Hypoxia-induced feedback of HIF-1α and lncRNA-CF129 contributes to pancreatic cancer progression through stabilization of p53 protein
Hypoxia-induced feedback of HIF-1α and lncRNA-CF129 contributes to pancreatic cancer progression through stabilization of p53 protein
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缺氧诱导的 HIF-1 α 和 lncRNA-CF129 反馈通过稳定 p53 蛋白促进胰腺癌进展
DOI：
10.7150/thno.30988
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Zhao, Gang
中科院分区：
文献类型：
--
作者：
Liu, Mingliang;Zhong, Jianxin;Zhao, Gang
基本原理：新出现的证据强调了lncRNA在人类癌症发展中的关键作用。本研究旨在探讨lncRNA-CF 129（CF 129）在胰腺癌（PC）中的生物学作用及其可能的机制。评估了CF 129在体外和体内的作用，进行RNA下拉和免疫沉淀测定以检测CF 129与p53和E3连接酶MKRN 1之间的相互作用。采用免疫沉淀法和荧光素酶法分别检测p53与FOXC 2启动子、HIF-1 α/HDAC 1复合物与CF 129启动子、FOXC 2与HIF-1 α启动子之间的相互作用。低CF 129表达预测PC患者的总生存期短。CF 129以FOXC 2依赖的方式抑制PC细胞的侵袭和转移。此外，CF 129通过与突变型p53结合来调节FOXC 2转录。CF 129直接与p53和E3连接酶MKRN 1结合，这种相互作用导致p53蛋白泛素化和降解。此外，CF 129是一种缺氧响应性lncRNA，其通过HIF-1 α/HDAC 1复合物与CF 129启动子之间的结合而转录下调。最后，研究表明HIF-1 α在转录水平上受FOXC 2的调控。结论：CF 129通过抑制FOXC 2的转录抑制胰腺细胞的增殖和侵袭，而FOXC 2的转录抑制依赖于MKRN 1介导的泛素依赖性p53降解。HIF-1 α/CF 129/p53/FOXC 2轴可能作为潜在的生物标志物和治疗靶点。
Rationale: Emerging evidences have highlighted the critical roles of lncRNAs in human cancer development. The work sought to assess the biological role and potential underlying mechanisms of lncRNA-CF129 (CF129) which is significantly reduced in pancreatic cancer (PC).Methods: CF129 expression and its association with multiple clinicopathologic characteristics in PC specimens were analyzed. The role of CF129 both in vitro and in vivo was assessed, with RNA pull-down and immunoprecipitation assays being performed to detect the interaction between CF129 and p53 and E3 ligase MKRN1. Chromatin immunoprecipitation and luciferase assays were utilized to identify the interaction between p53 and FOXC2 promoter, HIF-1 alpha/HDAC1 complex and CF129 promoter, FOXC2 and HIF-1 alpha promoter, respectively.Results: CF129 levels were markedly lower in PC compared with paired non-tumor adjacent tissues. Low CF129 expression predicted short overall survival in PC patients. CF129 inhibited invasion and metastasis of PC cells in a FOXC2-dependent manner. In addition, CF129 regulates FOXC2 transcription through association with mutant p53. CF129 directly binds to p53 and E3 ligase MKRN1, and such an interaction leading to p53 protein ubiquitination and degradation. Furthermore, CF129 is a hypoxia-responsive lncRNA, which is transcriptionally downregulated by binding between HIF-1 alpha/HDAC1 complex and CF129 promoter. Finally, it is revealed that HIF-1 alpha is reciprocally regulated by FOXC2 in transcriptional level. Clinically, CF129 downregulation coordinates overexpression of FOXC2.Conclusions: Our study suggests that CF129 inhibits pancreatic cell proliferation and invasion by suppression of FOXC2 transcription, which depends on MKRN1-mediated ubiquitin-dependent p53 degradation. The HIF-1 alpha/CF129/p53/FOXC2 axis may function as a potential biomarker and therapeutic target.