To date, few studies have investigated whether the RNA-editing enzymes adenosine deaminases acting on RNA (ADARs) influence RNA functioning in lung adenocarcinoma (LUAD). To investigate the role of ADAR in lung cancer, we leveraged the advantages of The Cancer Genome Atlas (TCGA) database, from which we obtained transcriptome data and clinical information from 539 patients with LUAD. First, we compared ARAR expression levels in LUAD tissues with those in normal lung tissues using paired and unpaired analyses. Next, we evaluated the influence of ADARs on multiple prognostic indicators, including overall survival at 1, 3 and 5 years, as well as disease-specific survival and progression-free interval, in patients with LUAD. We also used Kaplan-Meier survival curves to estimate overall survival and Cox regression analysis to assess covariates associated with prognosis. A nomogram was constructed to validate the impact of the ADARs and clinicopathological factors on patient survival probabilities. The volcano plot and heat map revealed the differentially expressed genes associated with ADARs in LUAD. Finally, we examined ADAR expression versus immune cell infiltration in LUAD using Spearman's analysis. Using the Gene Expression Profiling Interactive Analysis (GEPIA2) database, we identified the top 100 genes most significantly correlated with ADAR expression, constructed a protein-protein interaction network and performed a Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analysis on these genes. Our results demonstrate that ADARs are overexpressed in LUAD and correlated with poor patient prognosis. ADARs markedly increase the infiltration of T central memory, T helper 2 and T helper cells, while reducing the infiltration of immature dendritic, dendritic and mast cells. Most immune response markers, including T cells, tumor-associated macrophages, T cell exhaustion, mast cells, macrophages, monocytes and dendritic cells, are closely correlated with ADAR expression in LUAD.
Citation: Siqi Hu, Fang Wang, Junjun Yang, Xingxiang Xu. Elevated ADAR expression is significantly linked to shorter overall survival and immune infiltration in patients with lung adenocarcinoma[J]. Mathematical Biosciences and Engineering, 2023, 20(10): 18063-18082. doi: 10.3934/mbe.2023802
To date, few studies have investigated whether the RNA-editing enzymes adenosine deaminases acting on RNA (ADARs) influence RNA functioning in lung adenocarcinoma (LUAD). To investigate the role of ADAR in lung cancer, we leveraged the advantages of The Cancer Genome Atlas (TCGA) database, from which we obtained transcriptome data and clinical information from 539 patients with LUAD. First, we compared ARAR expression levels in LUAD tissues with those in normal lung tissues using paired and unpaired analyses. Next, we evaluated the influence of ADARs on multiple prognostic indicators, including overall survival at 1, 3 and 5 years, as well as disease-specific survival and progression-free interval, in patients with LUAD. We also used Kaplan-Meier survival curves to estimate overall survival and Cox regression analysis to assess covariates associated with prognosis. A nomogram was constructed to validate the impact of the ADARs and clinicopathological factors on patient survival probabilities. The volcano plot and heat map revealed the differentially expressed genes associated with ADARs in LUAD. Finally, we examined ADAR expression versus immune cell infiltration in LUAD using Spearman's analysis. Using the Gene Expression Profiling Interactive Analysis (GEPIA2) database, we identified the top 100 genes most significantly correlated with ADAR expression, constructed a protein-protein interaction network and performed a Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analysis on these genes. Our results demonstrate that ADARs are overexpressed in LUAD and correlated with poor patient prognosis. ADARs markedly increase the infiltration of T central memory, T helper 2 and T helper cells, while reducing the infiltration of immature dendritic, dendritic and mast cells. Most immune response markers, including T cells, tumor-associated macrophages, T cell exhaustion, mast cells, macrophages, monocytes and dendritic cells, are closely correlated with ADAR expression in LUAD.
