LncRNA-FEZFl-AS1 Promotes Tumor Proliferation and Metastasis in Colorectal Cancer by Regulating PKM2 Signaling
LncRNA-FEZFl-AS1 Promotes Tumor Proliferation and Metastasis in Colorectal Cancer by Regulating PKM2 Signaling
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LncRNA-FEZF1-AS1 通过调节 PKM2 信号传导促进结直肠癌肿瘤增殖和转移。
DOI：
10.1158/1078-0432.ccr-17-2967
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发表时间：
2018-10-01
影响因子：
11.5
通讯作者：
Huang, Zhaohui
中科院分区：
文献类型：
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作者：
Bian, Zehua;Zhang, Jiwei;Huang, Zhaohui
目的：长链非编码RNA（lncRNA）在人类肿瘤中起着重要作用。在这里，FEZFl-AS 1，一种在结直肠癌中高度过表达的lncRNA，通过lncRNA微阵列鉴定。本研究旨在探讨FEZF 1-AS 1在结直肠癌中的作用及其可能的分子机制。实验设计：采用lncRNA芯片和qRT-PCR技术检测结直肠癌组织中LncRNA的表达。FEZFl-AS 1在结直肠癌中的功能作用通过一系列体外和体内实验来证明。通过RNA pull-down、RNA免疫沉淀和荧光素酶分析，探讨FEZF 1-AS 1的作用机制。结果：通过lncRNA微阵列分析，我们发现了一系列在结直肠癌组织中差异表达的lncRNA，其中FEZF 1-AS 1的表达最高。在两个扩大的结直肠癌队列中的进一步验证证实了结直肠癌中FEZF 1-AS 1的上调，并揭示了FEZF 1-AS 1表达增加与生存率低相关。功能分析显示FEZF 1-AS 1促进结直肠癌细胞的增殖和转移。在机制上，FEZF 1-AS 1可以结合并增加丙酮酸激酶2（PKM 2）蛋白的稳定性，从而导致细胞质和细胞核PKM 2水平增加。增加的细胞质PKM 2促进丙酮酸激酶活性和乳酸产生（有氧糖酵解），而FEZF 1-AS 1诱导的核PKM 2上调进一步激活STAT 3信号。此外，PKM 2在结直肠癌组织中上调，并与FEZF 1-AS 1表达和患者survival.Conclusions：总之，这些数据提供了机制的见解FEZF 1-AS 1对STAT 3信号转导和糖酵解的调节结合PKM 2和增加其稳定性。（C）2018年AACR。
Purpose: Long non-coding RNAs (lncRNAs) play key roles in human cancers. Here, FEZFl-AS1, a highly overexpressed lncRNA in colorectal cancer, was identified by lncRNA microarrays. We aimed to explore the roles and possible molecular mechanisms of FEZF 1-AS1 in colorectal cancer.Experimental Design: LncRNA expression in colorectal cancer tissues was measured by lncRNA microarray and qRT-PCR. The functional roles of FEZFl-AS1 in colorectal cancer were demonstrated by a series of in vitro and in vivo experiments. RNA pull-down, RNA immunoprecipitation and luciferase analyses were used to demonstrate the potential mechanisms of FEZF1-AS1.Results: We identified a series of differentially expressed lncRNAs in colorectal cancer using lncRNA microarrays, and revealed that FEZF1 -AS1 is one of the most overexpressed. Further validation in two expanded colorectal cancer cohorts confirmed the upregulation of FEZF1-AS1 in colorectal cancer, and revealed that increased FEZF1 -AS1 expression is associated with poor survival. Functional assays revealed that FEZF1-AS1 promotes colorectal cancer cell proliferation and metastasis, Mechanistically, FEZF1-AS1 could bind and increase the stability of the pyruvate kinase 2 (PKM2) protein, resulting in increased cytoplasmic and nuclear PKM2 levels. Increased cytoplasmic PKM2 promoted pyruvate kinase activity and lactate production (aerobic glycolysis), whereas FEZF1-AS1-induced nuclear PKM2 upregulation further activated STAT3 signaling. In addition, PKM2 was upregulated in colorectal cancer tissues and correlated with FEZF1-AS1 expression and patient survival.Conclusions: Together, these data provide mechanistic insights into the regulation of FEZF1 -AS1 on both STAT3 signaling and glycolysis by binding PKM2 and increasing its stability. (C)2018 AACR.