期刊
CLINICAL CANCER RESEARCH
卷 24, 期 19, 页码 4808-4819出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-17-2967
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资金
- National Natural Science Foundation of China [81672328, 81272299, 81772636, 81572468]
- Natural Science Foundation of Jiangsu Province [BK20150004, BK20151108]
- Fundamental Research Funds for the Central Universities [NOJUSRP51619B, JUSRP51710A]
- Medical Key Professionals Program of Jiangsu Province [AF052141]
- Wuxi Medical Innovation Team [CXTP003]
- Key Medical Talents [ZDRC001]
- Hospital Management Centre of Wuxi [YGZXZ1401]
- National First-class Discipline Program of Food Science and Technology [JUFSTR20180101]
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.
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