LncRNA AFAP1-AS1 Induces Gefitinib Resistance of Lung Adenocarcinoma Through the miR-653-5p/AGR2 Axis.

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS ACS Applied Bio Materials Pub Date : 2023-01-05 eCollection Date: 2023-01-01 DOI:10.2147/TCRM.S374162

Tao Zuo, Ping Jiang, Jun Fu, Yongjian Zhang

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Abstract

Purpose: Gefitinib resistance limits the therapeutic efficacy of gefitinib to lung adenocarcinoma (LUAD). The goal of this research is to learn more about the lncRNA AFAP1-AS1 and how it functions in gefitinib-resistant LUAD cells.

Methods: RT-qPCR was performed to test the expression of AFAP1-AS1, miR-653-5p and AGR2 in LUAD tissues with acquired resistance to gefitinib or not as well as in gefitinib-resistant LUAD cells. Cell proliferation, invasion and apoptosis were measured by CCK8 assays, transwell invasion assays and flow cytometry, respectively. Luciferase reporter assay showed that miR-653-5p and AFAP1-AS1 or AGR2 interactions.

Results: In gefitinib-resistant LUAD cells and tissues, AFAP1-AS1 was overexpressed. Meanwhile, silencing AFAP1-AS1 reduced proliferation and migration while increasing apoptosis and gefitinib sensitivity. Mechanically, AFAP1-AS1 sequestered the miR-653-5p and blocked the inhibition of miR-653-5p to AGR2 and stepwise upregulated AGR2 overexpression in LUAD gefitinib resistant cells, resulting gefitinib resistance in LUAD.

Conclusion: AFAP1-AS1 promotes gefitinib-resistance LUAD cells through a previously unrecognized miR-653-5p/AGR2 axis, suggesting targeting AFAP1-AS1/miR-653-5p/AGR2 axis might be a promising way for LUAD intervention.

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LncRNA AFAP1-AS1 通过 miR-653-5p/AGR2 轴诱导吉非替尼对肺腺癌的耐药性

目的：吉非替尼耐药限制了吉非替尼对肺腺癌（LUAD）的疗效。本研究的目的是进一步了解 lncRNA AFAP1-AS1 及其在吉非替尼耐药的 LUAD 细胞中的功能：方法：采用RT-qPCR检测AFAP1-AS1、miR-653-5p和AGR2在吉非替尼获得性耐药或非获得性耐药LUAD组织以及吉非替尼耐药LUAD细胞中的表达。细胞增殖、侵袭和凋亡分别通过 CCK8 检测法、Transwell 侵袭检测法和流式细胞术进行检测。荧光素酶报告实验表明，miR-653-5p与AFAP1-AS1或AGR2相互作用：结果：在吉非替尼耐药的LUAD细胞和组织中，AFAP1-AS1表达过高。同时，沉默 AFAP1-AS1 可减少细胞增殖和迁移，同时增加细胞凋亡和吉非替尼敏感性。从机理上讲，AFAP1-AS1封存了miR-653-5p，阻断了miR-653-5p对AGR2的抑制作用，并逐步上调了AGR2在LUAD吉非替尼耐药细胞中的过表达，导致吉非替尼在LUAD中耐药：结论：AFAP1-AS1通过之前尚未认识到的miR-653-5p/AGR2轴促进吉非替尼耐药的LUAD细胞，这表明靶向AFAP1-AS1/miR-653-5p/AGR2轴可能是干预LUAD的一种有前景的方法。

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