High expression of SLC34A2 contributes to chemoresistance of non-small cell lung cancer against gefitinib: The critical role of miR-124–3p

IF 1.5 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2024-11-19 DOI:10.1016/j.mrfmmm.2024.111894

Chao Tan , Li Zhang , Sai Chen , Zhenzhen Tian , Nina Zhou , Yuling Li , Qi Wang , Lu Chen

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Abstract

Gefitinib is a therapeutic agent used to treat lung carcinoma, including non-small cell lung cancer (NSCLC). However, mechanisms underlying NSCLC cell resistance to gefitinib remain largely uncharacterized. In this study, we explored the association between the miR-124–3p/SLC34A2 axis and gefitinib resistance using a series of in vivo and in vitro assays. Data indicated that miR-124–3p is downregulated, while SLC34A2 is upregulated, in gefitinib-resistant NSCLC cells. Overexpression of miR-124–3p reduced NSCLC cell resistance to gefitinib by suppressing cell viability, inducing apoptosis, and decreasing N-cadherin expression. Conversely, inhibiting miR-124–3p in NSCLC cells led to increased cell viability and reduced apoptosis. Overexpression of SLC34A2 in NSCLC cells further heightened gefitinib resistance. In a xenograft mouse model, SLC34A2 overexpression promoted solid tumor growth and metastasis, while miR-124–3p overexpression inhibited these effects. Our results highlight that the interaction between miR-124–3p and SLC34A2 plays an indispensable role in determining gefitinib resistance in NSCLC cells.

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SLC34A2的高表达导致了非小细胞肺癌对吉非替尼的化疗耐药性：miR-124-3p 的关键作用。

吉非替尼是一种用于治疗包括非小细胞肺癌（NSCLC）在内的肺癌的药物。然而，NSCLC细胞对吉非替尼耐药的机制在很大程度上仍未定性。在这项研究中，我们利用一系列体内和体外试验探索了 miR-124-3p/SLC34A2 轴与吉非替尼耐药性之间的关联。数据表明，在吉非替尼耐药的 NSCLC 细胞中，miR-124-3p 下调，而 SLC34A2 上调。miR-124-3p的过表达通过抑制细胞活力、诱导细胞凋亡和减少N-cadherin的表达，降低了NSCLC细胞对吉非替尼的耐药性。相反，抑制NSCLC细胞中的miR-124-3p可提高细胞活力，减少细胞凋亡。NSCLC 细胞中 SLC34A2 的过表达进一步增强了吉非替尼的抗药性。在异种移植小鼠模型中，SLC34A2 的过表达促进了实体瘤的生长和转移，而 miR-124-3p 的过表达则抑制了这些效应。我们的研究结果突出表明，miR-124-3p与SLC34A2之间的相互作用在决定NSCLC细胞对吉非替尼的耐药性方面起着不可或缺的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis 生物-毒理学

CiteScore

4.90

自引率

0.00%

发文量

审稿时长

51 days

期刊介绍： Mutation Research (MR) provides a platform for publishing all aspects of DNA mutations and epimutations, from basic evolutionary aspects to translational applications in genetic and epigenetic diagnostics and therapy. Mutations are defined as all possible alterations in DNA sequence and sequence organization, from point mutations to genome structural variation, chromosomal aberrations and aneuploidy. Epimutations are defined as alterations in the epigenome, i.e., changes in DNA methylation, histone modification and small regulatory RNAs. MR publishes articles in the following areas: Of special interest are basic mechanisms through which DNA damage and mutations impact development and differentiation, stem cell biology and cell fate in general, including various forms of cell death and cellular senescence. The study of genome instability in human molecular epidemiology and in relation to complex phenotypes, such as human disease, is considered a growing area of importance. Mechanisms of (epi)mutation induction, for example, during DNA repair, replication or recombination; novel methods of (epi)mutation detection, with a focus on ultra-high-throughput sequencing. Landscape of somatic mutations and epimutations in cancer and aging. Role of de novo mutations in human disease and aging; mutations in population genomics. Interactions between mutations and epimutations. The role of epimutations in chromatin structure and function. Mitochondrial DNA mutations and their consequences in terms of human disease and aging. Novel ways to generate mutations and epimutations in cell lines and animal models.