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中国临床药理学与治疗学 ›› 2025, Vol. 30 ›› Issue (7): 929-934.doi: 10.12092/j.issn.1009-2501.2025.07.007

• 基础研究 • 上一篇    下一篇

miR-195-5p通过靶向GPRC5A逆转胃癌细胞对曲妥珠单抗的耐药性研究

朱显军1，张丹妮2，罗喜俊1，梁俊杰1，李涛1，唐兴奎1，何嘉琳1，李伟2   

  1. 1广州医科大学附属番禺中心医院普通外科，广州  510000，广东；2南华大学附属第二医院乳腺甲状腺外科，衡阳  421000，湖南

  • 收稿日期:2024-09-06 修回日期:2024-11-22 出版日期:2025-07-26 发布日期:2025-07-02
  • 通讯作者: 李伟，男，博士，主治医师，研究方向：肿瘤耐药机制、纳米药物递送及细胞程序性死亡。 E-mail： liwei0712@usc.edu.cn
  • 作者简介:朱显军，男，硕士研究生，主治医师，研究方向：胃肠肿瘤治疗及其机制研究。 E-mail： 1293023850@qq.com
  • 基金资助:
    消化道肿瘤基础与临床药理研究湖南省重点实验室（2023TP1014）；湖南省临床医疗技术创新引导项目（2020SK51706）；湖南省卫健委一般指导课题（202204013843）；番禺区科技计划项目（2022-Z04-024）

Reversal of trastuzumab resistance in gastric cancer cells by targeting GPRC5A with miR-195-5p

ZHU Xianjun1, ZHANG Danni2, LUO Xijun1, LIANG Junjie1, LI Tao1, TANG Xingkui1, HE Jialin1, LI Wei2   

  1. 1Department of General Surgery, The Affiliated Panyu Central Hospital of Guangzhou Medical University,Guangzhou 510000, Guangdong, China; 2Department of Breast and Thyroid Surgery, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, Hunan, China
  • Received:2024-09-06 Revised:2024-11-22 Online:2025-07-26 Published:2025-07-02

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摘要：

目的：探究微小核糖核酸miR-195-5p在调控胃癌对曲妥珠单抗耐药性中的作用，并验证其与靶基因GPRC5A作为治疗靶点的潜力。方法：建立曲妥珠单抗耐药的胃癌细胞系（NCI-N87和MKN45）。使用CCK-8实验评估曲妥珠单抗处理下的细胞存活率。通过RT-qPCR测定miR-195-5p的表达水平。转染miR-195-5p模拟物以评估曲妥珠单抗敏感性和增殖的变化。同样通过RT-qPCR测量GPRC5A的表达，并通过双荧光素酶报告基因实验确认miR-195-5p与GPRC5A之间的靶向关系。结果：与耐药细胞相比，亲本细胞对曲妥珠单抗更敏感，耐药细胞中miR-195-5p表达显著降低（P<0.01）。在耐药细胞中过表达miR-195-5p增强了对曲妥珠单抗的敏感性并减少了增殖（P<0.01）。GPRC5A在耐药细胞中上调（P<0.01），miR-195-5p直接靶向GPRC5A，影响曲妥珠单抗处理下的细胞增殖。结论：miR-195-5p可能通过靶向GPRC5A调节胃癌细胞对曲妥珠单抗的敏感性，表明其作为指导曲妥珠单抗治疗的分子标志物的潜力。

关键词: 胃癌, miR-195-5p, GPRC5A, 曲妥珠单抗, 耐药, 分子靶向治疗  

Abstract:

AIM: To explore the role of miR-195-5p in mediating trastuzumab resistance in gastric cancer and to validate its potential as a therapeutic target along with its target gene GPRC5A. METHODS: Trastuzumab-resistant gastric cancer cell lines (NCI-N87 and MKN45) were established. Cell viability under trastuzumab treatment was assessed using CCK-8 assays. Expression levels of miR-195-5p were determined by RT-qPCR. Transfection with miR-195-5p mimics was performed to evaluate changes in trastuzumab sensitivity and proliferation. GPRC5A expression was also measured by RT-qPCR, and the targeting relationship between miR-195-5p and GPRC5A was confirmed using a dual-luciferase reporter assay. RESULTS: Parental cells showed higher sensitivity to trastuzumab than resistant cells, with miR-195-5p expression significantly lower in the latter. Overexpression of miR-195-5p in resistant cells enhanced trastuzumab sensitivity and reduced proliferation. GPRC5A was found to be upregulated in resistant cells, and miR-195-5p directly targeted GPRC5A, affecting cell proliferation under trastuzumab treatment. CONCLUSION: miR-195-5p may regulate trastuzumab sensitivity in gastric cancer by targeting GPRC5A, suggesting potential as a molecular marker for trastuzumab therapy guidance.

Key words: Gastric Cancer, miR-195-5p, GPRC5A, Trastuzumab, Drug Resistance, Molecular Targeted Therapy

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