Early researches have revealed that circular RNA (circRNA) had the potential of biomarkers and could affect tumor progression through regulatory networks. However, few research focused on the function of circRNA in lung adenocarcinoma and the regulation mechanism of competitive endogenous RNA. In present study, through differential expression analysis, 10 circRNAs, 98 miRNAs(microRNA) and 2497 mRNAs were screened. Based on the 10 circRNAs and related databases, a competitive endogenous RNA regulatory network (ceRNA network) containing 7 circRNAs, 13 miRNAs and 147 mRNAs was constructed. KEGG and GO analysis suggested that 147 mRNAs were obviously enriched in biological pathway related to LUAD. By constructing a PPI network, 12 hub genes were identified by MCODE. The result of survival analysis showed that 10 hub genes (BIRC5, MKI67, CENPF, RRM2, BUB1, MELK, CEP55, CDK1, NEK2, TOP2A) were significantly related to the survival of LUAD. We randomly divided 483 clinical data into two parts: train set and validation set. The train set was used for Cox regression analysis, 3 prognostic factors (stage, T, CDK1) were screened. The nomogram model was constructed based on stage, T and CDK1. The model was evaluated by ROC curve, calibration chart, Kaplan-Meier (KM) curve and validation set data. The results indicated that the model has good accuracy. Our study elucidated the regulatory mechanism of circRNA in lung adenocarcinoma, and the nomogram model also provided insight for the clinical analysis of lung adenocarcinoma.
Citation: Pingping Song, Jing Chen, Xu Zhang, Xiaofeng Yin. Construction of competitive endogenous RNA network related to circular RNA and prognostic nomogram model in lung adenocarcinoma[J]. Mathematical Biosciences and Engineering, 2021, 18(6): 9806-9821. doi: 10.3934/mbe.2021481
Early researches have revealed that circular RNA (circRNA) had the potential of biomarkers and could affect tumor progression through regulatory networks. However, few research focused on the function of circRNA in lung adenocarcinoma and the regulation mechanism of competitive endogenous RNA. In present study, through differential expression analysis, 10 circRNAs, 98 miRNAs(microRNA) and 2497 mRNAs were screened. Based on the 10 circRNAs and related databases, a competitive endogenous RNA regulatory network (ceRNA network) containing 7 circRNAs, 13 miRNAs and 147 mRNAs was constructed. KEGG and GO analysis suggested that 147 mRNAs were obviously enriched in biological pathway related to LUAD. By constructing a PPI network, 12 hub genes were identified by MCODE. The result of survival analysis showed that 10 hub genes (BIRC5, MKI67, CENPF, RRM2, BUB1, MELK, CEP55, CDK1, NEK2, TOP2A) were significantly related to the survival of LUAD. We randomly divided 483 clinical data into two parts: train set and validation set. The train set was used for Cox regression analysis, 3 prognostic factors (stage, T, CDK1) were screened. The nomogram model was constructed based on stage, T and CDK1. The model was evaluated by ROC curve, calibration chart, Kaplan-Meier (KM) curve and validation set data. The results indicated that the model has good accuracy. Our study elucidated the regulatory mechanism of circRNA in lung adenocarcinoma, and the nomogram model also provided insight for the clinical analysis of lung adenocarcinoma.
