Abstract
Long non-coding RNAs (lncRNAs) appear to be the crucial modulators in various processes and critically influence the oncogenesis. As one of the LncRNAs, LncRNA CCAT1 has been reported to be closely associated with the progression multiple cancers, but its role in modulating the radioresistance of lung adenocarcinoma (LUAD) remains unclear. In our present study, we screened the potential radioresistance related LncRNAs in LUAD based on the data from The Cancer Genome Atlas (TCGA) database. Data suggested that CCAT1 was abundantly expressed in LUAD and CCAT1 was significantly associated with poor prognosis and radioresistance. Moreover, our in vitro experiments showed that radiation treatment could trigger elevated expression of CCAT1 in the human LUAD cell lines. Further loss/gain-of-function investigations indicated that CCAT1 knockdown significantly inhibited cell proliferation, migration and promoted cell apoptosis in NCI-H1299 cells under irradiation, whereas CCAT1 overexpression in A549 cells yield the opposite effects. In summary, we identified the promoting role of CCAT1 in radioresistance of LUAD, which may provide a theoretical basis for radiotherapy sensitization of LUAD.
Similar content being viewed by others
Data availability
The data generated in this study are available within the article and its supplementary data files.
References
Ali T, Grote P (2020) Beyond the RNA-dependent function of LncRNA genes. Elife 9
Allen KT, Chin-Sinex H, DeLuca T, Pomerening JR, Sherer J, Watkins JB III, Foley J, Jesseph JM, Mendonca MS (2015) Dichloroacetate alters Warburg metabolism, inhibits cell growth, and increases the X-ray sensitivity of human A549 and H1299 NSC lung cancer cells. Free Radic Biol Med 89:263–273
Belgioia L, Desideri I, Errico A, Franzese C, Daidone A, Marino L, Fiore M, Borghetti P, Greto D, Fiorentino A et al (2019) Safety and efficacy of combined radiotherapy, immunotherapy and targeted agents in elderly patients: a literature review. Crit Rev Oncol Hematol 133:163–170
Bi Z, Li Q, Dinglin X, Xu Y, You K, Hong H, Hu Q, Zhang W, Li C, Tan Y et al (2020) Nanoparticles (NPs)-Meditated LncRNA AFAP1-AS1 silencing to block Wnt/beta-Catenin signaling pathway for synergistic reversal of radioresistance and effective cancer radiotherapy. Adv Sci (Weinh) 7(18):2000915
Blighe K, Rana S, Lewis M (2019) EnhancedVolcano: Publication-ready volcano plots with enhanced colouring and labeling. R package version 1(0). https://bioconductor.org/packages/release/bioc/vignettes/EnhancedVolcano/inst/doc/EnhancedVolcano.html
Chen Y, Li WW, Peng P, Zhao WH, Tian YJ, Huang Y, Xia S, Chen Y (2019) mTORC1 inhibitor RAD001 (everolimus) enhances non-small cell lung cancer cell radiosensitivity in vitro via suppressing epithelial-mesenchymal transition. Acta Pharmacol Sin 40(8):1085–1094
Chen J, Liu A, Wang Z, Wang B, Chai X, Lu W, Cao T, Li R, Wu M, Lu Z et al (2020) LINC00173.v1 promotes angiogenesis and progression of lung squamous cell carcinoma by sponging mir-511-5p to regulate VEGFA expression. Mol Cancer 19(1):98
Delas MJ, Sabin LR, Dolzhenko E, Knott SR, Munera Maravilla E, Jackson BT, Wild SA, Kovacevic T, Stork EM, Zhou M et al (2017) lncRNA requirements for mouse acute myeloid leukemia and normal differentiation. Elife 6
Devarakonda S, Morgensztern D, Govindan R (2015) Genomic alterations in lung adenocarcinoma. Lancet Oncol 16(7):e342–e351
Du Y, Yuan S, Zhuang X, Zhang Q, Qiao T (2021) Multiomics differences in lung squamous cell carcinoma patients with high radiosensitivity index compared with those with low radiosensitivity index. Dis Markers 2021:p3766659
Falk AT, Hebert C, Tran A, Chand ME, Leysalle A, Thariat J, Dassonville O, Poissonnet G, Bozec A, Saada E et al (2017) Radiotherapy for elderly patients and cetuximab, a monocentric study. Eur Arch Otorhinolaryngol 274(2):1061–1065
Frankish A, Diekhans M, Ferreira AM, Johnson R, Jungreis I, Loveland J, Mudge JM, Sisu C, Wright J, Armstrong J et al (2019) GENCODE reference annotation for the human and mouse genomes. Nucleic Acids Res 47(D1):D766–D773
Guo Z, Wang YH, Xu H, Yuan CS, Zhou HH, Huang WH, Wang H, Zhang W (2021) LncRNA linc00312 suppresses radiotherapy resistance by targeting DNA-PKcs and impairing DNA damage repair in nasopharyngeal carcinoma. Cell Death Dis 12(1):69
