中国临床药理学杂志

二甲双胍对结直肠癌的影响及COX-2/PGE2通路机制研究

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余婉萱 ¹ , 王蓉 ² , 许斌斌 ³

中国临床药理学杂志 | 临床与基础桥接研究 2025,41(21): 3096-3102

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中国临床药理学杂志 |临床与基础桥接研究 2025 , 41 (21) : 3096 -3102

二甲双胍对结直肠癌的影响及COX-2/PGE2通路机制研究

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余婉萱¹, 王蓉², 许斌斌³

作者信息

^1.温州市中心医院，浙江温州 353200

^2.福建中医药大学附属人民医院，浙江温州 353200

^3.联勤保障部队第九〇〇医院，浙江温州 353200

通讯作者:

王蓉，主任医师，硕士生导师 MP: 18060580811 E-mail: ronglittle2003@163.com

作者简介:

余婉萱（1996-），女，医师，硕士研究生，主要从事结直肠癌方面的临床工作和研究

Research on effects of metformin in colorectal cancer and the COX-2/PGE2 pathway mechanism

Wan-xuan YU¹, Rong WANG², Bin-bin XU³

Affiliations

^1.Wenzhou Central Hospital, Wenzhou 353200, Zhejiang Province, China

^2.Fujian Provincial People’s Hospital, Wenzhou 353200, Zhejiang Province, China

^3.The 900 Hospital of the Joint Service Support Force of the People’s Liberation Army of China, Wenzhou 353200, Zhejiang Province, China

出版时间: 2025-11-17 doi: 10.13699/j.cnki.1001-6821.2025.21.016

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摘要

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目的

探讨二甲双胍不同剂量对结直肠癌（CRC）的抑制作用及其通过调节胆汁酸代谢和环氧合酶-2（COX-2）/前列腺素表皮生长因子受体（PGE2）通路的机制。

方法

60只BALB/c小鼠分为对照组、模型组、低剂量实验组、中剂量实验组和高剂量实验组，通过氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）诱导CRC模型。用游标卡尺测量肿瘤数量和直径；用液相色谱-质谱联用（LC-MS）法检测粪便中胆汁酸水平；用免疫组化法检测结肠组织中COX-2和PGE2蛋白表达。

结果

对照组、模型组和低、中、高剂量实验组的肿瘤数量分别为0、（11.58±7.13）、（7.83±3.38）、（3.33±2.06）和（2.83±1.40）个；肿瘤直径分别为0、（2.91±0.32）、（2.43±0.31）、（2.11±0.37）和（1.98±0.38）mm；总胆汁酸浓度分别为（20 989.00±306.69）、（43 256.50±187.08）、（32 265.26±325.08）、（23 035.72±136.33）和（22 351.51±145.36）ng·g^-1；脱氧胆酸（DCA）浓度分别为（3 160.14±113.31）、（16 684.58±4.39）、（11 544.47±7.86）、（5 472.60±25.03）和（5 201.36±79.95）ng·g^-1；石胆酸（LCA）浓度分别为（2 140.43±76.23）、（14 452.60±47.82）、（9 085.87±11.14）、（3 145.09±54.20）和（2 955.51±38.02）ng·g^-1；胆酸（CA）浓度分别为（6 917.71±51.12）、（2 051.41±88.47）、（3 181.64±23.79）、（5 564.01±35.45）和（5 866.10±63.80）ng·g^-1；鹅脱氧胆酸（CDCA）浓度分别为（5 720.33±53.07）、（1 135.43±48.38）、（1 530.56±37.57）、（4 060.14±37.09）和（4 542.83±27.39）ng·g^-1；牛磺胆酸（TCA）浓度分别为（497.24±59.29）、（1 560.15±26.03）、（958.13±28.00）、（705.21±3.66）、（669.24±33.00）ng·g^-1；牛磺鹅脱氧胆酸（TCDCA）浓度分别为（1 027.96±84.28）、（2 918.60±122.90）、（2 518.23±70.50）、（1 411.36±49.15）和（1 389.87±5.8）ng·g^-1；COX-2表达评分分别为未检测到表达、（5.75±0.97）、（4.50±1.78）、（2.75±1.66）和（2.67±0.89）分；PGE2表达评分分别为未检测到表达、（5.75±0.97）、（4.50±1.93）、（2.67±1.67）和（2.50±0.90）分，模型组的上述指标与对照组比较；低、中、高剂量实验组的上述指标与模型组比较，在统计学上差异均有统计学意义（均P<0.05）。中、高剂量实验组在降低肿瘤数量、直径及调节胆汁酸代谢方面效果均显著优于低剂量组（均P<0.05）。COX-2/PGE2表达抑制程度与二甲双胍剂量呈负相关。

结论

二甲双胍通过剂量依赖性调节胆汁酸代谢（降低DCA、LCA、TCA、TCDCA，恢复CA、CDCA水平）及抑制COX-2/PGE2信号通路，发挥抗结直肠癌作用，中、高剂量实验组（250~500 mg·kg^-1·d^-1）效果更显著。

关键词

二甲双胍 / 结直肠癌 / 胆汁酸代谢 / 环氧合酶-2/前列腺素表皮生长因子受体通路 / 剂量依赖性

Abstract

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Objective

To investigate the inhibitory effect of different doses of metformin on colorectal cancer (CRC) and its mechanism involving the regulation of bile acid metabolism and the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway.