| [1] |
F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, A. Jemal, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, Ca-Cancer J. Clin., 68 (2018), 394-424. doi: 10.3322/caac.21492
|
| [2] |
M. Saito, K. Shiraishi, H. Kunitoh, S. Takenoshita, J. Yokota, T. Kohno, Gene aberrations for precision medicine against lung adenocarcinoma, Cancer Sci., 107 (2016), 713-720. doi: 10.1111/cas.12941
|
| [3] |
H. Nakamura, H. Saji, Worldwide trend of increasing primary adenocarcinoma of the lung, Surg. Today, 44 (2014), 1004-1012. doi: 10.1007/s00595-013-0636-z
|
| [4] | L. Osmani, F. Askin, E. Gabrielson, Q. K. Li, Current WHO guidelines and the critical role of immunohistochemical markers in the subclassification of non-small cell lung carcinoma (NSCLC): Moving from targeted therapy to immunotherapy, Semin. Cancer Biol., 68 (2017), 103-109. |
| [5] |
L. Salmena, L. Poliseno, Y. Tay, L. Kats, P. Pandolfi, A ceRNA hypothesis, The Rosetta Stone of a hidden RNA language?, Cell, 146 (2011), 353-358. doi: 10.1016/j.cell.2011.07.014
|
| [6] |
S. Qu, X. Yang, X. Li, J. Wang, Y. Gao, R. Shang, et al., Circular RNA: A new star of noncoding RNAs, Cancer Lett., 365 (2015), 141-148. doi: 10.1016/j.canlet.2015.06.003
|
| [7] |
W. R. Jeck, J. A. Sorrentino, K. Wang, M. K. Slevin, C. E. Burd, J. Liu, et al., Circular RNAs are abundant, conserved, and associated with ALU repeats, RNA, 19 (2013), 141-157. doi: 10.1261/rna.035667.112
|
| [8] |
C. Wang, S. Tan, J. Li, W. R. Liu, Y. Peng, W. Li, CircRNAs in lung cancer-Biogenesis, function and clinical implication, Cancer Lett., 492(2020), 106-115. doi: 10.1016/j.canlet.2020.08.013
|
| [9] |
X. W. Li, W. H. Yang, J. Xu, Circular RNA in gastric cancer, Chin. Med. J., 133 (2020), 1868-1877. doi: 10.1097/CM9.0000000000000908
|
| [10] |
D. Xiong, R. He, Y. Dang, H. Wu, Z. Feng, G. Chen, The latest overview of circRNA in the progression, diagnosis, prognosis and drug resistance of hepatocellular carcinoma, Front. Oncol., 10 (2021), 608257. doi: 10.3389/fonc.2020.608257
|
| [11] |
Y. Li, Q. Zheng, C. Bao, S. Li, W. Guo, J. Zhao, et al., Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis, Cell Res., 25 (2015), 981-984. doi: 10.1038/cr.2015.82
|
| [12] |
J. Tian, X. Xi, J. Wang, J. Yu, Q. Huang, R. Ma, et al., CircRNA hsa_circ_0004585 as a potential biomarker for colorectal cancer, Cancer Manage. Res., 11 (2019), 5413-5423. doi: 10.2147/CMAR.S199436
|
| [13] |
Z. Li, Z. Chen, G. Hu, Y. Zhang, Y. Feng, Y. Jiang, et al., Profiling and integrated analysis of differentially expressed circRNAs as novel biomarkers for breast cancer, J. Cell. Physiol., 235 (2020), 7945-7959. doi: 10.1002/jcp.29449
|
| [14] |
Y. Zhong, Y. Du, X. Yang, Y. Mo, C. Fan, F. Xiong, et al., Circular RNAs function as ceRNAs to regulate and control human cancer progression, Mol. Cancer., 17 (2018), 79. doi: 10.1186/s12943-018-0827-8
|
| [15] |