Han F, Yang S, Wang W, Huang X, Huang D, Chen S (2020) Silencing of lncRNA LINC00857 enhances BIRC5-Dependent radio-sensitivity of lung adenocarcinoma cells by recruiting NF-kappaB1. Mol Ther Nucleic Acids 22:981–993
Herrera FG, Irving M, Kandalaft LE, Coukos G (2019) Rational combinations of immunotherapy with radiotherapy in ovarian cancer. Lancet Oncol 20(8):e417–e433
Hirsch FR, Scagliotti GV, Mulshine JL, Kwon R, Curran WJ Jr, Wu YL, Paz-Ares L (2017) Lung cancer: current therapies and new targeted treatments. Lancet 389(10066):299–311
Hu B, Zhang H, Wang Z, Zhang F, Wei H, Li L (2017) LncRNA CCAT1/miR-130a-3p axis increases cisplatin resistance in non-small-cell lung cancer cell line by targeting SOX4. Cancer Biol Ther 18(12):974–983
Kitagawa M, Kitagawa K, Kotake Y, Niida H, Ohhata T (2013) Cell cycle regulation by long non-coding RNAs. Cell Mol Life Sci 70(24):4785–4794
Lai C, Zhang J, Tan Z, Shen LF, Zhou RR, Zhang YY (2021) Maf1 suppression of ATF5-dependent mitochondrial unfolded protein response contributes to rapamycin-induced radio-sensitivity in lung cancer cell line A549. Aging 13(5):7300–7313
Li Z, Jiang D, Yang S (2020) MiR-490-3p inhibits the malignant progression of lung adenocarcinoma. Cancer Manag Res 12:10975–10984
Lin H, Cheng W, Yan H, Zhang X (2018) Overexpression of the long noncoding RNA CCAT1 promotes metastasis via epithelial-to-mesenchymal transition in lung adenocarcinoma. Oncol Lett 16(2):1809–1814
Liu Y, Ji Y, Qiu P (2013) Identification of thresholds for dichotomizing DNA methylation data. EURASIP J Bioinform Syst Biol 2013(1):8
Liu J, Lichtenberg T, Hoadley KA, Poisson LM, Lazar AJ, Cherniack AD, Kovatich AJ, Benz CC, Levine DA, Lee AV et al (2018) An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics. Cell 173(2):400-416.e411
Love MI, Huber W, Anders S (2014) Moderated estimation of Fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15(12):550
Matter MS, Chijioke O, Savic S, Bubendorf L (2020) Narrative review of molecular pathways of kinase fusions and diagnostic approaches for their detection in non-small cell lung carcinomas. Transl Lung Cancer Res 9(6):2645–2655
Nakadate Y, Kodera Y, Kitamura Y, Tachibana T, Tamura T, Koizumi F (2013) Silencing of poly(ADP-ribose) glycohydrolase sensitizes lung cancer cells to radiation through the abrogation of DNA damage checkpoint. Biochem Biophys Res Commun 441(4):793–798
Ozpiskin OM, Zhang L, Li JJ (2019) Immune targets in the tumor microenvironment treated by radiotherapy. Theranostics 9(5):1215–1231
Palacios DA, Miyake M, Rosser CJ (2013) Radiosensitization in prostate cancer: mechanisms and targets. BMC Urol 13:4
Pang L, Zhang Q, Wu Y, Yang Q, Zhang J, Liu Y, Li R (2021) Long non-coding RNA CCAT1 promotes non-small cell lung cancer progression by regulating the miR-216a-5p/RAP2B axis. Exp Biol Med (Maywood) 246(2):142–152
Qian X, Zhao J, Yeung PY, Zhang QC, Kwok CK (2019) Revealing lncRNA structures and interactions by sequencing-based approaches. Trends Biochem Sci 44(1):33–52
Reck M, Rabe KF (2017) Precision diagnosis and treatment for advanced non-small-cell lung cancer. N Engl J Med 377(9):849–861
Russo A, Mitchell J, Kinsella T, Morstyn G, Glatstein E (1985) Determinants radiosensitivity. Semin Oncol 12(3):332–349
Sahoo D, Dill DL, Tibshirani R, Plevritis SK (2007) Extracting binary signals from microarray time-course data. Nucleic Acids Res 35(11):3705–3712
Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA Cancer J Clin 69(1):7–34
Sirey TM, Roberts K, Haerty W, Bedoya-Reina O, Rogatti-Granados S, Tan JY, Li N, Heather LC, Carter RN, Cooper S et al (2019) The long non-coding RNA Cerox1 is a post transcriptional regulator of mitochondrial complex I catalytic activity. Elife 8
Son B, Lee S, Youn H, Kim E, Kim W, Youn B (2017) The role of tumor microenvironment in therapeutic resistance. Oncotarget 8(3):3933–3945
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102(43):15545–15550
Tan WL, Jain A, Takano A, Newell EW, Iyer NG, Lim WT, Tan EH, Zhai W, Hillmer AM, Tam WL et al (2016) Novel therapeutic targets on the horizon for lung cancer. Lancet Oncol 17(8):e347–e362
