MicroRNA-transcription factor network analysis reveals miRNAs cooperatively suppress RORA in oral squamous cell carcinoma.
MicroRNA-transcription factor network analysis reveals miRNAs cooperatively suppress RORA in oral squamous cell carcinoma.
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MicroRNA转录因子网络分析揭示miRNA在口腔鳞状细胞癌中协同抑制RORA
DOI：
10.1038/s41389-018-0089-8
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发表时间：
2018-10-08
期刊：
影响因子：
6.2
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Zheng X;Wu K;Liao S;Pan Y;Sun Y;Chen X;Zhang Y;Xia S;Hu Y;Zhang J
口腔鳞状细胞癌（OSCC）占口腔癌发病率的90%以上，但其肿瘤发生机制仍不清楚。在这项研究中，我们应用RNA-seq和microRNA-seq方法在四对癌症和邻近的正常组织中，通过构建一个全面的miRNA介导的mRNA调控网络来分析miRNA对肿瘤发生改变的功能通路的贡献。在至少两对癌组织中鉴定出213个差异表达（DE）miRNAs和2172个参与miRNA-mRNA负相互作用的DE mRNAs。GO分析显示，在OSCC中上调的microRNA显著促进了许多转录因子（TF）的整体下调。在所选miRNAs（133）和TF（167）之间的负调控网络中，由多个microRNAs同时调控的昼夜节律基因（RORA、RORB、RORC和CLOCK）特别令人感兴趣。例如，预测RORA转录物被25种共上调的miRNA靶向，其中miR-503- 5 p、miR-450 b-5 p、miR-27 a-3 p、miR-181 a-5 p和miR-183- 5 p被进一步验证为直接靶向RORA，从而一起产生对RORA抑制的更强作用。此外，RORα mRNA和蛋白表达水平在大部分口腔鳞癌中均显著降低，与临床分期和预后不良相关。RORα在体内外均能显著抑制口腔鳞癌细胞的增殖。减弱RORα可降低p53蛋白表达，抑制p53磷酸化活性。总之，我们的研究结果有力地表明了miRNAs在OSCC肿瘤发生过程中调节昼夜节律相关TF网络活性的重要性，并为理解昼夜节律与癌症治疗之间的临床联系提供了进一步的线索。
Oral squamous cell carcinoma (OSCC) represents over 90% of oral cancer incidence, while its mechanisms of tumorigenesis remain poorly characterized. In this study, we applied RNA-seq and microRNA-seq methodologies in four pairs of cancer and adjacent normal tissues to profile the contribution of miRNAs to tumorigenesis-altered functional pathways by constructing a comprehensive miRNA-mediated mRNA regulatory network. There were 213 differentially expressed (DE) miRNAs and 2172 DE mRNAs with the involvement of negative miRNA-mRNA interactions identified by at least two pairs of cancerous tissues. GO analysis revealed that the upregulated microRNAs significantly contributed to a global down-regulation of a number of transcription factors (TFs) in OSCC. Among the negative regulatory networks between the selected miRNAs (133) and TFs (167), circadian rhythm genes (RORA, RORB, RORC, and CLOCK) simultaneously regulated by multiple microRNAs were of particular interest. For instance, RORA transcript was predicted to be targeted by 25 co-upregulated miRNAs, of which, miR-503-5p, miR-450b-5p, miR-27a-3p, miR-181a-5p and miR-183-5p were further validated to directly target RORA, resulting in a stronger effect on RORA suppression together. In addition, we showed that the mRNA and protein expression levels of RORα were significantly decreased in most OSCC samples, associated with advanced clinical stage and poor prognosis. RORα significantly suppressed the proliferation of OSCC cells in vitro and in vivo. Attenuated RORα decreased p53 protein expression and suppressed p53 phosphorylation activity. Altogether, our results strongly suggest the importance of the role of miRNAs in regulating the activity of circadian rhythm-related TFs network during OSCC tumorigenesis, and provide further clues to understand the clinical link between circadian rhythm and cancer therapy.
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影响因子：
7
作者：
Erhard F;Haas J;Lieber D;Malterer G;Jaskiewicz L;Zavolan M;Dölken L;Zimmer R
通讯作者：
Zimmer R
影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1016/j.ymthe.2017.11.016
发表时间：
2018-02-07
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
Hsu YL;Hung JY;Chang WA;Jian SF;Lin YS;Pan YC;Wu CY;Kuo PL
通讯作者：
Kuo PL
影响因子：
64.8
作者：
Hamilton, BA;Frankel, WN;Lander, ES
通讯作者：
Lander, ES
影响因子：
9.3
作者：
Cursons, Joseph;Pillman, Katherine A.;Davis, Melissa J.
通讯作者：
Davis, Melissa J.