Skip to main content
Top
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Research article

Integrated analysis of lncRNA-miRNA-mRNA ceRNA network in squamous cell carcinoma of tongue

Authors: Rui-Sheng Zhou, En-Xin Zhang, Qin-Feng Sun, Zeng-Jie Ye, Jian-Wei Liu, Dai-Han Zhou, Ying Tang

Published in: BMC Cancer | Issue 1/2019

Login to get access

Abstract

Background

Numerous studies have highlighted that long non-coding RNAs (lncRNAs) can bind to microRNA (miRNA) sites as competing endogenous RNAs (ceRNAs), thereby affecting and regulating the expression of mRNAs and target genes. These lncRNA-associated ceRNAs have been theorized to play a significant role in cancer initiation and progression. However, the roles and functions of the lncRNA-miRNA-mRNA ceRNA network in squamous cell carcinoma of the tongue (SCCT) are still unclear.

Methods

The miRNA, mRNA and lncRNA expression profiles from 138 patients with SCCT were downloaded from The Cancer Genome Atlas database. We identified the differential expression of miRNAs, mRNAs, and lncRNAs using the limma package of R software. We used the clusterProfiler package for GO and KEGG pathway annotations. The survival package was used to estimate survival analysis according to the Kaplan-Meier curve. Finally, the GDCRNATools package was used to construct the lncRNA-miRNA-mRNA ceRNA network.

Results

In total, 1943 SCCT-specific mRNAs, 107 lncRNAs and 100 miRNAs were explored. Ten mRNAs (CSRP2, CKS2, ADGRG6, MB21D1, GMNN, RIPOR3, RAD51, PCLAF, ORC1, NAGS), 9 lncRNAs (LINC02560, HOXC13 − AS, FOXD2 − AS1, AC105277.1, AC099850.3, STARD4 − AS1, SLC16A1 − AS1, MIR503HG, MIR100HG) and 8 miRNAs (miR − 654, miR − 503, miR − 450a, miR − 379, miR − 369, miR − 190a, miR − 101, and let−7c) were found to be significantly associated with overall survival (log-rank p < 0.05). Based on the analysis of the lncRNA-miRNA-mRNA ceRNA network, one differentially expressed (DE) lncRNA, five DEmiRNAs, and three DEmRNAs were demonstrated to be related to the pathogenesis of SCCT.

