Qiao Zipeng, Xing Yu, Zhang Qingquan, Tang Yongjun, Feng Ruifa, Pang Weiyi
Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, Guilin Medical University, Guilin, Guangxi, China.
School of Public Health, Guilin Medical University, Guilin, Guangxi, China.
Front Cell Dev Biol. 2022 Nov 25;10:1023079. doi: 10.3389/fcell.2022.1023079. eCollection 2022.
Tamoxifen (TMX) is one of the most widely used drugs to treat breast cancer (BC). However, acquired drug resistance is still a major obstacle to its application, rendering it crucial to explore the mechanisms of TMX resistance in BC. This aims of this study were to identify the mechanisms of TMX resistance and construct ceRNA regulatory networks in breast cancer. GEO2R was used to screen for differentially expressed mRNAs (DEmRNAs) leading to drug resistance in BC cells. MiRTarbase and miRNet were used to predict miRNAs and lncRNAs upstream, and the competing endogenous RNA (ceRNA) regulatory network of BC cell resistance was constructed by starBase. We used the Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA) to analyze the expression and prognostic differences of genes in the ceRNA network with core axis, and qRT-PCR was used to further verify the above conclusions. We found that 21 DEmRNAs were upregulated and 43 DEmRNA downregulated in drug-resistant BC cells. DEmRNAs were noticeably enriched in pathways relevant to cancer. We then constructed a protein-protein interaction (PPI) network based on the STRING database and defined 10 top-ranked hub genes among the upregulated and downregulated DEmRNAs. The 20 DEmRNAs were predicted to obtain 113 upstream miRNAs and 501 lncRNAs. Among them, 7 mRNAs, 22 lncRNAs, and 11 miRNAs were used to structure the ceRNA regulatory network of drug resistance in BC cells. 4 mRNAs, 4 lncRNAs, and 3 miRNAs were detected by GEPIA and the Kaplan-Meier plotter to be significantly associated with BC expression and prognosis. The differential expression of the genes in BC cells was confirmed by qRT-PCR. The ceRNA regulatory network of TMX-resistant BC was successfully constructed and confirmed. This will provide an important resource for finding therapeutic targets for TMX resistance, where the discovery of candidate conventional mechanisms can aid clinical decision-making. In addition, this resource will help discover the mechanisms behind this type of resistance.
他莫昔芬（TMX）是治疗乳腺癌（BC）最常用的药物之一。然而，获得性耐药仍然是其应用的主要障碍，因此探索BC中TMX耐药的机制至关重要。本研究的目的是确定TMX耐药的机制，并构建乳腺癌中的ceRNA调控网络。使用GEO2R筛选导致BC细胞耐药的差异表达mRNA（DEmRNAs）。利用MiRTarbase和miRNet预测上游的miRNA和lncRNA，并通过starBase构建BC细胞耐药的竞争性内源RNA（ceRNA）调控网络。我们使用Kaplan-Meier绘图仪和基因表达谱交互式分析（GEPIA）分析具有核心轴的ceRNA网络中基因的表达和预后差异，并使用qRT-PCR进一步验证上述结论。我们发现，在耐药BC细胞中，21个DEmRNAs上调，43个DEmRNAs下调。DEmRNAs显著富集于与癌症相关的通路中。然后，我们基于STRING数据库构建了蛋白质-蛋白质相互作用（PPI）网络，并在上调和下调的DEmRNAs中定义了10个排名靠前的枢纽基因。预测这20个DEmRNAs可获得113个上游miRNA和501个lncRNA。其中，7个mRNA、22个lncRNA和11个miRNA用于构建BC细胞耐药的ceRNA调控网络。通过GEPIA和Kaplan-Meier绘图仪检测到4个mRNA、4个lncRNA和3个miRNA与BC表达和预后显著相关。通过qRT-PCR证实了BC细胞中基因的差异表达。成功构建并确认了TMX耐药BC的ceRNA调控网络。这将为寻找TMX耐药的治疗靶点提供重要资源，发现候选传统机制有助于临床决策。此外，该资源将有助于发现这种耐药类型背后的机制。
