LncRNA CBR3-AS1 regulates of breast cancer drug sensitivity as a competing endogenous RNA through the JNK1/MEK4-mediated MAPK signal pathway.
LncRNA CBR3-AS1 regulates of breast cancer drug sensitivity as a competing endogenous RNA through the JNK1/MEK4-mediated MAPK signal pathway.
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LncRNA CBR3-AS1作为竞争性内源RNA通过JNK1/MEK4介导的MAPK信号通路调节乳腺癌药物敏感性
DOI：
10.1186/s13046-021-01844-7
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发表时间：
2021-01-25
期刊：
影响因子：
--
通讯作者：
Zhao L
中科院分区：
文献类型：
--
作者：
Zhang M;Wang Y;Jiang L;Song X;Zheng A;Gao H;Wei M;Zhao L
阿霉素（ADR）耐药是改善乳腺癌患者临床预后的主要障碍之一。长链非编码RNA（lncRNAs）能够调节细胞行为，但这些RNA在乳腺癌抗ADR活性中的作用仍不明确。在此，我们旨在研究一种特定的长链非编码RNA——lncRNA CBR3反义RNA 1（CBR3 - AS1）的失衡情况及其在ADR耐药中的作用。
对耐ADR的乳腺癌细胞进行微阵列分析以鉴定CBR3 - AS1。采用CCK - 8和集落形成实验检测乳腺癌细胞对ADR的敏感性。利用双荧光素酶报告基因、RNA下拉、免疫组化和蛋白质印迹分析来验证CBR3 - AS1、微小RNA（miRNA）和靶基因表达之间的关系。在体内实验中，在异种移植肿瘤模型中观察CBR3 - AS1对乳腺癌耐药性的影响。通过来自癌症基因组图谱（TCGA）、癌细胞系百科全书（CCLE）和癌症药物敏感性基因组学数据库（GDSC）的临床乳腺癌标本验证了CBR3 - AS1在影响ADR敏感性方面的作用。
我们发现CBR3 - AS1在乳腺癌组织中的表达显著增加，且与不良预后密切相关。CBR3 - AS1过表达在体外和体内促进乳腺癌细胞的ADR耐药。从机制上讲，我们确定CBR3 - AS1通过吸附miR - 25 - 3p而作为一种竞争性内源性RNA发挥作用。确定丝裂原活化蛋白激酶（MAPK）通路中的MEK4和JNK1是乳腺癌细胞中CBR3 - AS1/miR - 25 - 3p轴的直接下游蛋白。
总之，我们的研究结果表明，CBR3 - AS1通过介导miR - 25 - 3p和MEK4/JNK1调控轴在乳腺癌的化疗耐药中起关键作用。确定了CBR3 - AS1作为乳腺癌可靶向的癌基因和治疗性生物标志物的潜力。
网络版包含补充材料，可在10.1186/s13046 - 2021 - 01844 - 7获取。
BackgroundAdriamycin (ADR) resistance is one of the main obstacles to improving the clinical prognosis of breast cancer patients. Long noncoding RNAs (lncRNAs) can regulate cell behavior, but the role of these RNAs in the anti-ADR activity of breast cancer remains unclear. Here, we aim to investigate the imbalance of a particular long noncoding RNA, lncRNA CBR3 antisense RNA 1 (CBR3-AS1), and its role in ADR resistance.MethodsMicroarray analysis of ADR-resistant breast cancer cells was performed to identify CBR3-AS1. CCK-8 and colony formation assays were used to detect the sensitivity of breast cancer cells to ADR. Dual-luciferase reporter, RNA pulldown, IHC and western blot analyses were used to verify the relationship between the expression of CBR3-AS1, miRNA and target genes. For in vivo experiments, the effect of CBR3-AS1 on breast cancer resistance was observed in a xenograft tumor model. The role of CBR3-AS1 in influencing ADR sensitivity was verified by clinical breast cancer specimens from the TCGA, CCLE, and GDSC databases.ResultsWe found that CBR3-AS1 expression was significantly increased in breast cancer tissues and was closely correlated with poor prognosis. CBR3-AS1 overexpression promoted ADR resistance in breast cancer cells in vitro and in vivo. Mechanistically, we identified that CBR3-AS1 functioned as a competitive endogenous RNA by sponging miR-25-3p. MEK4 and JNK1 of the MAPK pathway were determined to be direct downstream proteins of the CBR3-AS1/miR-25-3p axis in breast cancer cells.ConclusionsIn summary, our findings demonstrate that CBR3-AS1 plays a critical role in the chemotherapy resistance of breast cancer by mediating the miR-25-3p and MEK4/JNK1 regulatory axes. The potential of CBR3-AS1 as a targetable oncogene and therapeutic biomarker of breast cancer was identified.
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