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长链非编码 RNA FOXD2-AS1 通过与 Akt 和 E2F1 的正反馈环路促进膀胱癌的进展和复发。

The long non-coding RNA FOXD2-AS1 promotes bladder cancer progression and recurrence through a positive feedback loop with Akt and E2F1.

机构信息

Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510120, China.

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510120, China.

出版信息

Cell Death Dis. 2018 Feb 14;9(2):233. doi: 10.1038/s41419-018-0275-9.

DOI:10.1038/s41419-018-0275-9
PMID:29445134
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5833400/
Abstract

Long non-coding RNAs (lncRNAs) have been identified as significant regulators in cancer progression. Positive feedback loops between lncRNAs and transcription factors have attracted increasing attention. Akt pathway plays a crucial role in bladder cancer growth and recurrence. In the present study, we demonstrate a novel regulatory pattern involving FOXD2-AS1, Akt, and E2F1. FOXD2-AS1 is highly expressed in bladder cancer and is associated with tumor stage, recurrence, and poor prognosis. Further experiments showed that FOXD2-AS1 promotes bladder cancer cell proliferation, migration, and invasion in vitro and in vivo. Microarray analysis demonstrated that FOXD2-AS1 negatively regulates the expression of Tribbles pseudokinase 3 (TRIB3), a negative regulator of Akt. Mechanistically, FOXD2-AS1 forms an RNA-DNA complex with the promoter of TRIB3, the transcriptional activity of which is subsequently repressed, and leads to the activation of Akt, which further increases the expression of E2F1, a vital transcription factor involved in the G/S transition. Interestingly, E2F1 could bind to the FOXD2-AS1 promoter region and subsequently enhance its transcriptional activity, indicating that FOXD2-AS1/Akt/E2F1 forms a feedback loop. In summary, this regulatory pattern of positive feedback may be a novel target for the treatment of bladder cancer and FOXD2-AS1 has the potential to be a new recurrence predictor.

摘要

长链非编码 RNA（lncRNA）已被确定为癌症进展中的重要调节因子。lncRNA 和转录因子之间的正反馈回路引起了越来越多的关注。Akt 通路在膀胱癌的生长和复发中起着至关重要的作用。在本研究中，我们证明了一种涉及 FOXD2-AS1、Akt 和 E2F1 的新型调节模式。FOXD2-AS1 在膀胱癌中高表达，与肿瘤分期、复发和预后不良有关。进一步的实验表明，FOXD2-AS1 促进膀胱癌细胞在体外和体内的增殖、迁移和侵袭。微阵列分析表明，FOXD2-AS1 负调控 Akt 的负调节因子 Tribbles 假激酶 3（TRIB3）的表达。在机制上，FOXD2-AS1 与 TRIB3 启动子形成 RNA-DNA 复合物，其转录活性随后受到抑制，导致 Akt 激活，进而增加参与 G/S 转换的重要转录因子 E2F1 的表达。有趣的是，E2F1 可以结合到 FOXD2-AS1 启动子区域，随后增强其转录活性，表明 FOXD2-AS1/Akt/E2F1 形成正反馈回路。综上所述，这种正反馈的调节模式可能是治疗膀胱癌的新靶点，FOXD2-AS1 有可能成为新的复发预测因子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37b1/5833400/36e58ba35263/41419_2018_275_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37b1/5833400/4aa712d2ab4f/41419_2018_275_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37b1/5833400/c048ca48d2fd/41419_2018_275_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37b1/5833400/1eee0874813f/41419_2018_275_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37b1/5833400/c18d016154ae/41419_2018_275_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37b1/5833400/7e8d5dc7b452/41419_2018_275_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37b1/5833400/d6b93a1209ab/41419_2018_275_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37b1/5833400/36e58ba35263/41419_2018_275_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37b1/5833400/4aa712d2ab4f/41419_2018_275_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37b1/5833400/c048ca48d2fd/41419_2018_275_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37b1/5833400/1eee0874813f/41419_2018_275_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37b1/5833400/c18d016154ae/41419_2018_275_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37b1/5833400/7e8d5dc7b452/41419_2018_275_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37b1/5833400/d6b93a1209ab/41419_2018_275_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37b1/5833400/36e58ba35263/41419_2018_275_Fig7_HTML.jpg

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