| [1] |
C. Jin, G. K. Lagoudas, C. Zhao, S. Bullman, A. Bhutkar, B. Hu, et al., Commensal microbiota promote lung cancer development via γδ T cells, Cell, 176 (2019), 998–1013. https://doi.org/10.1016/j.cell.2018.12.040 doi: 10.1016/j.cell.2018.12.040
|
| [2] |
J. Huo, Y. Xu, T. Sheu, R. J. Volk, Y. T. Shih, Complication rates and downstream medical costs associated with invasive diagnostic procedures for lung abnormalities in the community setting, JAMA Int. Med., 179 (2019), 324–332. https://doi.org/10.1001/jamainternmed.2018.6277 doi: 10.1001/jamainternmed.2018.6277
|
| [3] |
R. K. Meleppat, C. R. Fortenbach, Y. Jian, E. S. Martinez, K. Wagner, B. S. Modjtahedi, et al., In vivo imaging of retinal and choroidal morphology and vascular plexuses of vertebrates using swept-source optical coherence tomography, Transl. Vis. Sci. Technol., 11 (2022), 11. https://doi.org/10.1167/tvst.11.8.11 doi: 10.1167/tvst.11.8.11
|
| [4] |
R. K. Meleppat, K. E. Ronning, S. J. Karlen, M. E. Burns, E. N. Pugh, R. J. Zawadzki, In vivo multimodal retinal imaging of disease-related pigmentary changes in retinal pigment epithelium, Sci. Rep., 11 (2021), 16252. https://doi.org/10.1038/s41598-021-95320-z doi: 10.1038/s41598-021-95320-z
|
| [5] |
K. S. Blandin, P. A. Crosbie, H. Balata, J. Chudziak, T. Hussell, C. Dive, Progress and prospects of early detection in lung cancer, Open Biol., 7 (2017), 170070. https://doi.org/10.1098/rsob.170070 doi: 10.1098/rsob.170070
|
| [6] |
P. C. Hoffman, A. M. Mauer, E. E. Vokes, Lung cancer, Lancet, 355 (2000), 479–485. https://doi.org/10.1016/S0140-6736(00)82038-3 doi: 10.1016/S0140-6736(00)82038-3
|
| [7] |
S. M. Park, E. Y. Choi, M. Bae, S. Kim, J. B. Park, H. Yoo, et al., Histone variant H3F3A promotes lung cancer cell migration through intronic regulation, Nat. Commun., 7 (2016), 12914. https://doi.org/10.1038/ncomms12914 doi: 10.1038/ncomms12914
|
| [8] |
B. L. Bass, RNA editing by adenosine deaminases that act on RNA, Annu. Rev. Biochem., 71 (2002), 817–846. https://doi.org/10.1146/annurev.biochem.71.110601.135501 doi: 10.1146/annurev.biochem.71.110601.135501
|
| [9] |
L. Bazak, A. Haviv, M. Barak, J. H. Jacob, P. Deng, R. Zhang, et al., A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes, Genome Res., 24 (2014), 365–376. https://doi.org/10.1101/gr.164749.113 doi: 10.1101/gr.164749.113
|
| [10] |
K. Licht, U. Kapoor, F. Amman, E. Picardi, D. Martin, P. Bajad, et al., A high resolution A-to-I editing map in the mouse identifies editing events controlled by pre-mRNA splicing, Genome Res., 29 (2019), 1453–1463. https://doi.org/10.1101/gr.242636.118 doi: 10.1101/gr.242636.118
|
| [11] |
K. Pestal, C. C. Funk, J. M. Snyder, N. D. Price, P. M. Treuting, D. B. Stetson, Isoforms of RNA-editing enzyme adar1 independently control nucleic acid sensor MDA5-driven autoimmunity and multi-organ development, Immunity, 43 (2015), 933–944. https://doi.org/10.1016/j.immuni.2015.11.001 doi: 10.1016/j.immuni.2015.11.001
|
| [12] |