Methods

A total of 60 BALB/c mice were divided into control, model, low-dose metformin, medium-dose metformin and high-dose metformin groups. A CRC model was induced using azoxymethane (AOM)/dextran sodium sulfate (DSS). Tumor number and diameter were measured with a caliper; fecal bile acid levels were detected by liquid chromatography-mass spectrometry (LC-MS); and protein expression of COX-2 and PGE2 in colon tissue was determined by immunohistochemistry.

Results

Tumor numbers in the control, model, low-, medium- and high-dose groups were 0, 11.58±7.13, 7.83±3.38, 3.33±2.06 and 2.83±1.40, respectively; tumor diameters were 0, (2.91±0.32), (2.43±0.31), (2.11±0.37) and (1.98±0.38) mm, respectively; total bile acid concentrations were (20 989.00±306.69), (43 256.50±187.08), (32 265.26±325.08), (23 035.72±136.33) and (22 351.51±145.36) ng·g^-1, respectively; deoxycholic acid (DCA) concentrations were (3 160.14±113.31), (16 684.58±4.39), (11 544.47±7.86), (5 472.60±25.03) and (5 201.36±79.95) ng·g^-1, respectively; lithocholic acid (LCA) concentrations were (2 140.43±76.23), (14 452.6±47.82), (9 085.87±11.14), (3 145.09±54.20) and (2 955.51±38.02) ng·g^-1, respectively; cholic acid (CA) concentrations were (6 917.71±51.12), (2 051.41±88.47), (3 181.64±23.79), (5 564.01±35.45) and (5 866.10±63.80) ng·g^-1, respectively; chenodeoxycholic acid (CDCA) concentrations were (5 720.33±53.07), (1 135.43±48.38), (1 530.56±37.57), (4 060.14±37.09) and (4 542.83±27.39) ng·g^-1, respectively; taurocholic acid (TCA) concentrations were (497.24±59.29), (1 560.15±26.03), (958.13±28.00), (705.21±3.66) and (669.24±33.00) ng·g^-1, respectively; taurochenodeoxycholic acid (TCDCA) concentrations were (1 027.96±84.28), (2 918.60±122.90), (2 518.23±70.50), (1 411.36±49.15) and (1 389.87±5.80) ng·g^-1, respectively; COX-2 staining scores in the model, low-, medium- and high-dose groups were (5.75±0.97), (4.50±1.78), (2.75±1.66) and (2.67±0.89) points, respectively; PGE2 staining scores were (5.75±0.97), (4.50±1.93), (2.67±1.67) and (2.50±0.90) points, respectively; compared with the control group, the aforementioned indicators in the model group showed statistically significant differences; compared with the model group, the indicators in the low-, medium- and high-dose groups showed statistically significant differences (all P<0.05). The medium- and high-dose groups were significantly more effective than the low-dose group in reducing tumor number and diameter and regulating bile acid metabolism (P<0.05). The inhibition of COX-2/PGE2 expression was negatively correlated with the dose of metformin.

Conclusion

Metformin exerts anti-CRC effects through dose-dependent regulation of bile acid metabolism (reducing DCA, LCA, TCA, TCDCA and restoring CA and CDCA levels) and inhibition of the COX-2/PGE2 signaling pathway. The medium- and high-dose groups (250-500 mg·kg^-1·d^-1) show more significant effects.

Key words

metformin / colorectal cancer / bile acid metabolism / cyclooxygenase-2/prostaglandin E2 pathway / dose-dependent

引用本文

余婉萱, 王蓉, 许斌斌. 二甲双胍对结直肠癌的影响及COX-2/PGE2通路机制研究. 中国临床药理学杂志, 2025 , 41 (21) : 3096 -3102 . DOI: 10.13699/j.cnki.1001-6821.2025.21.016

Wan-xuan YU, Rong WANG, Bin-bin XU. Research on effects of metformin in colorectal cancer and the COX-2/PGE2 pathway mechanism[J]. Chinese Journal of Clinical Pharmacology, 2025 , 41 (21) : 3096 -3102 . DOI: 10.13699/j.cnki.1001-6821.2025.21.016

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2025年第41卷第21期

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doi: 10.13699/j.cnki.1001-6821.2025.21.016

接收时间：2025-05-23
首发时间：2026-08-05
出版时间：2025-11-17

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收稿日期：2025-05-23

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作者信息

^1.温州市中心医院，浙江温州 353200

^2.福建中医药大学附属人民医院，浙江温州 353200

^3.联勤保障部队第九〇〇医院，浙江温州 353200

通讯作者:

王蓉，主任医师，硕士生导师 MP: 18060580811 E-mail: ronglittle2003@163.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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