Thakur SK, Singh DP, Choudhary J (2020) Lung cancer identification: a review on detection and classification. Cancer Metastasis Rev 39(3):989–998
Tomczak K, Czerwinska P, Wiznerowicz M (2015) The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol (Pozn) 19(1A):A68-77
Wang S, Zimmermann S, Parikh K, Mansfield AS, Adjei AA (2019) Current diagnosis and management of small-cell Lung Cancer. Mayo Clin Proc 94(8):1599–1622
Wang Y, Huang L, Wang Y, Luo W, Li F, Xiao J, Qin S, Wang Z, Song X, Wang Y et al (2020a) Single-cell RNA-sequencing analysis identifies host long noncoding RNA MAMDC2-AS1 as a co-factor for HSV-1 nuclear transport. Int J Biol Sci 16(9):1586–1603
Wang C, Chen F, Fan Z, Yao C, Xiao L (2020b) lncRNA CCAT1/miR-490-3p/MAPK1/c-Myc positive feedback loop drives progression of acute myeloid leukaemia. J Biochem 167(4):379–388
Wang W, Hou Z, Wen C, Ge L, Ge L (2020c) Long non-coding RNA colon cancer-associated transcript-1 promotes migration, invasion, and epithelial mesenchymal transition of lung adenocarcinoma by suppressing miR-219-1. Front Genet 11:929
Wang J, Sun N, Han W, Tong L, Xu T, Li G (2021) Long non-coding RNA CCAT1 sponges miR-490 to enhance cell proliferation and migration of non-small cell lung cancer. Thorac Cancer 12(3):364–371
Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z, Feng T, Zhou L, Tang W, Zhan L et al (2021) clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innov (N Y) 2(3):100141
Yang Y, Shen F, Huang W, Qin S, Huang JT, Sergi C, Yuan BF, Liu SM (2019) Glucose is involved in the dynamic regulation of m6A in patients with type 2 diabetes. J Clin Endocrinol Metab 104(3):665–673
Yang WC, Hsu FM, Yang PC (2020) Precision radiotherapy for non-small cell lung cancer. J Biomed Sci 27(1):82
Yesner R (2001) Heterogeneity of so-called neuroendocrine lung tumors. Exp Mol Pathol 70(3):179–182
You Z, Liu C, Wang C, Ling Z, Wang Y, Wang Y, Zhang M, Chen S, Xu B, Guan H et al (2019) LncRNA CCAT1 promotes prostate cancer cell proliferation by interacting with DDX5 and MIR-28-5P. Mol Cancer Ther 18(12):2469–2479
Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, Liu F, Pan W, Wang TT, Zhou CC et al (2014) A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell 25(5):666–681
Zhang E, Han L, Yin D, He X, Hong L, Si X, Qiu M, Xu T, De W, Xu L et al (2017) H3K27 acetylation activated-long non-coding RNA CCAT1 affects cell proliferation and migration by regulating SPRY4 and HOXB13 expression in esophageal squamous cell carcinoma. Nucleic Acids Res 45(6):3086–3101
Zhang J, Bai R, Li M, Ye H, Wu C, Wang C, Li S, Tan L, Mai D, Li G et al (2019) Excessive mir-25-3p maturation via N(6)-methyladenosine stimulated by cigarette smoke promotes pancreatic cancer progression. Nat Commun 10(1):1858
Zhang H, Guo L, Chen J (2020a) Rationale for lung adenocarcinoma prevention and drug development based on molecular biology during carcinogenesis. Onco Targets Ther 13:3085–3091
Zhang X, Xie K, Zhou H, Wu Y, Li C, Liu Y, Liu Z, Xu Q, Liu S, Xiao D et al (2020b) Role of non-coding RNAs and RNA modifiers in cancer therapy resistance. Mol Cancer 19(1):47
Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, Benner C, Chanda SK (2019) Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 10(1):1523
Zhu J, Chen S, Yang B, Mao W, Yang X, Cai J (2019) Molecular mechanisms of lncRNAs in regulating cancer cell radiosensitivity. Biosci Rep 39(8)
Funding
This research was supported by the Haiyan Fund Project of Harbin Medical University Cancer Hospital (JJZD 2016-06).
Author information
Authors and Affiliations
Contributions
Xiangying Xu conceived and designed this research. Jian Li, Shengnan Guo and Tianhao Li performed the experiments and Songliu Hu, Jianyu Xu conducted the data analysis. Jian Li and Shengnan Guo drafted the manuscript and that was reviewed by Xiangying Xu. All the authors have confirmed the submission of this manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Li, J., Guo, S., Li, T. et al. Long non-coding RNA CCAT1 acts as an oncogene to promote radiation resistance in lung adenocarcinoma: an epigenomics-based investigation. Funct Integr Genomics 24, 52 (2024). https://doi.org/10.1007/s10142-024-01330-1
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1007/s10142-024-01330-1