B. J. Liddicoat, A. M. Chalk, C. R. Walkley, ADAR1, inosine and the immune sensing system: distinguishing self from non-self, Wiley. Interdiscip. Rev. RNA., 7 (2016), 157–172. https://doi.org/10.1002/wrna.1322 doi: 10.1002/wrna.1322
|
| [13] |
B. J. Liddicoat, R. Piskol, A. M. Chalk, G. Ramaswami, M. Higuchi, J. C. Hartner, et al., RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself, Science, 349 (2015), 1115–1120. https://doi.org/10.1126/science.aac7049 doi: 10.1126/science.aac7049
|
| [14] |
G. I. Rice, P. R. Kasher, G. M. Forte, N. M. Mannion, S. M. Greenwood, M. Szynkiewicz, et al., Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type Ⅰ interferon signature, Nat. Genet., 44 (2012), 1243–1248. https://doi.org/10.1038/ng.2414 doi: 10.1038/ng.2414
|
| [15] |
Y. Miyamura, T. Suzuki, M. Kono, K. Inagaki, S. Ito, N. Suzuki, et al., Mutations of the RNA-specific adenosine deaminase gene (DSRAD) are involved in dyschromatosis symmetrica hereditaria, Am. J. Hum. Genet., 73 (2003), 693–699. https://doi.org/10.1086/378209 doi: 10.1086/378209
|
| [16] |
X. J. Zhang, P. P. He, M. Li, C. D. He, K. L. Yan, Y. Cui, et al., Seven novel mutations of the ADAR gene in Chinese families and sporadic patients with dyschromatosis symmetrica hereditaria (DSH), Hum. Mutat., 23 (2004), 629–630. https://doi.org/10.1002/humu.9246 doi: 10.1002/humu.9246
|
| [17] |
T. H. Chan, C. H. Lin, L. Qi, J. Fei, Y. Li, K. J. Yong, et al., A disrupted RNA editing balance mediated by ADARs (Adenosine De Aminases that act on RNA) in human hepatocellular carcinoma, Gut, 63 (2014), 832–843. https://doi.org/10.1136/gutjnl-2012-304037 doi: 10.1136/gutjnl-2012-304037
|
| [18] |
L. Han, L. Diao, S. Yu, X. Xu, J. Li, R. Zhang, et al., The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers, Cancer Cell, 28 (2015), 515–528. https://doi.org/10.1016/j.ccell.2015.08.013 doi: 10.1016/j.ccell.2015.08.013
|
| [19] |
X. Peng, X. Xu, Y, Wang, D. H. Hawke, S. Yu, L. Han, et al., A-to-I RNA editing contributes to proteomic diversity in cancer, Cancer Cell, 35 (2018), 817–828. https://doi.org/10.1016/j.ccell.2018.03.026 doi: 10.1016/j.ccell.2018.03.026
|
| [20] |
H. Liu, J. Golji, L. K. Brodeur, F. S. Chung, J. T. Chen, R. S. deBeaumont, et al., Tumor-derived IFN triggers chronic pathway agonism and sensitivity to ADAR loss, Nat. Med., 25 (2019), 95–102. https://doi.org/10.1038/s41591-018-0302-5 doi: 10.1038/s41591-018-0302-5
|
| [21] |
J. J. Ishizuka, R. T. Manguso, C. K. Cheruiyot, K. Bi, A. Panda, A. V. Iracheta, et al., Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade, Nature, 565 (2019), 43–48. https://doi.org/10.1038/s41586-018-0768-9 doi: 10.1038/s41586-018-0768-9
|
| [22] |
K. Fritzell, L. D. Xu, M. Otrocka, C. Andréasson, M. Öhman, Sensitive ADAR editing reporter in cancer cells enables high-throughput screening of small molecule libraries, Nucleic Acids Res., 47 (2019), 22. https://doi.org/10.1093/nar/gky1228 doi: 10.1093/nar/gky1228
|
| [23] |
J. Vivian, A. A. Rao, F. A. Nothaft, C. Ketchum, J. Armstrong, A. Novak, et al., Toil enables reproducible, open source, big biomedical data analyses, Nat. Biotechnol., 35 (2017), 314–316. https://doi.org/10.1038/nbt.3772 doi: 10.1038/nbt.3772
