lnc-AC004893 是一种在骨髓增殖性肿瘤中过度表达的长非编码 RNA，它调控 STAT5 的磷酸化和与 SHP1 的相互作用。
Regulation of STAT5 phosphorylation and interaction with SHP1 by lnc-AC004893, a long non-coding RNA overexpressed in myeloproliferative neoplasms.
机构信息
Department of Laboratory Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
Department of Hematology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
出版信息
Hematology. 2024 Dec;29(1):2375045. doi: 10.1080/16078454.2024.2375045. Epub 2024 Jul 16.
OBJECTIVES
Constitutive activation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription (STAT) signaling pathway is central to the pathogenesis of myeloproliferative neoplasms (MPNs). Long noncoding RNAs (lncRNAs) regulate diverse biological processes. However, the role of lncRNAs in MPN pathogenesis is not well studied.
METHODS
The expression of lnc-AC004893 in MPN patients was measured by quantitative real-time PCR (qRT-PCR). Gene-specific short hairpin RNAs (shRNAs) were designed to inhibit the expression of lnc-AC004893, and western blot was performed to explore the role of lnc-AC004893 via regulating the JAK2/STAT5 signaling pathway. Furthermore, co-IP was performed to determine the binding ability of lnc-AC004893 and STAT5 protein. Finally, the BaF3-JAK2V617F-transplanted mouse model was used to assess the biological role of lnc-ac004893 .
RESULTS
We report that lnc-AC004893, a poorly conserved pseudogene-209, is substantially upregulated in MPN cells compared with normal controls (NCs). Knockdown of lnc-AC004893 by specific shRNAs suppressed cell proliferation and decreased colony formation. Furthermore, the knockdown of lnc-AC004893 reduced the expression of p-STAT5 but not total STAT5 in HEL and murine IL-3-dependent Ba/F3 cells, which present constitutive and inducible activation of JAK2/STAT5 signaling. In addition, inhibition of murine lnc-ac004893 attenuated BaF3-JAK2V617F-transplanted phenotypes and extended the overall survival. Mechanistically, knockdown of lnc-AC004893 enhanced the binding ability of STAT5 and protein tyrosine phosphatase SHP1. Furthermore, knockdown of lnc-AC004893 decreased STAT5-lnc-AC004893 interaction but not SHP1-lnc-AC004893 interaction.
CONCLUSION
Lnc-AC004893 regulates STAT5 phosphorylation by affecting the interaction of STAT5 and SHP1. Lnc-AC004893 might be a potential therapeutic target for MPN patients.
目的
Janus 激酶 2（JAK2）/信号转导和转录激活因子（STAT）信号通路的组成性激活是骨髓增殖性肿瘤（MPN）发病机制的核心。长链非编码 RNA（lncRNA）调节多种生物学过程。然而，lncRNA 在 MPN 发病机制中的作用尚未得到很好的研究。
方法
通过实时定量 PCR（qRT-PCR）测量 MPN 患者中 lnc-AC004893 的表达。设计基因特异性短发夹 RNA（shRNA）以抑制 lnc-AC004893 的表达，并通过 Western blot 探讨通过调节 JAK2/STAT5 信号通路发挥作用的 lnc-AC004893。此外，进行 co-IP 以确定 lnc-AC004893 和 STAT5 蛋白的结合能力。最后，使用 BaF3-JAK2V617F 移植小鼠模型评估 lnc-ac004893 的生物学作用。
结果
我们报告说，与正常对照（NC）相比，MPN 细胞中大量上调了 poorly conserved pseudogene-209 长链非编码 RNA（lnc-AC004893）。特异性 shRNA 敲低 lnc-AC004893 可抑制细胞增殖并减少集落形成。此外，lnc-AC004893 的敲低降低了 HEL 和小鼠 IL-3 依赖性 Ba/F3 细胞中 p-STAT5 的表达，但不影响总 STAT5，这些细胞表现出 JAK2/STAT5 信号的组成性和诱导性激活。此外，抑制小鼠 lnc-ac004893 减弱了 BaF3-JAK2V617F 移植表型并延长了总生存期。机制上，lnc-AC004893 的敲低增强了 STAT5 和蛋白酪氨酸磷酸酶 SHP1 的结合能力。此外，lnc-AC004893 的敲低降低了 STAT5-lnc-AC004893 相互作用，但不影响 SHP1-lnc-AC004893 相互作用。
结论
lnc-AC004893 通过影响 STAT5 和 SHP1 的相互作用来调节 STAT5 磷酸化。lnc-AC004893 可能是 MPN 患者的潜在治疗靶点。
Zotero 插件