Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun 130021, China.
College of Animal Science, Jilin University, Changchun, Jilin 130062, China.
Biosci Rep. 2021 Feb 26;41(2). doi: 10.1042/BSR20203890.
Breast cancer is one of the most prevalent and recurring cancer types that leads to deaths 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 competitive endogenous ribonucleic acids (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 down-regulated after 6-TG treatment. The coexpression network consisted of 18 microRNAs (miRNAs), 9 long noncoding RNAs (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.
乳腺癌是导致女性死亡的最常见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。许多研究都集中在寻找药物作为乳腺癌的替代治疗方法。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，竞争性内源性核糖核酸（ceRNA）参与了癌症过程。然而，6-TG 调节 lncRNA-miRNA-mRNAs 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，并对用 6-TG 处理的 MDA-MB-231 细胞的 RNA-Seq 数据进行了全面分析。我们的结果表明，6-TG 阻断了大多数肿瘤途径。枢纽基因是 FN1、FLNA、FLNB、VCL、GSN、MYH10、ACTN4、KDR 和 EREG，它们在 6-TG 处理后均下调。共表达网络由 18 个 microRNAs（miRNAs）、9 个长非编码 RNA（lncRNAs）和 20 个 mRNAs 组成。Hsa-mir-16-5p 和 Hsa-mir-335-5p 靶向网络中最多的 mRNAs。这些分子可以与 PAX8-AS1 结合，消除对靶 mRNA 表达的抑制。我们表明 PAX8-AS1 是受 6-TG 影响的主要 lncRNA，PAX8-AS1 通过与 miR-16-5p 和 miR-335-5p 竞争结合来调节肿瘤途径中的枢纽基因。
