1/S transition possibly via inhibiting the p53 pathway.

Key words: gastric cancer, GPSM2, prognosis, cell cycle, p53

宋雪, 陈悦, 张敏, 张诺, 左芦根, 李静, 耿志军, 张小凤, 王月月, 王炼, 胡建国. GPSM2在胃癌组织中高表达并通过促进肿瘤细胞的增殖影响患者预后[J]. 南方医科大学学报, 2025, 45(2): 229-238.

Xue SONG, Yue CHEN, Min ZHANG, Nuo ZHANG, Lugen ZUO, Jing LI, Zhijun GENG, Xiaofeng ZHANG, Yueyue WANG, Lian WANG, Jianguo HU. GPSM2 is highly expressed in gastric cancer to affect patient prognosis by promoting tumor cell proliferation[J]. Journal of Southern Medical University, 2025, 45(2): 229-238.

图/表 9

图1 GEPIA在胃癌组织中高表达

Fig.1 GEPIA is highly expressed in gastric cancer tissues. A: Expression of GPSM2 in pan-cancer. B: Expression of GPSM2 in gastric cancer. C: Immunohistochemical staining of GPSM2. D: Relative integrated optical density (IOD) value of GPSM2. *P<0.05 vs adjacent tissue.

图2 GPSM2高表达与临床病理参数相关

Fig.2 Association of GPSM2 expression level with clinicopathological parameters of gastric cancer patients. A, B: Expression levels of GPSM2 gene in tumor specimens with different cancer stages and lymph node metastasis status in the UALCAN database. **P<0.01 vs normal.

表1 胃癌组织中GPSM2表达量与临床病理参数间的关系

Tab.1 Relationship between GPSM2 expression in gastric cancer tissues and clinicopathological parameters of the patients

Clinicopathological parameters	Number of cases	GPSM2		χ ²	P
Clinicopathological parameters	Number of cases	Low expression (n=54)	High expression (n=55)	χ ²	P
Gender				0.002	0.962
Female	87	43	44
Male	22	11	11
Age (year)				2.080	0.149
<60	45	26	19
≥60	64	28	36
Tumor size (cm)				0.446	0.504
<5	41	22	19
≥5	68	32	36
Histological Grading				12.759	<0.001
G₁-G₂	60	39	21
G₃-G₄	49	15	34
T Stage				11.370	<0.001
T₁-T₂	59	38	21
T₃-T₄	50	16	34
N Stage				4.975	0.026
N₀-N₁	61	36	25
N₂-N₃	48	18	30
CEA (μg/L)				14.026	<0.001
<5	49	34	15
≥5	60	20	40
CA19-9 (kU/L)				12.556	<0.001
<37	52	35	17
≥37	57	19	38

图3 GPSM2高表达降低胃癌患者术后5年生存率

Fig.3 High GPSM2 expression levels are associated with a decreased postoperative 5-year survival rate in gastric cancer patients. A-D: Analysis of the association of GPSM2 expression levels with over survival (OS), overall survival at 60 months (OS-5), first progression (FP) and post-progression survival (PPS) using Kaplan-Meier Plotter. E: Kaplan-Meier survival analysis demonstrating the impact of GPSM2 expression on 5-year survival rate of gastric cancer patients after gastrectomy. F: ROC curve analysis for evaluating the predictive value of GPSM2 expression for 5-year survival rates in gastric cancer patients following gastrectomy.

表2 单因素结合Cox多因素分析影响胃癌患者术后5年生存率的因素

Tab.2 Univariate and multivariate Cox regression analysis of factors influencing 5-year survival rate of gastric cancer patients

Clinicopathological parameters	Univariate analysis		Multivariate analysis
Clinicopathological parameters	Log-rank χ²	P	HR	95% CI	P
Gender (female vs male)	0.157	0.692
Age (≥60 year vs <60 year)	1.188	0.276
Tumor size (≥5 cm vs <5 cm)	0.004	0.949
GPSM2 expression (high vs low)	32.418	<0.001	3.365	1.689-6.705	<0.001
G Stage (G₃-G₄vs G₁-G₂)	15.761	<0.001	1.421	0.769-2.626	0.262
T Stage (T₃-T₄vs T₁-T₂)	26.397	<0.001	3.406	1.762-6.584	<0.001
N Stage (N₂-N₃vs N₀-N₁)	21.542	<0.001	2.130	1.115-4.068	0.022
CEA (≥5 μg/L vs <5 μg/L )	37.810	<0.001	2.717	1.175-6.283	0.019
CA19-9 (≥37 kU/L vs <37 kU/L)	37.429	<0.001	3.592	1.577-8.183	0.002

图4 GPSM2对胃癌细胞周期的影响

Fig.4 Effect of GPSM2 knockdown (KD) and overexpression (OE) on cell cycle of gastric cancer cells. A: GO enrichment analysis. B, C: GPSM2 protein expression in MGC803 cells analyzed by Western blotting. D: Results of CCK-8 assay. E, F: Colony-forming assay. G, H: Effect of GPSM2 on cell cycle of MGC803 cells detected by flow cytometry. I, J: Expression of CDK2 and CDK4 analyzed by Western blotting. n=3, *P<0.05 vs NC group.

图5 GPSM2促进裸鼠皮下移植瘤生长

Fig.5 GPSM2 overexpression promotes subcutaneous graft tumor growth in nude mice. A: Gross observation of the dissected tumors in each group. B: Quantitative assessment of tumor volume in different groups (n=5). C, D: Expression of CDK2 and CDK4 in the xenografts. E, F: Expression of CDK2 and CDK4 in tumor tissues detected by immunohistochemical staining. n=5, *P<0.05 vs NC group.

图6 GPSM2高表达抑制p53信号通路

Fig.6 GPSM2 overexpression suppresses expression of the p53 signaling pathway. A: KEGG enrichment analysis. B, C: Analysis of p53 and p21 expression in different groups of MGC803 cells. D, E: Analysis of p53 and p21 expression in the transplanted tumors from nude mice. n=3, *P<0.05 vs NC group.

图7 GPSM2通过抑制p53信号通路蛋白表达从而促进胃癌细胞的增殖

Fig.7 GPSM2 overexpression promotes proliferation of gastric cancer cells possibly by suppressing expressions of proteins in the p53 signaling pathway. A, B: Measurement of p53 and p21 expression levels in the transplanted tumors. C, D: Expression of p53 and p21 in MGC803 cells. E, F: Colony-forming assay. n=3, *P<0.05 vs OE group.

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GPSM2在胃癌组织中高表达并通过促进肿瘤细胞的增殖影响患者预后

GPSM2 is highly expressed in gastric cancer to affect patient prognosis by promoting tumor cell proliferation

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