miR-375 targeting YAP1 modulates trastuzumab resistance through epithelial-mesenchymal transition in breast cancer cells

叶星明; 王　淋; 贾　静; 吴秀凤; 陈　颖

doi:10.19401/j.cnki.1007-3639.2021.01.004

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miR-375 targeting YAP1 modulates trastuzumab resistance through epithelial-mesenchymal transition in breast cancer cells

更新时间：2026-01-27

- miR-375 targeting YAP1 modulates trastuzumab resistance through epithelial-mesenchymal transition in breast cancer cells
- China Oncology Vol. 31, Issue 1, Pages: 27-34(2021)
- 作者机构：
  
  1. 福建省肿瘤医院，福建医科大学附属肿瘤医院中心实验室,福建,福州,350014
  2. 福建省肿瘤医院，福建医科大学附属肿瘤医院乳腺外科,福建,福州,350014
- 作者简介：
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2021.01.004
  CLC： R737.9
- Published Online：20 February 2021，
  
  Published：20 February 2021
- 稿件说明：
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叶星明, 王　淋, 贾　静, 吴秀凤, 陈　颖 . miR-375靶向YAP1调控上皮-间质转化参与乳腺癌细胞曲妥珠单抗的耐药[J]. 中国癌症杂志, 2021, 31(1): 27-34.

叶星明, 王　淋, 贾　静, et al. miR-375 targeting YAP1 modulates trastuzumab resistance through epithelial-mesenchymal transition in breast cancer cells[J]. China Oncology, 2021, 31(1): 27-34.
叶星明, 王　淋, 贾　静, 吴秀凤, 陈　颖 . miR-375靶向YAP1调控上皮-间质转化参与乳腺癌细胞曲妥珠单抗的耐药[J]. 中国癌症杂志, 2021, 31(1): 27-34. DOI： 10.19401/j.cnki.1007-3639.2021.01.004.

叶星明, 王　淋, 贾　静, et al. miR-375 targeting YAP1 modulates trastuzumab resistance through epithelial-mesenchymal transition in breast cancer cells[J]. China Oncology, 2021, 31(1): 27-34. DOI： 10.19401/j.cnki.1007-3639.2021.01.004.

摘要

背景与目的：曲妥珠单抗作为人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）常用靶向抗体药物，其耐药问题日益凸显。探讨miR-375靶向Yes相关蛋白1（Yes-associated protein 1，YAP1）介导上皮-间质转化（epithelial-mesenchymal transition，EMT）参与乳腺癌细胞曲妥珠单抗的耐药。方法：建立HER2阳性乳腺癌曲妥珠单抗耐药的细胞株，转染miR-375 mimic来上调其表达，采用实时荧光定量聚合酶链反应（real-time fluorescence quantitative polymerase chain reaction，RTFQ-PCR）检测miR-375的表达情况，采用蛋白质印迹法（Western blot）检测其EMT标志蛋白波形蛋白（vimentin）、E-钙黏蛋白（E-cadherin）的表达变化情况。采用MTT实验和平板克隆实验检测其药物敏感性及增殖能力的变化。双荧光素酶报告基因实验验证miR-375与YAP1 3’-UTR的靶向关系，采用RTFQ-PCR检测临床水平上两者的相关性。对细胞株共转染miR-375 mimic和YAP1-MUT载体后，采用Western blot检测其EMT蛋白表达的恢复情况，采用MTT实验和平板克隆形成实验检测其药物敏感性和增殖能力的恢复情况。结果：与NC组比较，miR-375 mimic组的药物敏感性、平板克隆形成能力均下调（P均0.01），其EMT标志蛋白vimentin、E-cadherin表达也发生逆转（P均0.05）。双荧光素酶报告基因实验结果证实，YAP1是miR-375的靶基因，miR-375与YAP1在乳腺癌患者肿瘤组织中呈负相关（r=-0.586 8，P=0.002 8）。miR-375 mimic组同时过表达YAP1后可恢复其药物敏感性（P0.01）、克隆形成能力（P0.05）和EMT标志蛋白vimentin、E-cadherin表达情况（P均0.05）。结论：miR-375通过靶向YAP1在曲妥珠单抗耐药细胞株中介导EMT，进而调控曲妥珠单抗耐药细胞株的药物敏感性。

Abstract

Background and purpose: As the targeted antibody of human epidermal growth factor receptor 2 (HER2)

trastuzumab resistance gets more and more attention. This study aimed to explore the role of miR-375 in the occurrence of trastuzumab resistance in breast cancer cells through regulating epithelial-mesenchymal transition (EMT) by targeting Yes-associated protein 1 (YAP1). Methods: Trastuzumab-resistant breast cancer cell line was established. miR-375 mimic and recombinant plasmid YAP1 were transfected into SK-BR-3R cells. The sensitivities of each breast cancer cell line to trastuzumab were detected by MTT assay

and proliferation was detected by colony formation assay. Real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) and Western blot were applied to detect mRNA and protein expressions of miR-375

vimentin

E-cadherin and YAP1. Dual-luciferase reporter gene assay was conducted to verify the role of miR-375 in regulation of YAP1 transcription. A total of 25 breast cancer tissues from patients were collected to detect correlation in clinical performance. Results: Compared with NC group

after transfection with miR-375 mimic

the sensitivity to trastuzumab (P0.01) and capacity of colony formation (P0.01) for SK- BR-3R (resistance) cell line were decreased significantly

and the expression of vimentin was significantly downregulated

whereas E-cadherin was significantly upregulated (all P0.05). YAP1 as downstream target gene of miR-375 was observed (P0.01). MiR- 375 was negatively correlated with YAP1 in breast cancer tissues (r=-0.586 8

P=0.002 8). After miR-375 mimic and YAP1-MUT co- transfection in SK-BR-3R

compared with the control

the sensitivity to trastuzumab (P0.01)

capacity of colony formation (P0.05) and the expressions of vimentin and E-cadherin were restored (P0.05). Conclusion: miR-375 takes part in trastuzumab resistance of breast cancer cells through regulating EMT

which is mediated by targeting YAP1.

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