|
| [24] |
M. Uhlén, L. Fagerberg, B. M. Hallström, C. Lindskog, P. Oksvold, A. Mardinoglu, et al., Tissue-based map of the human proteome, Science, 347 (2015), 1260419. https://doi.org/10.1126/science.1260419 doi: 10.1126/science.1260419
|
| [25] |
S. Hänzelmann, R. Castelo, J. Guinney, GSVA: Gene set variation analysis for microarray and RNA-seq data, BMC. Bioinf., 14 (2013), 7. https://doi.org/10.1186/1471-2105-14-7 doi: 10.1186/1471-2105-14-7
|
| [26] |
Z. Tang, B. Kang, C. Li, T. Chen, Z. Zhang, GEPIA2: An enhanced web server for large-scale expression profiling and interactive analysis, Nucleic Acids Res., 47 (2019), w556–w560. https://doi.org/10.1093/nar/gkz430 doi: 10.1093/nar/gkz430
|
| [27] |
R. S. Herbst, J. V. Heymach, S. M. Lippman, Lung cancer, N. Engl. J. Med., 359 (2008), 1367–1380. https://doi.org/10.1056/NEJMra0802714 doi: 10.1056/NEJMra0802714
|
| [28] |
B. J. Booth, S. Nourreddine, D. Katrekar, Y. Savva, D. Bose, T. J. Long, et al., RNA editing: Expanding the potential of RNA therapeutics, Mol. Ther., 31 (2023), 533–549. https://doi.org/10.1016/j.ymthe.2023.01.005 doi: 10.1016/j.ymthe.2023.01.005
|
| [29] |
B. Song, Y. Shiromoto, M. Minakuchi, K. Nishikura, The role of RNA editing enzyme ADAR1 in human disease, Wiley. Interdiscip. Rev. RNA, 13 (2022), 1665. https://doi.org/10.1002/wrna.1665 doi: 10.1002/wrna.1665
|
| [30] |
J. Quin, J. Sedmík, D. Vukić, A. Khan, L. P. Keegan, M. A. O'Connell, ADAR RNA modifications, the epitranscriptome and innate immunity, Trends. Biochem. Sci., 46 (2021), 758–771. https://doi.org/10.1016/j.tibs.2021.02.002 doi: 10.1016/j.tibs.2021.02.002
|
| [31] |
G. Lev-Maor, R. Sorek, E. Y. Levanon, N. Paz, E. Eisenberg, G. Ast, RNA-editing-mediated exon evolution, Genome Biol., 8 (2007), 29. https://doi.org/10.1186/gb-2007-8-2-r29 doi: 10.1186/gb-2007-8-2-r29
|
| [32] |
L. Chen, Y. Li, C. H. Lin, T. H. Chan, R. K. Chow, Y. Song, et al., Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma, Nat. Med., 19 (2013), 209–216. https://doi.org/10.1038/nm.3043 doi: 10.1038/nm.3043
|
| [33] |
S. Takeda, K. Shigeyasu, Y. Okugawa, K. Yoshida, Y. Mori, S. Yano, et al., Activation of AZIN1 RNA editing is a novel mechanism that promotes invasive potential of cancer-associated fibroblasts in colorectal cancer, Cancer Lett., 444 (2019), 127–135. https://doi.org/10.1016/j.canlet.2018.12.009 doi: 10.1016/j.canlet.2018.12.009
|
| [34] |
Y. Li, N. X. Wang, C. Yin, S. S. Jiang, J. C. Li, S. Y. Yang, RNA editing enzyme ADAR1 regulates METTL3 in an editing dependent manner to promote breast cancer progression via METTL3/ARHGAP5/YTHDF1 Axis, Int. J. Mol. Sci., 23 (2022), 9656. https://doi.org/10.3390/ijms23179656 doi: 10.3390/ijms23179656
|
| [35] |
B. A. Chua, D. W. Van, C. Jamieson, R. A. J. Signer, Post-Transcriptional regulation of homeostatic, stressed, and malignant stem cells, Cell. Stem. Cell., 26 (2020), 138–159. https://doi.org/10.1016/j.stem.2020.01.005 doi: 10.1016/j.stem.2020.01.005
|
| [36] |