Conclusions

In this study, we described the gene regulation by the lncRNA-miRNA-mRNA ceRNA network in the progression of SCCT. We propose a new lncRNA-associated ceRNA that could help in the diagnosis and treatment of SCCT.
Appendix
Available only for authorised users
Literature
1.
go back to reference Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.CrossRef Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.CrossRef
2.
go back to reference Murphy CT, Galloway TJ, Handorf EA, Egleston BL, Wang LS, Mehra R, Flieder DB, Ridge JA. Survival impact of increasing time to treatment initiation for patients with head and neck Cancer in the United States. J Clin Oncol. 2016;34(2):169–78.PubMedCrossRef Murphy CT, Galloway TJ, Handorf EA, Egleston BL, Wang LS, Mehra R, Flieder DB, Ridge JA. Survival impact of increasing time to treatment initiation for patients with head and neck Cancer in the United States. J Clin Oncol. 2016;34(2):169–78.PubMedCrossRef
3.
go back to reference Adelstein DJ, Li Y, Adams GL, Wagner H Jr, Kish JA, Ensley JF, Schuller DE, Forastiere AA. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. 2003;21(1):92–8.PubMedCrossRef Adelstein DJ, Li Y, Adams GL, Wagner H Jr, Kish JA, Ensley JF, Schuller DE, Forastiere AA. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. 2003;21(1):92–8.PubMedCrossRef
4.
go back to reference Al-Sarraf M, Pajak TF, Marcial VA, Mowry P, Cooper JS, Stetz J, Ensley JF, Velez-Garcia E. Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study. Cancer. 1987;59(2):259–65.PubMedCrossRef Al-Sarraf M, Pajak TF, Marcial VA, Mowry P, Cooper JS, Stetz J, Ensley JF, Velez-Garcia E. Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study. Cancer. 1987;59(2):259–65.PubMedCrossRef
6.
go back to reference Mascitti M, Orsini G, Tosco V, Monterubbianesi R, Balercia A, Putignano A, Procaccini M, Santarelli A. An overview on current non-invasive diagnostic devices in Oral oncology. Front Physiol. 2018;9:1510.PubMedPubMedCentralCrossRef Mascitti M, Orsini G, Tosco V, Monterubbianesi R, Balercia A, Putignano A, Procaccini M, Santarelli A. An overview on current non-invasive diagnostic devices in Oral oncology. Front Physiol. 2018;9:1510.PubMedPubMedCentralCrossRef
7.
go back to reference Gao L, Wang FQ, Li HM, Yang JG, Ren JG, He KF, Liu B, Zhang W, Zhao YF. CCL2/EGF positive feedback loop between cancer cells and macrophages promotes cell migration and invasion in head and neck squamous cell carcinoma. Oncotarget. 2016;7(52):87037–51.PubMedPubMedCentral Gao L, Wang FQ, Li HM, Yang JG, Ren JG, He KF, Liu B, Zhang W, Zhao YF. CCL2/EGF positive feedback loop between cancer cells and macrophages promotes cell migration and invasion in head and neck squamous cell carcinoma. Oncotarget. 2016;7(52):87037–51.PubMedPubMedCentral
8.
9.
go back to reference Quinn JJ, Chang HY. Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet. 2016;17(1):47–62.PubMedCrossRef Quinn JJ, Chang HY. Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet. 2016;17(1):47–62.PubMedCrossRef
12.
go back to reference Slaby O, Laga R, Sedlacek O. Therapeutic targeting of non-coding RNAs in cancer. Biochem J. 2017;474(24):4219–51.PubMedCrossRef Slaby O, Laga R, Sedlacek O. Therapeutic targeting of non-coding RNAs in cancer. Biochem J. 2017;474(24):4219–51.PubMedCrossRef
13.
go back to reference Sui J, Li YH, Zhang YQ, Li CY, Shen X, Yao WZ, Peng H, Hong WW, Yin LH, Pu YP, et al. Integrated analysis of long non-coding RNAassociated ceRNA network reveals potential lncRNA biomarkers in human lung adenocarcinoma. Int J Oncol. 2016;49(5):2023–36.PubMedCrossRef Sui J, Li YH, Zhang YQ, Li CY, Shen X, Yao WZ, Peng H, Hong WW, Yin LH, Pu YP, et al. Integrated analysis of long non-coding RNAassociated ceRNA network reveals potential lncRNA biomarkers in human lung adenocarcinoma. Int J Oncol. 2016;49(5):2023–36.PubMedCrossRef
14.
go back to reference Wang X, Chen X, Meng Q, Jing H, Lu H, Yang Y, Cai L, Zhao Y. MiR-181b regulates cisplatin chemosensitivity and metastasis by targeting TGFbetaR1/Smad signaling pathway in NSCLC. Sci Rep. 2015;5:17618.PubMedPubMedCentralCrossRef Wang X, Chen X, Meng Q, Jing H, Lu H, Yang Y, Cai L, Zhao Y. MiR-181b regulates cisplatin chemosensitivity and metastasis by targeting TGFbetaR1/Smad signaling pathway in NSCLC. Sci Rep. 2015;5:17618.PubMedPubMedCentralCrossRef
15.
go back to reference Wang X, Yin H, Zhang H, Hu J, Lu H, Li C, Cao M, Yan S, Cai L. NF-kappaB-driven improvement of EHD1 contributes to erlotinib resistance in EGFR-mutant lung cancers. Cell Death Dis. 2018;9(4):418.PubMedPubMedCentralCrossRef Wang X, Yin H, Zhang H, Hu J, Lu H, Li C, Cao M, Yan S, Cai L. NF-kappaB-driven improvement of EHD1 contributes to erlotinib resistance in EGFR-mutant lung cancers. Cell Death Dis. 2018;9(4):418.PubMedPubMedCentralCrossRef
16.
17.
go back to reference Gennarino VA, D'Angelo G, Dharmalingam G, Fernandez S, Russolillo G, Sanges R, Mutarelli M, Belcastro V, Ballabio A, Verde P, et al. Identification of microRNA-regulated gene networks by expression analysis of target genes. Genome Res. 2012;22(6):1163–72.PubMedPubMedCentralCrossRef Gennarino VA, D'Angelo G, Dharmalingam G, Fernandez S, Russolillo G, Sanges R, Mutarelli M, Belcastro V, Ballabio A, Verde P, et al. Identification of microRNA-regulated gene networks by expression analysis of target genes. Genome Res. 2012;22(6):1163–72.PubMedPubMedCentralCrossRef
18.
go back to reference Li L, Wang D, Xue M, Mi X, Liang Y, Wang P. UTR shortening identifies high-risk cancers with targeted dysregulation of the ceRNA network. Sci Rep. 2014;4(3):5406.PubMedPubMedCentral Li L, Wang D, Xue M, Mi X, Liang Y, Wang P. UTR shortening identifies high-risk cancers with targeted dysregulation of the ceRNA network. Sci Rep. 2014;4(3):5406.PubMedPubMedCentral
19.
20.
go back to reference Ebert MS, Neilson JR, Sharp PA. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods. 2007;4(9):721–6.PubMedCrossRef Ebert MS, Neilson JR, Sharp PA. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods. 2007;4(9):721–6.PubMedCrossRef
21.
go back to reference Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature. 2010;465(7301):1033–8.PubMedPubMedCentralCrossRef Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature. 2010;465(7301):1033–8.PubMedPubMedCentralCrossRef
22.
go back to reference Wang J, Liu X, Wu H, Ni P, Gu Z, Qiao Y, Chen N, Sun F, Fan Q. CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer. Nucleic Acids Res. 2010;38(16):5366–83.PubMedPubMedCentralCrossRef Wang J, Liu X, Wu H, Ni P, Gu Z, Qiao Y, Chen N, Sun F, Fan Q. CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer. Nucleic Acids Res. 2010;38(16):5366–83.PubMedPubMedCentralCrossRef
23.
go back to reference Lee DY, Jeyapalan Z, Fang L, Yang J, Zhang Y, Yee AY, Li M, Du WW, Shatseva T, Yang BB. Expression of versican 3′-untranslated region modulates endogenous microRNA functions. PLoS One. 2010;5(10):e13599.PubMedPubMedCentralCrossRef Lee DY, Jeyapalan Z, Fang L, Yang J, Zhang Y, Yee AY, Li M, Du WW, Shatseva T, Yang BB. Expression of versican 3′-untranslated region modulates endogenous microRNA functions. PLoS One. 2010;5(10):e13599.PubMedPubMedCentralCrossRef
24.
go back to reference Jeyapalan Z, Deng Z, Shatseva T, Fang L, He C, Yang BB. Expression of CD44 3′-untranslated region regulates endogenous microRNA functions in tumorigenesis and angiogenesis. Nucleic Acids Res. 2011;39(8):3026–41.PubMedCrossRef Jeyapalan Z, Deng Z, Shatseva T, Fang L, He C, Yang BB. Expression of CD44 3′-untranslated region regulates endogenous microRNA functions in tumorigenesis and angiogenesis. Nucleic Acids Res. 2011;39(8):3026–41.PubMedCrossRef
26.
go back to reference Zhao Y, Wang J, Ma K. Knockdown of lncRNA SNHG6 inhibites the proliferation and epithelial mesenchymal transition in tongue cancer cells. Xi bao yu fen zi mian yi xue za zhi. 2018;34(9):806–11.PubMed Zhao Y, Wang J, Ma K. Knockdown of lncRNA SNHG6 inhibites the proliferation and epithelial mesenchymal transition in tongue cancer cells. Xi bao yu fen zi mian yi xue za zhi. 2018;34(9):806–11.PubMed
27.
go back to reference Zhang S, Ma H, Zhang D, Xie S, Wang W, Li Q, Lin Z, Wang Y. LncRNA KCNQ1OT1 regulates proliferation and cisplatin resistance in tongue cancer via miR-211-5p mediated Ezrin/Fak/Src signaling. Cell Death Dis. 2018;9(7):742.PubMedPubMedCentralCrossRef Zhang S, Ma H, Zhang D, Xie S, Wang W, Li Q, Lin Z, Wang Y. LncRNA KCNQ1OT1 regulates proliferation and cisplatin resistance in tongue cancer via miR-211-5p mediated Ezrin/Fak/Src signaling. Cell Death Dis. 2018;9(7):742.PubMedPubMedCentralCrossRef
28.
go back to reference Yin H, Wang X, Zhang X, Wang Y, Zeng Y, Xiong Y, Li T, Lin R, Zhou Q, Ling H, et al. Integrated analysis of long noncoding RNA associated-competing endogenous RNA as prognostic biomarkers in clear cell renal carcinoma. Cancer Sci. 2018;109(10):3336–49.PubMedPubMedCentralCrossRef Yin H, Wang X, Zhang X, Wang Y, Zeng Y, Xiong Y, Li T, Lin R, Zhou Q, Ling H, et al. Integrated analysis of long noncoding RNA associated-competing endogenous RNA as prognostic biomarkers in clear cell renal carcinoma. Cancer Sci. 2018;109(10):3336–49.PubMedPubMedCentralCrossRef
29.
go back to reference Guo LL, Song CH, Wang P, Dai LP, Zhang JY, Wang KJ. Competing endogenous RNA networks and gastric cancer. World J Gastroenterol. 2015;21(41):11680–7.PubMedPubMedCentralCrossRef Guo LL, Song CH, Wang P, Dai LP, Zhang JY, Wang KJ. Competing endogenous RNA networks and gastric cancer. World J Gastroenterol. 2015;21(41):11680–7.PubMedPubMedCentralCrossRef
30.
go back to reference Li R, Qu H, Wang S, Wei J, Zhang L, Ma R, Lu J, Zhu J, Zhong WD, Jia Z. GDCRNATools: an R/Bioconductor package for integrative analysis of lncRNA, miRNA and mRNA data in GDC. Bioinformatics. 2018;34(14):2515–7.PubMedCrossRef Li R, Qu H, Wang S, Wei J, Zhang L, Ma R, Lu J, Zhu J, Zhong WD, Jia Z. GDCRNATools: an R/Bioconductor package for integrative analysis of lncRNA, miRNA and mRNA data in GDC. Bioinformatics. 2018;34(14):2515–7.PubMedCrossRef
31.
go back to reference Smoot ME, Ono K, Ruscheinski J, Wang PL, Ideker T. Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics. 2011;27(3):431–2.PubMedCrossRef Smoot ME, Ono K, Ruscheinski J, Wang PL, Ideker T. Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics. 2011;27(3):431–2.PubMedCrossRef
32.
go back to reference Maere S, Heymans K, Kuiper M. BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics. 2005;21(16):3448–9.PubMedCrossRef Maere S, Heymans K, Kuiper M. BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics. 2005;21(16):3448–9.PubMedCrossRef
33.
go back to reference Otsuka Y, Sato H, Oikawa T, Onodera Y, Nam JM, Hashimoto A, Fukunaga K, Hatanaka KC, Hatanaka Y, Matsuno Y, et al. High expression of EPB41L5, an integral component of the Arf6-driven mesenchymal program, correlates with poor prognosis of squamous cell carcinoma of the tongue. Cell Commun Signal. 2016;14(1):28.PubMedPubMedCentralCrossRef Otsuka Y, Sato H, Oikawa T, Onodera Y, Nam JM, Hashimoto A, Fukunaga K, Hatanaka KC, Hatanaka Y, Matsuno Y, et al. High expression of EPB41L5, an integral component of the Arf6-driven mesenchymal program, correlates with poor prognosis of squamous cell carcinoma of the tongue. Cell Commun Signal. 2016;14(1):28.PubMedPubMedCentralCrossRef
34.
go back to reference Tripathi V, Shen Z, Chakraborty A, Giri S, Freier SM, Wu X, Zhang Y, Gorospe M, Prasanth SG, Lal A, et al. Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B-MYB. PLoS Genet. 2013;9(3):e1003368.PubMedPubMedCentralCrossRef Tripathi V, Shen Z, Chakraborty A, Giri S, Freier SM, Wu X, Zhang Y, Gorospe M, Prasanth SG, Lal A, et al. Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B-MYB. PLoS Genet. 2013;9(3):e1003368.PubMedPubMedCentralCrossRef
35.
go back to reference Ying L, Huang Y, Chen H, Wang Y, Xia L, Chen Y, Liu Y, Qiu F. Downregulated MEG3 activates autophagy and increases cell proliferation in bladder cancer. Mol BioSyst. 2013;9(3):407–11.PubMedCrossRef Ying L, Huang Y, Chen H, Wang Y, Xia L, Chen Y, Liu Y, Qiu F. Downregulated MEG3 activates autophagy and increases cell proliferation in bladder cancer. Mol BioSyst. 2013;9(3):407–11.PubMedCrossRef
36.
go back to reference Cesana M, Cacchiarelli D, Legnini I, Santini T, Sthandier O, Chinappi M, Tramontano A, Bozzoni I. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell. 2011;147(2):358–69.PubMedPubMedCentralCrossRef Cesana M, Cacchiarelli D, Legnini I, Santini T, Sthandier O, Chinappi M, Tramontano A, Bozzoni I. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell. 2011;147(2):358–69.PubMedPubMedCentralCrossRef
37.
go back to reference Wang Y, Xu Z, Jiang J, Xu C, Kang J, Xiao L, Wu M, Xiong J, Guo X, Liu H. Endogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal. Dev Cell. 2013;25(1):69–80.PubMedCrossRef Wang Y, Xu Z, Jiang J, Xu C, Kang J, Xiao L, Wu M, Xiong J, Guo X, Liu H. Endogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal. Dev Cell. 2013;25(1):69–80.PubMedCrossRef
38.
go back to reference Kallen AN, Zhou XB, Xu J, Qiao C, Ma J, Yan L, Lu L, Liu C, Yi JS, Zhang H, et al. The imprinted H19 lncRNA antagonizes let-7 microRNAs. Mol Cell. 2013;52(1):101–12.PubMedCrossRef Kallen AN, Zhou XB, Xu J, Qiao C, Ma J, Yan L, Lu L, Liu C, Yi JS, Zhang H, et al. The imprinted H19 lncRNA antagonizes let-7 microRNAs. Mol Cell. 2013;52(1):101–12.PubMedCrossRef
39.
go back to reference Danielsen SA, Eide PW, Nesbakken A, Guren T, Leithe E, Lothe RA. Portrait of the PI3K/AKT pathway in colorectal cancer. Biochim Biophys Acta. 2015;1855(1):104–21.PubMed Danielsen SA, Eide PW, Nesbakken A, Guren T, Leithe E, Lothe RA. Portrait of the PI3K/AKT pathway in colorectal cancer. Biochim Biophys Acta. 2015;1855(1):104–21.PubMed
41.
go back to reference Zhang H, Zeitz MJ, Wang H, Niu B, Ge S, Li W, Cui J, Wang G, Qian G, Higgins MJ, et al. Long noncoding RNA-mediated intrachromosomal interactions promote imprinting at the Kcnq1 locus. J Cell Biol. 2014;204(1):61–75.PubMedPubMedCentralCrossRef Zhang H, Zeitz MJ, Wang H, Niu B, Ge S, Li W, Cui J, Wang G, Qian G, Higgins MJ, et al. Long noncoding RNA-mediated intrachromosomal interactions promote imprinting at the Kcnq1 locus. J Cell Biol. 2014;204(1):61–75.PubMedPubMedCentralCrossRef
42.
43.
go back to reference Zhang Z, Weaver DL, Olsen D, deKay J, Peng Z, Ashikaga T, Evans MF. Long non-coding RNA chromogenic in situ hybridisation signal pattern correlation with breast tumour pathology. J Clin Pathol. 2016;69(1):76–81.PubMedCrossRef Zhang Z, Weaver DL, Olsen D, deKay J, Peng Z, Ashikaga T, Evans MF. Long non-coding RNA chromogenic in situ hybridisation signal pattern correlation with breast tumour pathology. J Clin Pathol. 2016;69(1):76–81.PubMedCrossRef
44.
go back to reference Wan J, Huang M, Zhao H, Wang C, Zhao X, Jiang X, Bian S, He Y, Gao Y. A novel tetranucleotide repeat polymorphism within KCNQ1OT1 confers risk for hepatocellular carcinoma. DNA Cell Biol. 2013;32(11):628–34.PubMedCrossRef Wan J, Huang M, Zhao H, Wang C, Zhao X, Jiang X, Bian S, He Y, Gao Y. A novel tetranucleotide repeat polymorphism within KCNQ1OT1 confers risk for hepatocellular carcinoma. DNA Cell Biol. 2013;32(11):628–34.PubMedCrossRef
Metadata
Title
Integrated analysis of lncRNA-miRNA-mRNA ceRNA network in squamous cell carcinoma of tongue
Authors
Rui-Sheng Zhou
En-Xin Zhang
Qin-Feng Sun
Zeng-Jie Ye
Jian-Wei Liu
Dai-Han Zhou
Ying Tang
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-5983-8

Other articles of this Issue 1/2019

BMC Cancer 1/2019 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine