LncRNA TROJAN promotes proliferation and resistance to CDK4/6 inhibitor via CDK2 transcriptional activation in ER plus breast cancer
LncRNA TROJAN promotes proliferation and resistance to CDK4/6 inhibitor via CDK2 transcriptional activation in ER plus breast cancer
复制标题
LncRNA TROJAN 通过 CDK2 转录激活促进 ER 乳腺癌的增殖和对 CDK4/6 抑制剂的耐药性
DOI：
10.1186/s12943-020-01210-9
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发表时间：
2020-05-11
期刊：
影响因子：
37.3
通讯作者：
Jiang, Yizhou
中科院分区：
文献类型：
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作者：
Jin, Xi;Ge, Li-Ping;Jiang, Yizhou
雌激素受体阳性(ER+)乳腺癌约占所有乳腺癌的三分之二，且有持续的晚期复发风险。细胞周期蛋白依赖性激酶4和6(CDK4/6)抑制剂在ER阳性乳腺癌中显示出显著的疗效。然而，它们的效果仍然受到耐药性的限制。本研究旨在探讨长非编码RNA特洛伊木马在ER+乳腺癌中的作用。方法采用实时定量聚合酶链式反应技术检测特洛伊木马在乳腺癌组织和细胞系中的表达水平。体外和体内检测以及患者来源的有机物被用来探索ER+乳腺癌中特洛伊木马的表型。通过RNA下拉、质谱仪、RNA免疫共沉淀、基因芯片、双荧光素酶报告基因和染色质免疫共沉淀等方法对特洛伊-NKRF-CDK2轴进行筛选和验证。特洛伊可促进细胞增殖和对CDK4/6抑制剂的耐药性，并与ER+乳腺癌的低生存率有关。特洛伊木马可以与NKRF结合并抑制其与RelA的相互作用，上调CDK2的表达。特洛伊木马的抑制取消了CDK2的活性，逆转了对CDK4/6抑制剂的抗性。特洛伊木马反义寡核苷酸在体内外对CDK4/6抑制剂Palbociclib增敏乳腺癌细胞和类有机物。结论TROJAN促进ER+乳腺癌增殖，是逆转CDK4/6抑制剂耐药性的潜在靶点。
BackgroundEstrogen receptor-positive (ER+) breast cancers represent approximately two-thirds of all breast cancers and have a sustained risk of late disease recurrence. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown significant efficacy in ER+ breast cancer. However, their effects are still limited by drug resistance. In this study, we aim to explore the role of long noncoding RNA TROJAN in ER+ breast cancer.MethodsThe expression level of TROJAN in breast cancer tissue and cell lines was determined by quantitative real-time PCR. In vitro and in vivo assays as well as patient derived organoid were preformed to explore the phenotype of TROJAN in ER+ breast cancer. The TROJAN-NKRF-CDK2 axis were screened and validated by RNA pull-down, mass spectrometry, RNA immunoprecipitation, microarray, dual-luciferase reporter and chromatin immunoprecipitation assays.ResultsHerein, we showed that TROJAN was highly expressed in ER+ breast cancer. TROJAN promoted cell proliferation and resistance to a CDK4/6 inhibitor and was associated with poor survival in ER+ breast cancer. TROJAN can bind to NKRF and inhibit its interaction with RELA, upregulating the expression of CDK2. The inhibition of TROJAN abolished the activity of CDK2, reversing the resistance to CDK4/6 inhibitor. A TROJAN antisense oligonucleotide sensitized breast cancer cells and organoid to the CDK4/6 inhibitor palbociclib both in vitro and in vivo.ConclusionsTROJAN promotes ER+ breast cancer proliferation and is a potential target for reversing CDK4/6 inhibitor resistance.