PM2.5 promotes NSCLC carcinogenesis through translationally and transcriptionally activating DLAT-mediated glycolysis reprograming.
PM2.5 promotes NSCLC carcinogenesis through translationally and transcriptionally activating DLAT-mediated glycolysis reprograming.
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PM2.5通过翻译和转录激活DLAT介导的糖酵解重编程促进NSCLC癌变
DOI：
10.1186/s13046-022-02437-8
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发表时间：
2022-07-22
期刊：
影响因子：
--
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中科院分区：
文献类型：
--
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空气中的细颗粒物（PM2.5）与从不吸烟者的肺癌发展和进展有关。然而，PM2.5诱导肺癌的分子机制在很大程度上仍然未知。本研究旨在探讨PM2.5在非小细胞肺癌（NSCLC）发生发展中的作用机制。利用核糖体测序（Ribo-seq）和RNA测序（RNA-seq）技术对PM2.5相关基因进行鉴定。采用定量真实的时间-PCR（qRT-PCR）、蛋白质印迹和免疫组织化学（IHC）测定组织和细胞中的mRNA和蛋白质表达水平。通过功能获得和丧失实验、生化分析和海马XF糖酵解应激试验，评估了PM2.5和PM2.5失调基因的生物学作用。采用人体组织芯片分析和NSCLC患者的18F-FDG PET/CT扫描来验证实验结果。多核糖体分离实验，染色质免疫沉淀（ChIP），和双荧光素酶报告分析，以探讨分子机制。我们发现，PM2.5诱导翻译转向糖酵解途径基因和增加糖酵解代谢，证明了增加L-乳酸和丙酮酸浓度或更高的细胞外酸化率（ECAR）在体外和体内。特别是PM2.5增强了糖酵解基因DLAT的表达，这促进了糖酵解，但抑制了乙酰辅酶A的产生，并增强了NSCLC细胞的恶性度。临床上，DLAT的高表达与NSCLC患者的肿瘤大小、较差的预后和18F-FDG-PET/CT扫描的SUVmax值呈正相关。机制上，PM2.5激活eIF 4 E，从而上调多聚核糖体中DLAT的表达水平。PM2.5还能刺激转录因子Sp1的表达，进一步增强DLAT启动子的转录活性。本研究表明，PM2.5激活的DLAT过表达和糖酵解代谢增强有助于NSCLC的发生，提示DLAT相关通路可能是NSCLC的治疗靶点。在线版本包含补充材料，可通过10.1186/s13046-022-02437-8获得。
Airborne fine particulate matter (PM2.5) has been associated with lung cancer development and progression in never smokers. However, the molecular mechanisms underlying PM2.5-induced lung cancer remain largely unknown. The aim of this study was to explore the mechanisms by which PM2.5 regulated the carcinogenesis of non-small cell lung cancer (NSCLC). Paralleled ribosome sequencing (Ribo-seq) and RNA sequencing (RNA-seq) were performed to identify PM2.5-associated genes for further study. Quantitative real time-PCR (qRT-PCR), Western blot, and immunohistochemistry (IHC) were used to determine mRNA and protein expression levels in tissues and cells. The biological roles of PM2.5 and PM2.5-dysregulated gene were assessed by gain- and loss-of-function experiments, biochemical analyses, and Seahorse XF glycolysis stress assays. Human tissue microarray analysis and 18F-FDG PET/CT scans in patients with NSCLC were used to verify the experimental findings. Polysome fractionation experiments, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assay were implemented to explore the molecular mechanisms. We found that PM2.5 induced a translation shift towards glycolysis pathway genes and increased glycolysis metabolism, as evidenced by increased L-lactate and pyruvate concentrations or higher extracellular acidification rate (ECAR) in vitro and in vivo. Particularly, PM2.5 enhanced the expression of glycolytic gene DLAT, which promoted glycolysis but suppressed acetyl-CoA production and enhanced the malignancy of NSCLC cells. Clinically, high expression of DLAT was positively associated with tumor size, poorer prognosis, and SUVmax values of 18F-FDG-PET/CT scans in patients with NSCLC. Mechanistically, PM2.5 activated eIF4E, consequently up-regulating the expression level of DLAT in polysomes. PM2.5 also stimulated transcription factor Sp1, which further augmented transcription activity of DLAT promoter. This study demonstrated that PM2.5-activated overexpression of DLAT and enhancement in glycolysis metabolism contributed to the tumorigenesis of NSCLC, suggesting that DLAT-associated pathway may be a therapeutic target for NSCLC. The online version contains supplementary material available at 10.1186/s13046-022-02437-8.
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影响因子：
8.8
作者：
Das, Ananya;Habib, Gazala;Kumar, Arun
通讯作者：
Kumar, Arun
DOI：
10.1038/nrm4069
发表时间：
2015-11
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Brar GA;Weissman JS
通讯作者：
Weissman JS
影响因子：
20.1
作者：
Doroudgar, Shirin;Hofmann, Christoph;Voelkers, Mirko
通讯作者：
Voelkers, Mirko
影响因子：
64.8
作者：
Hsieh, Andrew C.;Liu, Yi;Edlind, Merritt P.;Ingolia, Nicholas T.;Janes, Matthew R.;Sher, Annie;Shi, Evan Y.;Stumpf, Craig R.;Christensen, Carly;Bonham, Michael J.;Wang, Shunyou;Ren, Pingda;Martin, Michael;Jessen, Katti;Feldman, Morris E.;Weissman, Jonathan S.;Shokat, Kevan M.;Rommel, Christian;Ruggero, Davide
通讯作者：
Ruggero, Davide
影响因子：
10.4
作者：
Coleman, Nathan C.;Burnett, Richard T.;Pope, C. Arden, III
通讯作者：
Pope, C. Arden, III