Z. Dou, L. Gao, W. Ren, H. Zhang, X. Wang, S.Li, et al., CiRS-7 functions as a ceRNA of RAF-1/PIK3CD to promote metastatic progression of oral squamous cell carcinoma via MAPK/AKT signaling pathways, Exp. Cell Res., 396 (2020), 112290. doi: 10.1016/j.yexcr.2020.112290
|
| [16] |
X. Wang, X. Zhu, H. Zhang, S. Wei, Y. Chen, Y. Chen, et al., Increased circular RNA hsa_circ_0012673 acts as a sponge of miR-22 to promote lung adenocarcinoma proliferation, Biochem. Biophys. Res. Commun., 496 (2018), 1069-1075. doi: 10.1016/j.bbrc.2018.01.126
|
| [17] |
Z. Sun, Circular RNA hsa_circ_0001588 promotes the malignant progression of lung adenocarcinoma by modulating miR-524-3p/NACC1 signaling, Life Sci., 259(2020), 118157. doi: 10.1016/j.lfs.2020.118157
|
| [18] |
L. Liang, L. Zhang, J. Zhang, S. Bai, H. Fu, Identification of circRNA-miRNA-mRNA networks for exploring the fundamental mechanism in lung adenocarcinoma, Onco Targets Ther., 13 (2020), 2945-2955. doi: 10.2147/OTT.S235664
|
| [19] |
X. X. Liu, Y. E. Yang, X. Liu, M. Y. Zhang, R. Li, Y. H. Yin, et al., A two-circular RNA signature as a noninvasive diagnostic biomarker for lung adenocarcinoma, J. Transl. Med., 17 (2019), 50. doi: 10.1186/s12967-019-1800-z
|
| [20] |
S. Xia, J. Feng, K. Chen, Y. Ma, J. Gong, F. Cai, et al., CSCD: a database for cancer-specific circular RNAs, Nucleic Acids Res., 46 (2018), D925-D929. doi: 10.1093/nar/gkx863
|
| [21] |
C. H. Chou, S. Shrestha, C. D. Yang, N. W. Chang, Y. L. Lin, K. W. Liao, et al., miRTarBase update 2018: a resource for experimentally validated microRNA-target interactions, Nucleic Acids Res., 46 (2018), D296-D302. doi: 10.1093/nar/gkx1067
|
| [22] |
V. Agarwal, G. W. Bell, J. W. Nam, D. P. Bartel, Predicting effective microRNA target sites in mammalian mRNAs, eLife, 4 (2015), e05005. doi: 10.7554/eLife.05005
|
| [23] |
P. Shannon, A. Markiel, O. Ozier, N. S. Baliga, J. T. Wang, D. Ramage, et al., Cytoscape: a software environment for integrated models of biomolecular interaction networks, Genome Res., 13 (2003), 2498-2504. doi: 10.1101/gr.1239303
|
| [24] |
D. W. Huang, B. T. Sherman, R. A. Lempicki, Systematic and integrative analysis of large gene lists using DAVID Bioinformatics Resources, Nat. Protoc., 4 (2009), 44-57. doi: 10.1038/nprot.2008.211
|
| [25] |
D. W. Huang, B. T. Sherman, R. A. Lempicki, Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists, Nucleic Acids Res., 37 (2009), 1-13. doi: 10.1093/nar/gkn923
|
| [26] | D. Szklarczyk, A. L. Gable, D. Lyon, A. Junge, S. Wyder, J. Huerta-Cepas, et al., STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets, Nucleic Acids Res., 47 (2009), D607-D613. |
| [27] | G. D. Bader, C. W. Hogue, An automated method for finding molecular complexes in large protein interaction networks, BMC Bioinf.. 4 (2003). |
| [28] |
Z. Tang, C. Li, B. Kang, G. Gao, C. Li, Z. Zhang, GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses, Nucleic Acids Res., 45 (2017), W98-W102. doi: 10.1093/nar/gkx247
|
| [29] |
D. S. Chandrashekar, B. Bashel, S. A. H. Balasubramanya, C. J. Creighton, I. Ponce-Rodriguez, B. V. Chakravarthi, et al., UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses, Neoplasia., 19 (2017), 649-658. doi: 10.1016/j.neo.2017.05.002
