p53 靶向 lincRNA-p21 通过抑制头颈部鳞状细胞癌中的 JAK2/STAT3 信号通路发挥肿瘤抑制作用。

p53-targeted lincRNA-p21 acts as a tumor suppressor by inhibiting JAK2/STAT3 signaling pathways in head and neck squamous cell carcinoma.

机构信息

Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No 639, Zhizaoju Rd, Shanghai, 200011, China.

National Clinical Research Center for Oral Diseases, Shanghai, 200011, China.

出版信息

Mol Cancer. 2019 Mar 11;18(1):38. doi: 10.1186/s12943-019-0993-3.

DOI:10.1186/s12943-019-0993-3

PMID:30857539

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6410525/

Abstract

BACKGROUND

Long 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).

METHODS

RNAscope 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.

RESULTS

Lower 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.

CONCLUSIONS

Our 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.

摘要

背景

长链非编码 RNA p21（lncRNA-p21）被认为是野生型 p53 的靶标，但关于其突变型 p53 的调控及其在头颈部鳞状细胞癌（HNSCC）进展过程中的功能知之甚少。

方法

使用 RNAscope 检测 lincRNA-p21 的表达和分布。进行染色质免疫沉淀和电泳迁移率变动分析，以分析 HNSCC 细胞中 lincRNA-p21 的转录调控。在体外和体内研究 lincRNA-p21 的生物学功能。使用 RNA 免疫沉淀和下拉测定来检测 lincRNA-p21 的直接结合。

结果

在 HNSCC 组织中观察到较低的 lincRNA-p21 表达，预示着预后较差。野生型和突变型 p53 均转录调控 lincRNA-p21，但核转录因子 Y 亚基α（NF-YA）对于突变型 p53 调控 lincRNA-p21 是必需的。异位表达 lincRNA-p21 显著抑制体外和体内的细胞增殖能力，反之亦然。此外，lincRNA-p21 的过表达诱导 G1 期阻滞和细胞凋亡。敲低 NF-YA 表达可逆转突变型 p53 细胞而非野生型 p53 细胞中 lincRNA-p21 的肿瘤抑制激活。在 HNSCC 组织中观察到 lincRNA-p21 与信号转导和转录激活因子 3（p-STAT3）的磷酸化之间呈负相关。高 lincRNA-p21 表达抑制了 Janus 激酶 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 与 STAT3 的直接结合，从而抑制了 STAT3 诱导的致癌潜能。