Breast cancer is one of the most prevalent and reoccurring cancer types that leads to death in women. Triple-negative breast cancer (TNBC) is difficult to treat due to the lack of therapeutic targets. Many studies have focused on identifying drugs for use as alternative treatments for breast cancer. Thioguanine (6-TG) exerts antitumor effects in cancer. Increasing evidence has demonstrated that ceRNAs are involved in cancer processes. However, the mechanism by which 6-TG regulates lncRNA-miRNA-mRNAs has not been elucidated. We evaluated the antitumor effect of 6-TG in MDA-MB-231 cells and comprehensively analyzed the RNA-Seq data of MDA-MB-231 cells treated with 6-TG. Our results showed that most tumor pathways were blocked by 6-TG. The hub genes were FN1, FLNA, FLNB, VCL, GSN, MYH10, ACTN4, KDR and EREG, and they were all downregulated after 6-TG treatment. The coexpression network consisted of 18 miRNAs, 9 lncRNAs and 20 mRNAs. Hsa-mir-16-5p and Hsa-mir-335-5p targeted the greatest number of mRNAs in the network. These molecules could bind to PAX8-AS1 and eliminate the inhibition of target mRNA expression. We showed that PAX8-AS1 is the main lncRNA affected by 6-TG and that PAX8-AS1 regulates the hub genes in tumor pathways by competitively binding with miR-16-5p and miR-335-5p.

中文翻译：

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6-TG对三阴性乳腺癌细胞系lncRNA-miRNA-mRNA ceRNA网络的调控作用。

乳腺癌是导致女性死亡的最普遍和最易复发的癌症类型之一。由于缺乏治疗靶点，三阴性乳腺癌 (TNBC) 难以治疗。许多研究都集中在确定用作乳腺癌替代疗法的药物。硫鸟嘌呤 (6-TG) 在癌症中发挥抗肿瘤作用。越来越多的证据表明，ceRNA 与癌症过程有关。然而，6-TG 调控 lncRNA-miRNA-mRNA 的机制尚未阐明。我们评估了 6-TG 在 MDA-MB-231 细胞中的抗肿瘤作用，并综合分析了 6-TG 处理的 MDA-MB-231 细胞的 RNA-Seq 数据。我们的结果表明，大多数肿瘤通路被 6-TG 阻断。枢纽基因为 FN1、FLNA、FLNB、VCL、GSN、MYH10、ACTN4、KDR 和 EREG，6-TG处理后均下调。共表达网络由 18 个 miRNA、9 个 lncRNA 和 20 个 mRNA 组成。Hsa-mir-16-5p 和 Hsa-mir-335-5p 靶向网络中最多的 mRNA。这些分子可以与 PAX8-AS1 结合并消除对目标 mRNA 表达的抑制。我们发现 PAX8-AS1 是受 6-TG 影响的主要 lncRNA，并且 PAX8-AS1 通过与 miR-16-5p 和 miR-335-5p 竞争性结合来调节肿瘤通路中的枢纽基因。