|
| [30] |
Z. R. Zhou, W. W. Wang, Y. Li, K. R. Jin, X. Y. Wang, Z. W. Wang, et al., In-depth mining of clinical data: the construction of clinical prediction model with R, Ann. Transl. Med., 7 (2019), 796. doi: 10.21037/atm.2019.08.63
|
| [31] |
Y. Zhang, H. Yao, Y. Li, L. Yang, L. Zhang, J. Chen, et al., Circular RNA TADA2A promotes proliferation and migration via modulating of miR-638/KIAA0101 signal in non-small cell lung cancer, Oncol. Rep., 46 (2021), 201. doi: 10.3892/or.2021.8152
|
| [32] |
H. Zhao, H. Wei, J. He, D. Wang, W. Li, Y. Wang, et al., Propofol disrupts cell carcinogenesis and aerobic glycolysis by regulating circTADA2A/miR-455-3p/FOXM1 axis in lung cancer, Cell Cycle, 19 (2020), 2538-2552. doi: 10.1080/15384101.2020.1810393
|
| [33] | Z. Wu, M. Zheng, Y. Zhang, M. Xie, S. Tian, T. Ding, et al., Hsa_circ_0043278 functions as competitive endogenous RNA to enhance glioblastoma multiforme progression by sponging miR-638, Aging (Albany NY), 12 (2020), 21114-21128. |
| [34] |
C. Liu, T. Han, Y. Shi, The decreased expression of hsa_circ_0043278 and its relationship with clinicopathological features of breast cancer, Gland Surg., 9 (2020), 2044-2053. doi: 10.21037/gs-20-825
|
| [35] |
F. Tian, C. T. Yu, W. D. Ye, Q. Wang, Cinnamaldehyde induces cell apoptosis mediated by a novel circular RNA hsa_circ_0043256 in non-small cell lung cancer, Biochem. Biophys. Res. Commun., 493 (2017), 1260-1266. doi: 10.1016/j.bbrc.2017.09.136
|
| [36] |
Q. Wang, T. Wang, Y. Hu, W. Jiang, C. Lu, W. Zheng, et al., Circ-EIF4G3 promotes the development of gastric cancer by sponging miR-335, Pathol., Res. Pract., 215 (2019), 152507. doi: 10.1016/j.prp.2019.152507
|
| [37] |
W. Zhang, Z. Wang, G. Cai, P. Huang, Circ_DOCK1 regulates USP11 through miR-132-3p to control colorectal cancer progression, World J. Surg. Oncol., 19 (2021), 67. doi: 10.1186/s12957-021-02173-x
|
| [38] | L. G. Di, C. M. Croce, miRNA profiling of cancer, Curr. Opin. Genet. Dev., 23 (2013), 3-11. |
| [39] | R. Q. He, L. Gao, J. Ma, Z. Y. Li, X. H. Hu, G.Chen, Oncogenic role of miR-183-5p in lung adenocarcinoma: A comprehensive study of qPCR, in vitro experiments and bioinformatic analysis, Oncol. Rep., 40 (2018), 83-100. |
| [40] |
Y. Lin, Q. Gu, Z. Sun, B. Sheng, C. Qi, B. Liu, et al., Upregulation of miR-3607 promotes lung adenocarcinoma proliferation by suppressing APC expression, Biomed. Pharmacother., 95 (2017), 497-503. doi: 10.1016/j.biopha.2017.08.052
|
| [41] |
Y. L. Wan, H. J. Dai, W. Liu, H. T. Ma, miR-767-3p inhibits growth and migration of lung adenocarcinoma cells by regulating CLDN18, Oncol. Res., 26(2018), 637-644. doi: 10.3727/096504017X15112639918174
|
| [42] |
X. Wu, T. Liu, O. Fang, W. Dong, F. Zhang, L. Leach, et al., MicroRNA-708-5p acts as a therapeutic agent against metastatic lung cancer, Oncotarget., 7(2016), 2417-2432. doi: 10.18632/oncotarget.6594
|
| [43] |
