NNT-induced tumor cell "slimming" reverses the pro-carcinogenesis effect of HIF2a in tumors.
NNT-induced tumor cell "slimming" reverses the pro-carcinogenesis effect of HIF2a in tumors.
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NNT诱导的肿瘤细胞“瘦身”逆转了肿瘤中HIF2a的促癌作用
DOI：
10.1002/ctm2.264
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发表时间：
2021-01
影响因子：
10.6
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Xiong Z;Xiong W;Xiao W;Yuan C;Shi J;Huang Y;Wang C;Meng X;Chen Z;Yang H;Chen K;Zhang X
HIF 2a和脂质积聚在肾透明细胞癌（ccRCC）的进展中起关键作用。肿瘤细胞“瘦身”是一个新概念，即脂质异常的肿瘤细胞高效消耗脂质以抑制肿瘤进展，而不产生额外的ATP。但各自的监管机制仍不清楚。本研究的目的是揭示ccRCC的这三个关键要素之间的联系，以阐明ccRCC代谢异常的新机制，并为ccRCC的新药开发提供基础。根据TCGA-KIRC数据库在ccRCC中进行生物信息学筛选和分析。使用qRT-PCR、荧光素酶报告基因测定、蛋白质印迹、染色质免疫沉淀（ChIP）测定和其他生物学方法探索和验证相关途径。采用多种细胞系模型和动物模型进行相关功能实验。基于HIF 2a敲低后的测序数据和三个独立的线粒体代谢相关基因集的筛选显示，烟酰胺核苷酸转氢酶（NNT）是HIF 2a与肿瘤细胞“瘦身”之间的介导者。进一步的研究表明，NNT具有显著的预后预测价值，并且在ccRCC中下调。受HIF 2a调控，可显著激活脂质布朗宁介导的肿瘤细胞“瘦身”。机制研究表明，HIF 2a通过与miR-455 - 5 p启动子中HIF 2a相关的反应元件结合来增强miR-455 - 5 p的表达，该元件通过与其3′非翻译区结合来抑制NNT表达。我们的研究揭示了一种新的机制，HIF 2a通过抑制肿瘤细胞“瘦身”的microRNA降低NNT水平，导致ccRCC的进展。这种机制为ccRCC中的脂质积累提供了一个新的视角，并可能有助于治疗脂质代谢异常的肿瘤的新策略。可以提出一种模型，其中HIF 2a通过与miR-455 - 5 p启动子中的HIF 2a反应元件结合来增加miR-455 - 5 p表达，该启动子通过与其3 'UTR结合来抑制NNT表达。同时，NNT促进脂质布朗宁以消耗脂质，导致ccRCC进展的抑制。
HIF2a and lipid accumulation play key roles in the progression of clear cell renal cell carcinoma (ccRCC). Tumor cell “slimming” is a new concept in which tumor cells with abnormal lipids efficiently consume lipids to inhibit tumor progression without producing additional ATP. However, their respective regulatory mechanisms are still unclear. The purpose of this study is uncovering the links between these three key elements of ccRCC to elucidate new mechanisms of ccRCC metabolic abnormalities and providing a basis for new drug development for ccRCC. Bioinformatics screening and analyses were performed in ccRCC according to TCGA‐KIRC database. qRT‐PCR, luciferase reporter assay, western blot, chromatin immunoprecipitation (ChIP) assays, and other biological methods were used to explore and verify related pathways. Various cell line models and animal models were used to perform related functional experiments. Screening based on sequencing data after HIF2a knockdown and three independent mitochondrial metabolism‐related gene sets showed that nicotinamide nucleotide transhydrogenase (NNT) was a mediator between HIF2a and tumor cells “slimming.” Further research showed that NNT had significant prognostic predictive value and was downregulated in ccRCC. It is regulated by HIF2a and can significantly activate lipid browning‐mediated tumor cell “slimming.” Mechanistic investigations indicated that HIF2a enhanced the expression of miR‐455‐5p via binding to HIF2a‐related response elements in the miR‐455‐5p promoter, which suppresses NNT expression by binding to its 3′ untranslated region. Our study revealed a novel mechanism by which HIF2a decreased NNT level through a microRNA that suppressed tumor cell “slimming,” resulting in the progression of ccRCC. This mechanism provides a fresh perspective of lipid accumulation in ccRCC and may help target novel strategies for the treatment of tumors with abnormal lipid metabolism. A model could be suggested in which HIF2a increases miR‐455‐5p expression by binding to HIF2a response elements in the miR‐455‐5p promoter, which suppresses NNT expression by binding to its 3'UTR. Meanwhile, NNT promotes lipid browning to consume lipids, resulting in the suppression of ccRCC progression.
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影响因子：
4.8
作者：
Gameiro, Paulo A.;Laviolette, Laura A.;Stephanopoulos, Gregory
通讯作者：
Stephanopoulos, Gregory
DOI：
10.1038/nrc2442
发表时间：
2008-08
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.9
作者：
Nicholson, Anthony;Reifsnyder, Peter C.;Malcolm, Rachel D.;Lucas, Charlotte A.;MacGregor, Grant R.;Zhang, Weidong;Leiter, Edward H.
通讯作者：
Leiter, Edward H.
影响因子：
64.5
作者：
Dodd GT;Decherf S;Loh K;Simonds SE;Wiede F;Balland E;Merry TL;Münzberg H;Zhang ZY;Kahn BB;Neel BG;Bence KK;Andrews ZB;Cowley MA;Tiganis T
通讯作者：
Tiganis T
密集的脂肪内交感神经树枝化对于寒冷诱导的小鼠白色脂肪组织米色化至关重要
影响因子：
29
作者：
Jiang, Haochen;Ding, Xiaofan;Zeng, Wenwen
通讯作者：
Zeng, Wenwen