p53-targeted lincRNA-p21 acts as a tumor suppressor by inhibiting JAK2/STAT3 signaling pathways in head and neck squamous cell carcinoma
p53-targeted lincRNA-p21 acts as a tumor suppressor by inhibiting JAK2/STAT3 signaling pathways in head and neck squamous cell carcinoma
复制标题
p53 靶向 lincRNA-p21 通过抑制头颈鳞状细胞癌中的 JAK2/STAT3 信号通路发挥肿瘤抑制因子的作用
DOI：
10.1186/s12943-019-0993-3
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发表时间：
2019-03-11
期刊：
影响因子：
37.3
通讯作者：
Zhang, Zhiyuan
中科院分区：
文献类型：
--
作者：
Jin, Shufang;Yang, Xi;Zhang, Zhiyuan
长基因间非编码RNA p21 （lincRNA-p21）被认为是野生型p53的靶点，但关于突变型p53对其的调控及其在头颈部鳞状细胞癌（HNSCC）进展中的功能知之甚少。方法采用srnascope检测lincRNA-p21的表达及分布。采用染色质免疫沉淀法和电泳迁移位移法分析lincRNA-p21在HNSCC细胞中的转录调控作用。在体外和体内研究了lincRNA-p21的生物学功能。采用RNA免疫沉淀法和拉下法检测lincRNA-p21的直接结合。结果HNSCC组织中lincRNA-p21表达较低，预后较差。野生型和突变型p53均可转录调控lincRNA-p21，但核转录因子Y亚单位α (NF-YA)是突变型p53调控lincRNA-p21所必需的。异位表达lincRNA-p21显著抑制体外和体内细胞增殖能力，反之亦然。此外，lincRNA-p21过表达可诱导G1阻滞和细胞凋亡。在突变型p53细胞中，NF-YA表达下调可逆转肿瘤抑制因子lincRNA-p21的激活，而非野生型p53细胞。在HNSCC组织中，lincRNA-p21与转录激活因子3 （p-STAT3）的磷酸化呈负相关。lincRNA-p21高表达抑制Janus kinase 2 (JAK2)/STAT3信号激活，反之亦然。此外，我们在HNSCC细胞中观察到lincRNA-p21直接与STAT3结合，从而抑制STAT3诱导的致癌潜能。结论突变体p53/NF-YA复合物对HNSCC中lincRNA-p21的转录调控作用。LincRNA-p21在HNSCC进展中发挥肿瘤抑制作用，这归因于直接结合STAT3并阻断JAK2/STAT3信号传导。
BackgroundLong intergenic noncoding RNA p21 (lincRNA-p21) is considered a target of wild-type p53, but little is known about its regulation by mutant p53 and its functions during the progression of head and neck squamous cell carcinoma (HNSCC).MethodsRNAscope was used to detect the expression and distribution of lincRNA-p21. Chromatin immunoprecipitation and electrophoretic mobility shift assays were performed to analyze the transcriptional regulation of lincRNA-p21 in HNSCC cells. The biological functions of lincRNA-p21 were investigated in vitro and in vivo. RNA immunoprecipitation and pull-down assays were used to detect the direct binding of lincRNA-p21.ResultsLower lincRNA-p21 expression was observed in HNSCC tissues and indicated worse prognosis. Both wild and mutant type p53 transcriptionally regulated lincRNA-p21, but nuclear transcription factor Y subunit alpha (NF-YA) was essential for mutant p53 in the regulation of lincRNA-p21. Ectopic expression of lincRNA-p21 significantly inhibited cell proliferation capacity in vitro and in vivo and vice versa. Moreover, the overexpression of lincRNA-p21 induced G1 arrest and apoptosis. Knockdown NF-YA expression reversed tumor suppressor activation of lincRNA-p21 in mutant p53 cells, not wild-type p53 cells. A negative correlation was observed between lincRNA-p21 and the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) in HNSCC tissues. High lincRNA-p21 expression inhibited Janus kinase 2 (JAK2)/STAT3 signal activation and vice versa. Further, we observed direct binding to STAT3 by lincRNA-p21 in HNSCC cells, which suppressed STAT3-induced oncogenic potential.ConclusionsOur results revealed the transcriptional regulation of lincRNA-p21 by the mutant p53/NF-YA complex in HNSCC. LincRNA-p21 acted as a tumor suppressor in HNSCC progression, which was attributed to direct binding to STAT3 and blocking of JAK2/STAT3 signaling.