W. Zhou, R. Li, microRNA-605 inhibits the oncogenicity of non-small-cell lung cancer by directly targeting Forkhead Box P1, Onco Targets Ther., 12 (2019), 3765-3777. doi: 10.2147/OTT.S193675
|
| [44] |
Y. Wei, Y. Liao, Y. Deng, Y. Zu, B. Zhao, F. Li, MicroRNA-503 inhibits non-small cell lung cancer progression by targeting PDK1/PI3K/AKT pathway, Onco Targets Ther., 12 (2019), 9005-9016. doi: 10.2147/OTT.S213059
|
| [45] |
G. Fan, J. Jiao, F. Shen, Q. Ren, Q. Wang, F. Chu, Long non-coding RNA HCG11 sponging miR-522-3p inhibits the tumorigenesis of non-small cell lung cancer by upregulating SOCS5, Thorac. Cancer., 11 (2020), 2877-2886. doi: 10.1111/1759-7714.13624
|
| [46] |
W. Han, L. Wang, L. Zhang, Y. Wang, Y. Li, Circular RNA circ-RAD23B promotes cell growth and invasion by miR-593-3p/CCND2 and miR-653-5p/TIAM1 pathways in non-small cell lung cancer, Biochem. Biophys. Res. Commun., 510 (2019), 462-466. doi: 10.1016/j.bbrc.2019.01.131
|
| [47] |
J. H. Li, S. S. Sun, N. Li, P. Lv, S. Y. Xie, P. Y. Wang, MiR-205 as a promising biomarker in the diagnosis and prognosis of lung cancer, Oncotarget., 8 (2017), 91938-91949. doi: 10.18632/oncotarget.20262
|
| [48] |
D. B. Mendonça, J. T. Nguyen, F. Haidar, A. L. Fox, C. Ray, H. Amatullah, et al., MicroRNA-1911-3p targets mEAK-7 to suppress mTOR signaling in human lung cancer cells, Heliyon, 6 (2020), e05734. doi: 10.1016/j.heliyon.2020.e05734
|
| [49] |
B. R. Druliner, J. A. Fincher, B. S. Sexton, D. L. Vera, M. Roche, S. Lyle, et al., Chromatin patterns associated with lung adenocarcinoma progression, Cell Cycle, 12 (2013), 1536-43. doi: 10.4161/cc.24664
|
| [50] |
T. Eguchi, K. Kadota, J. Chaft, B. Evans, J. Kidd, K. S. Tan, et al., Cell cycle progression score is a marker for five-year lung cancer-specific mortality risk in patients with resected stage I lung adenocarcinoma, Oncotarget, 7 (2016), 35241-35256. doi: 10.18632/oncotarget.9129
|
| [51] |
J. Zhu, H. Ao, M. Liu, K. Cao, J. Ma, UBE2T promotes autophagy via the p53/AMPK/mTOR signaling pathway in lung adenocarcinoma, J. Transl. Med., 19 (2021), 374. doi: 10.1186/s12967-021-03056-1
|
| [52] |
Y. Tian, X. Tian, X. Han, Y. Chen, C. Y. Song, Y. B. Zhang, et al., Expression of ATP binding cassette E1 enhances viability and invasiveness of lung adenocarcinoma cells in vitro, Mol. Med. Rep., 14 (2016), 1345-50. doi: 10.3892/mmr.2016.5388
|
| [53] |
C. C. Wang, Y. L. Hsu, C. J. Chang, C. J. Wang, T. H. Hsiao, S. H. Pan, Inhibitor of DNA-binding protein 4 suppresses cancer metastasis through the regulation of epithelial mesenchymal transition in lung adenocarcinoma, Cancers, 11(2019), 2021. doi: 10.3390/cancers11122021
|
 mbe-18-06-481-supplementary.zip |
 |
Figures(8) / Tables(2)
Pingping Song, Jing Chen, Xu Zhang, Xiaofeng Yin. Construction of competitive endogenous RNA network related to circular RNA and prognostic nomogram model in lung adenocarcinoma[J]. Mathematical Biosciences and Engineering, 2021, 18(6): 9806-9821. doi: 10.3934/mbe.2021481
DownLoad: