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FEZF1-AS1/miR-107/ZNF312B 轴促进胰腺导管腺癌的进展和瓦博格效应。

FEZF1-AS1/miR-107/ZNF312B axis facilitates progression and Warburg effect in pancreatic ductal adenocarcinoma.

机构信息

Department of Hepatopancreatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.

出版信息

Cell Death Dis. 2018 Jan 18;9(2):34. doi: 10.1038/s41419-017-0052-1.

DOI:10.1038/s41419-017-0052-1
PMID:29348628
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5833349/
Abstract

Long non-coding RNAs (lncRNAs) play a pivotal role in pathological processes. However, little information has been published regarding the underlying functions and mechanisms of lncRNAs in pancreatic ductal adenocarcinoma (PDAC). A novel lncRNA FEZF1-AS1 and its sense-cognate gene ZNF312B were found to be highly expressed in human PDAC tissues and cell lines, which is associated with disease progression and predicts clinical outcome in PDAC patients. Of note, bioinformatics analysis, luciferase assays and RNA immunoprecipitation assays indicated that FEZF1-AS1 may act as an endogenous sponge by competing for miR-107, thereby modulating the derepression of ZNF312B. Downregulation of FEZF1-AS1 or ZNF312B significantly inhibited proliferation, colony formation, migration, and invasion of PDAC cells in vitro, whereas the miR-107 inhibitor abrogated the effect of dow-regulation of FEZF1-AS1 or ZNF312B in reducing oncogenic capacities of PDAC cells. In addition, FEZF1-AS1/miR-107/ZNF312B axis-induced promotion of PDAC cells proliferation appeared to be mediated by modulation of the apoptosis and the G1-S checkpoint. Furthermore, downregulation of FEZF1-AS1 repressed tumor growth in mouse xenograft models. In particular, our results highlight the contribution of FEZF1-AS1/miR-107/ZNF312B axis to Warburg effect maintenance of PDAC cells. Collectively, our findings demonstrate that the FEZF1-AS1/miR-107/ZNF312B axis regulatory network might provide a potential new therapeutic strategy for PDAC.

摘要

长链非编码 RNA(lncRNA)在病理过程中发挥着关键作用。然而,关于 lncRNA 在胰腺导管腺癌(PDAC)中的潜在功能和机制,目前发表的信息很少。我们发现一种新型 lncRNA FEZF1-AS1 及其有意义的同源基因 ZNF312B 在人 PDAC 组织和细胞系中高度表达,与疾病进展相关,并可预测 PDAC 患者的临床结局。值得注意的是,生物信息学分析、荧光素酶报告基因实验和 RNA 免疫沉淀实验表明,FEZF1-AS1 可能作为内源性海绵通过与 miR-107 竞争,从而调节 ZNF312B 的去抑制。下调 FEZF1-AS1 或 ZNF312B 显著抑制 PDAC 细胞在体外的增殖、集落形成、迁移和侵袭,而 miR-107 抑制剂消除了下调 FEZF1-AS1 或 ZNF312B 降低 PDAC 细胞致癌能力的作用。此外,FEZF1-AS1/miR-107/ZNF312B 轴诱导的 PDAC 细胞增殖促进似乎是通过调节细胞凋亡和 G1-S 检验点来介导的。此外,下调 FEZF1-AS1 抑制了小鼠异种移植模型中的肿瘤生长。特别是,我们的研究结果强调了 FEZF1-AS1/miR-107/ZNF312B 轴对 PDAC 细胞 Warburg 效应维持的贡献。总之,我们的研究结果表明,FEZF1-AS1/miR-107/ZNF312B 轴调控网络可能为 PDAC 提供一种潜在的新治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1c/5833349/093b5c0480a8/41419_2017_52_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1c/5833349/2ab1cd7c8e63/41419_2017_52_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1c/5833349/cb0843e84fa5/41419_2017_52_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1c/5833349/bf288e535fe0/41419_2017_52_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1c/5833349/ff9813be2fe8/41419_2017_52_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1c/5833349/f8757790f5ca/41419_2017_52_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1c/5833349/ad7d3605f4fe/41419_2017_52_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1c/5833349/316fa49a3013/41419_2017_52_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1c/5833349/093b5c0480a8/41419_2017_52_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1c/5833349/2ab1cd7c8e63/41419_2017_52_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1c/5833349/cb0843e84fa5/41419_2017_52_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1c/5833349/bf288e535fe0/41419_2017_52_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1c/5833349/ff9813be2fe8/41419_2017_52_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1c/5833349/f8757790f5ca/41419_2017_52_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1c/5833349/ad7d3605f4fe/41419_2017_52_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1c/5833349/316fa49a3013/41419_2017_52_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1c/5833349/093b5c0480a8/41419_2017_52_Fig8_HTML.jpg

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