D. A. Silvestris, C. Scopa, S. Hanchi, F. Locatelli, A. Gallo, De Novo A-to-I RNA editing discovery in lncRNA, Cancers (Basel), 12 (2020), 2959. https://doi.org/10.3390/cancers12102959 doi: 10.3390/cancers12102959
|
| [37] |
L. Nair, H. Chung, U. Basu, Regulation of long non-coding RNAs and genome dynamics by the RNA surveillance machinery, Nat. Rev. Mol. Cell. Biol., 21 (2020), 123–136. https://doi.org/10.1038/s41580-019-0209-0 doi: 10.1038/s41580-019-0209-0
|
| [38] |
H. Wang, S. Chen, J. Wei, G. Song, Y. Zhao, A-to-I RNA editing in cancer: From evaluating the editing level to exploring the editing effects, Front Oncol., 10 (2020), 632187. https://doi.org/10.3389/fonc.2020.632187 doi: 10.3389/fonc.2020.632187
|
| [39] |
J. M. Ramírez, A. R. Baker, F. J. Slack, P. Santisteban, ADAR1-mediated RNA editing is a novel oncogenic process in thyroid cancer and regulates miR-200 activity, Oncogene, 39 (2020), 3738–3753. https://doi.org/10.1038/s41388-020-1248-x doi: 10.1038/s41388-020-1248-x
|
| [40] |
P. R. de Santiago, A. Blanco, F. Morales, K. Marcelain, O. Harismendy, M. H. Sjöberg, et al., Immune-related IncRNA LINC00944 responds to variations in ADAR1 levels and it is associated with breast cancer prognosis, Life Sci., 268 (2021), 118956. https://doi.org/10.1016/j.lfs.2020.118956 doi: 10.1016/j.lfs.2020.118956
|
| [41] |
C. Ma, X. Wang, F. Yang, Y. Zang, J. Liu, X. Wang, et al., Circular RNA HSA_CIRC_0004872 inhibits gastric cancer progression via the miR-224/Smad4/ADAR1 successive regulatory circuit, Mol. Cancer, 19 (2020), 157. https://doi.org/10.1186/s12943-020-01268-5 doi: 10.1186/s12943-020-01268-5
|
| [42] |
T. Zhang, C. Yin, A. Fedorov, L. Qiao, H. Bao, N. Beknazarov, et al., ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis, Nature, 606 (2022), 594–602. https://doi.org/10.1038/s41586-022-04753-7 doi: 10.1038/s41586-022-04753-7
|
| [43] |
M. C. Garassino, S. Gadgeel, E. Esteban, E. Felip, G. Speranza, M. Domine, et al., Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): A multicentre, double-blind, randomised, placebo-controlled, phase 3 trial, Lancet Oncol., 21 (2020), 387–397. https:/doi.org/10.1016/s1470-2045(19)30801-0 doi: 10.1016/S1470-2045(19)30801-0
|
| [44] |
D. Fujimoto, S. Miura, K. Yoshimura, K. Wakuda, Y. Oya, T. Yokoyama, et al., Pembrolizumab plus chemotherapy-induced pneumonitis in chemo-naïve patients with non-squamous non-small cell lung cancer: A multicentre, retrospective cohort study, Eur. J. Cancer, 150 (2021), 63–72. https://doi.org/10.1016/j.ejca.2021.03.016 doi: 10.1016/j.ejca.2021.03.016
|
| [45] |
Z. Tang, T. Zhang, B. Yang, J. Su, Q. Song, spaCI: deciphering spatial cellular communications through adaptive graph model, Brief Bioinform., 24 (2023), bbac563. https://doi.org/10.1093/bib/bbac563 doi: 10.1093/bib/bbac563
|
Figures(9) / Tables(2)
Siqi Hu, Fang Wang, Junjun Yang, Xingxiang Xu. Elevated ADAR expression is significantly linked to shorter overall survival and immune infiltration in patients with lung adenocarcinoma[J]. Mathematical Biosciences and Engineering, 2023, 20(10): 18063-18082. doi: 10.3934/mbe.2023802
DownLoad: