Top

BMC Cancer

Published in:

Open Access 01-12-2021 | Biomarkers | Research

Construction and comprehensive analysis of a ceRNA network to reveal potential prognostic biomarkers for lung adenocarcinoma

Authors: Lei Gao, Ling Zhang

Published in: BMC Cancer | Issue 1/2021

Abstract

Background

More and more studies have proven that circular RNAs (circRNAs) play vital roles in cancer development via sponging miRNAs. However, the expression pattern of competing endogenous RNA (ceRNA) in lung adenocarcinoma (LUAD) remains largely unclear. The current study explored functional roles and the regulatory mechanisms of circRNA as ceRNAs in LUAD and their potential impact on LUAD patient prognosis.

Methods

In this study, we systematically screened differential expression circRNAs (DEcircRNAs), miRNAs (DEmiRNAs) and mRNAs (DEGs) associated with LUAD. Then, DEcircRNAs, DEmiRNAs and DEGs were selected to construct a circRNA–miRNA–mRNA prognosis-related regulatory network based on interaction information from the ENCORI database. Subsequently, the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on the genes in the network to predict the potential underlying mechanisms and functions of circRNAs in LUAD. In addition, Kaplan–Meier survival analysis was performed to evaluate clinical outcomes of LUAD patients, and drug sensitivity analysis was used to screen potential biomarkers for drug treatment of patients with LUAD.

Results

As a result, 10 circRNAs were aberrantly expressed in LUAD tissues. The ceRNA network was built, which included 3 DEcircRNAs, 6 DEmiRNAs and 157 DEGs. The DEGs in the ceRNA network of hsa_circ_0049271 enriched in biological processes of cell proliferation and the Jak-STAT signaling pathway. We also detected 7 mRNAs in the ceRNA network of hsa_circ_0049271 that were significantly associated with the overall survival of LUAD patients (P < 0.05). Importantly, four genes (PDGFB, CCND2, CTF1, IL7R) identified were strongly associated with STAT3 activation and drugs sensitivity in GDSC.

Conclusions

In summary, a ceRNA network of hsa_circ_0049271 was successfully constructed, which including one circRNA, two miRNAs, and seven mRNAs. Seven mRNAs (PDGFB, TNFRSF19, CCND2, CTF1, IL11RA, IL7R and MAOA) were remarkably associated with the prognosis of LUAD patients. Among seven mRNA species, four genes (PDGFB, CCND2, CTF1, and IL7R) could be considered as drug targets in LUAD. Our research will provide new insights into the prognosis-related ceRNA network in LUAD.

Available only for authorised users

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30. https://doi.org/10.3322/caac.21590.CrossRefPubMed

Qi L, Li Y, Qin Y, Shi G, Li T, Wang J, et al. An individualised signature for predicting response with concordant survival benefit for lung adenocarcinoma patients receiving platinum-based chemotherapy. Br J Cancer. 2016;115(12):1513–9. https://doi.org/10.1038/bjc.2016.370.CrossRefPubMedPubMedCentral

Hirsch FR, Scagliotti GV, Mulshine JL, Kwon R, Curran WJ, Wu Y-L, et al. Lung cancer: current therapies and new targeted treatments. Lancet. 2017;389(10066):299–311. https://doi.org/10.1016/S0140-6736(16)30958-8.CrossRefPubMed

Vo JN, Cieslik M, Zhang Y, Shukla S, Xiao L, Zhang Y, et al. The Landscape of Circular RNA in Cancer. Cell. 2019;176:869–881.e13.CrossRefPubMedPubMedCentral

Rybak-Wolf A, Stottmeister C, Glažar P, Jens M, Pino N, Giusti S, et al. Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Mol Cell. 2015;58(5):870–85. https://doi.org/10.1016/j.molcel.2015.03.027.CrossRefPubMed

Hang D, Zhou J, Qin N, Zhou W, Ma H, Jin G, et al. A novel plasma circular RNA circFARSA is a potential biomarker for non-small cell lung cancer. Cancer Med. 2018;7(6):2783–91. https://doi.org/10.1002/cam4.1514.CrossRefPubMedPubMedCentral

Shang Q, Yang Z, Jia R, Ge S. The novel roles of circRNAs in human cancer. Mol Cancer. 2019;18(1):6. https://doi.org/10.1186/s12943-018-0934-6.CrossRefPubMedPubMedCentral

Kristensen LS, Hansen TB, Venø MT, Kjems J. Circular RNAs in cancer: opportunities and challenges in the field. Oncogene. 2018;37(5):555–65. https://doi.org/10.1038/onc.2017.361.CrossRefPubMed

Holdt LM, Kohlmaier A, Teupser D. Molecular roles and function of circular RNAs in eukaryotic cells. Cell Mol Life Sci. 2018;75(6):1071–98. https://doi.org/10.1007/s00018-017-2688-5.CrossRefPubMed

10.

Li X, Yang L, Chen L-L. The biogenesis, functions, and challenges of circular RNAs. Mol Cell. 2018;71(3):428–42. https://doi.org/10.1016/j.molcel.2018.06.034.CrossRefPubMed

11.

Zhong Z, Huang M, Lv M, He Y, Duan C, Zhang L, et al. Circular RNA MYLK as a competing endogenous RNA promotes bladder cancer progression through modulating VEGFA/VEGFR2 signaling pathway. Cancer Lett. 2017;403:305–17. https://doi.org/10.1016/j.canlet.2017.06.027.CrossRefPubMed

12.

Zeng K, Chen X, Xu M, Liu X, Hu X, Xu T, et al. CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7. Cell Death Dis. 2018;9(4):417. https://doi.org/10.1038/s41419-018-0454-8.CrossRefPubMedPubMedCentral

13.

Zhang X, Wang S, Wang H, Cao J, Huang X, Chen Z, et al. Circular RNA circNRIP1 acts as a microRNA-149-5p sponge to promote gastric cancer progression via the AKT1/mTOR pathway. Mol Cancer. 2019;18(1):20. https://doi.org/10.1186/s12943-018-0935-5.CrossRefPubMedPubMedCentral

14.

Zeng K, He B, Yang BB, Xu T, Chen X, Xu M, et al. The pro-metastasis effect of circANKS1B in breast cancer. Mol Cancer. 2018;17(1):160. https://doi.org/10.1186/s12943-018-0914-x.CrossRefPubMedPubMedCentral

15.

Ying X, Zhu J, Zhang Y. Circular RNA circ-TSPAN4 promotes lung adenocarcinoma metastasis by upregulating ZEB1 via sponging miR-665. Mol Genet Genomic Med. 2019;7:e991.CrossRefPubMedPubMedCentral

16.

Du J, Zhang G, Qiu H, Yu H, Yuan W. The novel circular RNA circ-CAMK2A enhances lung adenocarcinoma metastasis by regulating the miR-615-5p/fibronectin 1 pathway. Cell Mol Biol Lett. 2019;24(1):72. https://doi.org/10.1186/s11658-019-0198-1.CrossRefPubMedPubMedCentral

17.

Yao Y, Hua Q, Zhou Y. CircRNA has_circ_0006427 suppresses the progression of lung adenocarcinoma by regulating miR-6783-3p/DKK1 axis and inactivating Wnt/β-catenin signaling pathway. Biochem Biophys Res Commun. 2019;508(1):37–45. https://doi.org/10.1016/j.bbrc.2018.11.079.CrossRefPubMed

18.

Wang X, Zhu X, Zhang H, Wei S, Chen Y, Chen Y, et al. Increased circular RNA hsa_circ_0012673 acts as a sponge of miR-22 to promote lung adenocarcinoma proliferation. Biochem Biophys Res Commun. 2018;496(4):1069–75. https://doi.org/10.1016/j.bbrc.2018.01.126.CrossRefPubMed

19.

Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495(7441):384–8. https://doi.org/10.1038/nature11993.CrossRefPubMed

20.

Chen J, Song Y, Li M, Zhang Y, Lin T, Sun J, et al. Comprehensive analysis of ceRNA networks reveals prognostic lncRNAs related to immune infiltration in colorectal cancer. BMC Cancer. 2021;21(1):255. https://doi.org/10.1186/s12885-021-07995-2.CrossRefPubMedPubMedCentral

21.

Zhao J, Li L, Wang Q, Han H, Zhan Q, Xu M. CircRNA expression profile in early-stage lung adenocarcinoma patients. Cell Physiol Biochem. 2017;44(6):2138–46. https://doi.org/10.1159/000485953.CrossRefPubMed

22.

Chen T, Yang Z, Liu C, Wang L, Yang J, Chen L, et al. Circ_0078767 suppresses non-small-cell lung cancer by protecting RASSF1A expression via sponging miR-330-3p. Cell Prolif. 2019;52(2):e12548. https://doi.org/10.1111/cpr.12548.CrossRefPubMed

23.

Ma L, Huang Y, Zhu W, Zhou S, Zhou J, Zeng F, et al. An integrated analysis of miRNA and mRNA expressions in non-small cell lung cancers. PLoS One. 2011;6(10):e26502. https://doi.org/10.1371/journal.pone.0026502.CrossRefPubMedPubMedCentral

24.

Goldman MJ, Craft B, Hastie M, Repečka K, McDade F, Kamath A, et al. Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol. 2020;38(6):675–8. https://doi.org/10.1038/s41587-020-0546-8.CrossRefPubMedPubMedCentral

25.

Glažar P, Papavasileiou P, Rajewsky N. circBase: a database for circular RNAs. RNA. 2014;20(11):1666–70. https://doi.org/10.1261/rna.043687.113.CrossRefPubMedPubMedCentral

26.

Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ. miRBase: tools for microRNA genomics. Nucleic Acids Res. 2008;36(suppl_1):D154–8.PubMed

27.

Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.CrossRefPubMedPubMedCentral

28.

Li R, Qu H, Wang S, Wei J, Zhang L, Ma R, et al. GDCRNATools: an R/Bioconductor package for integrative analysis of lncRNA, miRNA and mRNA data in GDC. Bioinformatics. 2018;34(14):2515–7. https://doi.org/10.1093/bioinformatics/bty124.CrossRefPubMed

29.

Kanehisa M, Furumichi M, Sato Y, Ishiguro-Watanabe M, Tanabe M. KEGG: integrating viruses and cellular organisms. Nucleic Acids Res. 2020;49:D545–51.CrossRefPubMedCentral

30.

Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545–50. https://doi.org/10.1073/pnas.0506580102.CrossRefPubMedPubMedCentral

31.

Liu C-J, Hu F-F, Xia M-X, Han L, Zhang Q, Guo A-Y. GSCALite: a web server for gene set cancer analysis. Bioinformatics. 2018;34(21):3771–2. https://doi.org/10.1093/bioinformatics/bty411.CrossRefPubMed

32.

Iorio F, Knijnenburg TA, Vis DJ, Bignell GR, Menden MP, Schubert M, et al. A landscape of Pharmacogenomic interactions in Cancer. Cell. 2016;166(3):740–54. https://doi.org/10.1016/j.cell.2016.06.017.CrossRefPubMedPubMedCentral

33.

Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012;483(7391):570–5. https://doi.org/10.1038/nature11005.CrossRefPubMedPubMedCentral

34.

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492.CrossRefPubMed

35.

Han B, Chao J, Yao H. Circular RNA and its mechanisms in disease: from the bench to the clinic. Pharmacol Ther. 2018;187:31–44. https://doi.org/10.1016/j.pharmthera.2018.01.010.CrossRefPubMed

36.

Gao N, Ye B. Circ-SOX4 drives the tumorigenesis and development of lung adenocarcinoma via sponging miR-1270 and modulating PLAGL2 to activate WNT signaling pathway. Cancer Cell Int. 2020;20(1):2. https://doi.org/10.1186/s12935-019-1065-x.CrossRefPubMedPubMedCentral

37.

Liang Z-Z, Guo C, Zou M-M, Meng P, Zhang T-T. circRNA-miRNA-mRNA regulatory network in human lung cancer: an update. Cancer Cell Int. 2020;20:173.CrossRefPubMedPubMedCentral

38.

Wang J, Zhao X, Wang Y, Ren F, Sun D, Yan Y, et al. circRNA-002178 act as a ceRNA to promote PDL1/PD1 expression in lung adenocarcinoma. Cell Death Dis. 2020;11:1–11.CrossRefPubMedPubMedCentral

39.

Liang L, Zhang L, Zhang J, Bai S, Fu H. Identification of circRNA-miRNA-mRNA networks for exploring the fundamental mechanism in lung adenocarcinoma. Onco Targets Ther. 2020;13:2945–55. https://doi.org/10.2147/OTT.S235664.CrossRefPubMedPubMedCentral

40.

Li R, Qu H, Wang S, Wang X, Cui Y, Yu L, et al. CancerMIRNome: a web server for interactive analysis and visualization of cancer miRNome data. bioRxiv. 2020; 2020.10.04.325670.

41.

Yang X, Tang Z, Zhang P, Zhang L. Research advances of JAK/STAT signaling pathway in lung Cancer. Zhongguo Fei Ai Za Zhi. 2019;22(1):45–51. https://doi.org/10.3779/j.issn.1009-3419.2019.01.09.CrossRefPubMed

42.

Eskiler GG, Bezdegumeli E, Ozman Z, Ozkan AD, Bilir C, Kucukakca BN, et al. IL-6 mediated JAK/STAT3 signaling pathway in cancer patients with cachexia. Bratisl Lek Listy. 2019;66(11):819–26. https://doi.org/10.4149/BLL_2019_136.CrossRefPubMed

43.

Ahn HK, Jeon K, Yoo H, Han B, Lee SJ, Park H, et al. Successful treatment with crizotinib in mechanically ventilated patients with ALK positive non-small-cell lung cancer. J Thorac Oncol. 2013;8(2):250–3. https://doi.org/10.1097/JTO.0b013e3182746772.CrossRefPubMed

44.

Lu H, Wu S, Chen H, Huang Y, Qiu G, Liu L, et al. Crizotinib induces apoptosis of lung cancer cells through JAK-STAT pathway. Oncol Lett. 2018;16(5):5992–6. https://doi.org/10.3892/ol.2018.9387.CrossRefPubMedPubMedCentral

Title: Construction and comprehensive analysis of a ceRNA network to reveal potential prognostic biomarkers for lung adenocarcinoma
Authors: Lei Gao
Ling Zhang
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Biomarkers
Published in: BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-021-08462-8

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

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

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2021

Angiogenesis-related lncRNAs predict the prognosis signature of stomach adenocarcinoma

Ovarian cycle stage critically affects 21-gene recurrence scores in Mmtv-Pymt mouse mammary tumours

The value of lncRNAs as prognostic biomarkers on clinical outcomes in osteosarcoma: a meta-analysis

Tumor-infiltrating B cells and T cells correlate with postoperative prognosis in triple-negative carcinoma of the breast

Changes after cancer diagnosis and return to work: experience of Korean cancer patients

Active surveillance for thyroid Cancer: a qualitative study of barriers and facilitators to implementation

Keynote webinar | Spotlight on antibody–drug conjugates in cancer