Epigenetic modifications in early stage lung cancer: pathogenesis, biomarkers, and early diagnosis

Abstract

The integration of liquid biopsy with epigenetic markers offers significant potential for early lung cancer detection and personalized treatment. Epigenetic alterations, including DNA methylation, histone modifications, and noncoding RNA changes, often precede genetic mutations and are critical in cancer progression. In this study, we explore how liquid biopsy, combined with epigenetic markers, can provide early detection of lung cancer, potentially predicting onset up to 4 years before clinical diagnosis. We discuss the challenges of targeting epigenetic regulators, which could disrupt cellular balance if overexploited, and the need for maintaining key gene expressions in therapeutic applications. This review highlights the promise and challenges of using liquid biopsy and epigenetic markers for early-stage lung cancer diagnosis, with a focus on optimizing treatment strategies for personalized and precision medicine.

Keywords

DNA methylation / epigenetics / histone modification / lung cancer / noncoding RNA regulation

References

[1] Zheng RS, Chen R, Han BF, et al. [Cancer incidence and mortality in China, 2022]. Zhonghua Zhong Liu Za Zhi. 2024; 46(3): 221-231.

[2] Qiu X, Zhang H, Zhao Y, et al. Application of circulating genetically abnormal cells in the diagnosis of early-stage lung cancer. J Cancer Res Clin Oncol. 2022; 148(3): 685-695.

[3] Quaranta V, Linkous A. Organoids as a systems platform for SCLC brain metastasis. Front Oncol. 2022; 12: 881989.

[4] Gridelli C, Rossi A, Carbone DP, et al. Non-small-cell lung cancer. Nat Rev Dis Primers. 2015; 1: 15009.

[5] Qian C, Zou X, Li W, Li Y, Yu W. The outpost against cancer: universal cancer only markers. Cancer Biol Med. 2023; 20(11): 806-815.

[6] Pierce SE, Granja JM, Corces MR, et al. LKB1 inactivation modulates chromatin accessibility to drive metastatic progression. Nat Cell Biol. 2021; 23(8): 915-924.

[7] Wang Y, Douville C, Cohen JD, et al. Detection of rare mutations, copy number alterations, and methylation in the same template DNA molecules. Proc Nat Acad Sci USA. 2023; 120(15): e2220704120.

[8] Lim WH, Lee KH, Lee JH, et al. Diagnostic performance and prognostic value of CT-defined visceral pleural invasion in early-stage lung adenocarcinomas. Eur Radiol. 2024; 34(3): 1934-1945.

[9] Silvestri GA, Goldman L, Tanner NT, et al. Outcomes from more than 1 million people screened for lung cancer with low-dose CT imaging. Chest. 2023; 164(1): 241-251.

[10] Nagasaka M, Uddin MH, Al-Hallak MN, et al. Liquid biopsy for therapy monitoring in early-stage non-small cell lung cancer. Mol Cancer. 2021; 20(1): 82.

[11] Li P, Liu S, Du L, Mohseni G, Zhang Y, Wang C. Liquid biopsies based on DNA methylation as biomarkers for the detection and prognosis of lung cancer. Clinical epigenetics. 2022; 14(1): 118.

[12] Shields MD, Chen K, Dutcher G, Patel I, Pellini B. Making the rounds: exploring the role of circulating tumor DNA (ctDNA) in non-small cell lung cancer. Int J Mol Sci. 2022; 23(16): 9006.

[13] Wadowska K, Bil-Lula I, Trembecki Ł, Śliwińska-Mossoń M. Genetic markers in lung cancer diagnosis: a review. Int J Mol Sci. 2020; 21(13): 4569.

[14] Tomasetti M, Amati M, Neuzil J, Santarelli L. Circulating epigenetic biomarkers in lung malignancies: from early diagnosis to therapy. Lung cancer (Amsterdam, Netherlands)ss. 2017; 107: 65-72.

[15] Nooreldeen R, Bach H. Current and future development in lung cancer diagnosis. Int J Mol Sci. 2021; 22(16): 8661.

[16] Inamura K. Clinicopathological characteristics and mutations driving development of early lung adenocarcinoma: tumor initiation and progression. Int J Mol Sci. 2018; 19(4): 1259.

[17] Wang B, Shen XY, Pan LY, et al. The HDAC2-MTA3 interaction induces nonsmall cell lung cancer cell migration and invasion by targeting c-Myc and cyclin D1. Mol Carcinog. 2023; 62(11): 1630-1644.

[18] Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011; 6(2): 244-285.

[19] Yotsukura M, Asamura H, Motoi N, et al. Long-term prognosis of patients with resected adenocarcinoma in situ and minimally invasive adenocarcinoma of the lung. J Thorac Oncol. 2021; 16(8): 1312-1320.

[20] Tan X, Zhang S, Gao H, et al. Hypermethylation of the PTTG1IP promoter leads to low expression in early-stage non-small cell lung cancer. Oncol Lett. 2019; 18(2): 1278-1286.

[21] Lin J, Zandi R, Shao R, et al. A miR-SNP biomarker linked to an increased lung cancer survival by miRNA-mediated down-regulation of FZD4 expression and Wnt signaling. Sci Rep. 2017; 7(1): 9029.

[22] Gao Q, Lin YP, Li BS, et al. Unintrusive multi-cancer detection by circulating cell-free DNA methylation sequencing (THUNDER): development and independent validation studies. Ann Oncol. 2023; 34(5): 486-495.

[23] Yang R, Peng W, Shi S, et al. The NLRP11 protein bridges the histone lysine acetyltransferase KAT7 to acetylate vimentin in the early stage of lung adenocarcinoma. Advanced Science (Weinheim, Baden-Wurttemberg, Germany). 2023; 10(25): e2300971.

[24] Peng H, Wu X, Zhong R, et al. Profiling tumor immune microenvironment of non-small cell lung cancer using multiplex immunofluorescence. Front Immunol. 2021; 12: 750046.

[25] Tan Y, Johnson M, Zhou J, Zhao Y, Kamal MA, Qu X. Antrodia cinnamomea inhibits growth and migration of lung cancer cells through regulating p53-Bcl2 and MMPs pathways. Am J Chin Med. 2020; 48(8): 1941-1953.

[26] Shen KH, Hung JH, Liao YC, Tsai ST, Wu MJ, Chen PS. Sinomenine inhibits migration and invasion of human lung cancer cell through downregulating expression of miR-21 and MMPs. Int J Mol Sci. 2020; 21(9): 3080.

[27] Chen P, Rojas FR, Hu X, et al. Pathomic features reveal immune and molecular evolution from lung preneoplasia to invasive adenocarcinoma. Mod Pathol. 2023; 36(12): 100326.

[28] Malyla V, Paudel KR, De Rubis G, Hansbro NG, Hansbro PM, Dua K. Cigarette smoking induces lung cancer tumorigenesis via upregulation of the WNT/β-catenin signaling pathway. Life Sci. 2023; 326: 121787.

[29] Bao Y, Zhang S, Zhang X, et al. RBM10 loss promotes EGFR-driven lung cancer and confers sensitivity to spliceosome inhibition. Cancer Res. 2023; 83(9): 1490-1502.

[30] Savari O, Febres-Aldana C, Chang JC, et al. Non-small cell lung carcinomas with diffuse coexpression of TTF1 and p40: clinicopathological and genomic features of 14 rare biphenotypic tumours. Histopathology. 2023; 82(2): 242-253.

[31] George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015; 524(7563): 47-53.

[32] Duan J, Zhong B, Fan Z, et al. DNA methylation in pulmonary fibrosis and lung cancer. Expert Rev Respir Med. 2022; 16(5): 519-528.

[33] Ramazi S, Daddzadi M, Sahafnejad Z, Allahverdi A. Epigenetic regulation in lung cancer. MedComm. 2023; 4(6): e401.

[34] Xu Q, Wang C, Zhou JX, et al. Loss of TET reprograms Wnt signaling through impaired demethylation to promote lung cancer development. Proc Nat Acad Sci USA. 2022; 119(6): e2107599119.

[35] Boo HJ, Min HY, Park CS, et al. Dual impact of IGF2 on alveolar stem cell function during tobacco-induced injury repair and development of pulmonary emphysema and cancer. Cancer Res. 2023; 83(11): 1782-1799.

[36] Ebisudani T, Hamamoto J, Togasaki K, et al. Genotype-phenotype mapping of a patient-derived lung cancer organoid biobank identifies NKX2-1-defined Wnt dependency in lung adenocarcinoma. Cell Rep. 2023; 42(3): 112212.

[37] Jin C, Wang T, Zhang D, et al. Acetyltransferase NAT10 regulates the Wnt/β-catenin signaling pathway to promote colorectal cancer progression via ac(4)C acetylation of KIF23 mRNA. J Exp Clin Cancer Res. 2022; 41(1): 345.

[38] Satpathy S, Krug K, Jean Beltran PM, et al. A proteogenomic portrait of lung squamous cell carcinoma. Cell. 2021; 184(16): 4348-4371.e4340.

[39] Sun Y, Sun J, Ying K, et al. EP300 regulates the SLC16A1-AS1-AS1/TCF3 axis to promote lung cancer malignancies through the Wnt signaling pathway. Heliyon. 2024; 10(6): e27727.

[40] Teng PC, Liang Y, Yarmishyn AA, et al. RNA modifications and epigenetics in modulation of lung cancer and pulmonary diseases. Int J Mol Sci. 2021; 22(19): 10592.

[41] Chi Y, Wang D, Wang J, Yu W, Yang J. Long non-coding RNA in the pathogenesis of cancers. Cells. 2019; 8(9): 1015.

[42] Zhao J, Guo C, Ma Z, Liu H, Yang C, Li S. Identification of a novel gene expression signature associated with overall survival in patients with lung adenocarcinoma: A comprehensive analysis based on TCGA and GEO databases. Lung Cancer. 2020; 149: 90-96.

[43] Miyoshi J, Zhu Z, Luo A, et al. A microRNA-based liquid biopsy signature for the early detection of esophageal squamous cell carcinoma: a retrospective, prospective and multicenter study. Mol Cancer. 2022; 21(1): 44.

[44] Li W, Liu S, Su S, Chen Y, Sun G. Construction and validation of a novel prognostic signature of microRNAs in lung adenocarcinoma. PeerJ. 2021; 9: e10470.

[45] Lee TJ, Yuan X, Kerr K, et al. Strategies to modulate microRNA functions for the treatment of cancer or organ injury. Pharmacol Rev. 2020; 72(3): 639-667.

[46] Yang H, Liu Y, Chen L, et al. MiRNA-based therapies for lung cancer: opportunities and challenges? Biomolecules. 2023; 13(6): 877.

[47] Huang YH, Chiu LY, Tseng JS, et al. Attenuation of PI3K-Akt-mTOR pathway to reduce cancer stemness on chemoresistant lung cancer cells by shikonin and synergy with BEZ235 inhibitor. Int J Mol Sci. 2024; 25(1): 616.

[48] Liu M, Hu S, Yan N, Popowski KD, Cheng K. Inhalable extracellular vesicle delivery of IL-12 mRNA to treat lung cancer and promote systemic immunity. Nat Nanotechnol. 2024; 19(4): 565-575.

[49] Wan G, Liu Y, Zhu J, et al. SLFN5 suppresses cancer cell migration and invasion by inhibiting MT1-MMP expression via AKT/GSK-3β/β-catenin pathway. Cell Signalling. 2019; 59: 1-12.

[50] Zhang J, Zhang X, Yang S, Bao Y, Xu D, Liu L. FOXH1 promotes lung cancer progression by activating the Wnt/β-catenin signaling pathway. Cancer Cell Int. 2021; 21(1): 293.

[51] D’Ambrosi S, Giannoukakos S, Antunes-Ferreira M, et al. Combinatorial blood platelets-derived circRNA and mRNA signature for early-stage lung cancer detection. Int J Mol Sci. 2023; 24(5): 4881.

[52] Liu W, Powell CA, Wang Q. Tumor microenvironment in lung cancer-derived brain metastasis. Chin Med J (Engl). 2022; 135(15): 1781-1791.

[53] Hinshaw DC, Shevde LA. The tumor microenvironment innately modulates cancer progression. Cancer Res. 2019; 79(18): 4557-4566.

[54] Xu K, Zhang C, Du T, et al. Progress of exosomes in the diagnosis and treatment of lung cancer. Biomed Pharmacother. 2021; 134: 111111.

[55] Enfield KSS, Colliver E, Lee C, et al. Spatial architecture of myeloid and T cells orchestrates immune evasion and clinical outcome in lung cancer. Cancer Discov. 2024; 14(6): 1018-1047.

[56] Nikanjam M, Kato S, Kurzrock R. Liquid biopsy: current technology and clinical applications. J Hematol Oncol. 2022; 15(1): 131.

[57] Li W, Liu JB, Hou LK, et al. Liquid biopsy in lung cancer: significance in diagnostics, prediction, and treatment monitoring. Mol Cancer. 2022; 21(1): 25.

[58] Baca SC, Seo JH, Davidsohn MP, et al. Liquid biopsy epigenomic profiling for cancer subtyping. Nat Med. 2023; 29(11): 2737-2741.

[59] Kubiliute R, Jarmalaite S. Epigenetic biomarkers of renal cell carcinoma for liquid biopsy tests. Int J Mol Sci. 2021; 22(16): 8846.

[60] Heeke S, Gay CM, Estecio MR, et al. Tumor-and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes. Cancer Cell. 2024; 42(2): 225-237.e225.

[61] Yu D, Li Y, Wang M, et al. Exosomes as a new frontier of cancer liquid biopsy. Mol Cancer. 2022; 21(1): 56.

[62] Jiang C, Zhang N, Hu X, Wang H. Tumor-associated exosomes promote lung cancer metastasis through multiple mechanisms. Mol Cancer. 2021; 20(1): 117.

[63] Khan FH, Reza MJ, Shao YF, et al. Role of exosomes in lung cancer: a comprehensive insight from immunomodulation to theragnostic applications. Biochimica et biophysica acta Reviews on cancer. 2022; 1877(5): 188776.

[64] Mattei AL, Bailly N, Meissner A. DNA methylation: a historical perspective. Trends Genet. 2022; 38(7): 676-707.

[65] Horvath S, Raj K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet. 2018; 19(6): 371-384.

[66] Liang W, Zhao Y, Huang W, et al. Non-invasive diagnosis of early-stage lung cancer using high-throughput targeted DNA methylation sequencing of circulating tumor DNA (ctDNA). Theranostics. 2019; 9(7): 2056-2070.

[67] Karlow JA, Pehrsson EC, Xing X, et al. Non-small cell lung cancer epigenomes exhibit altered DNA methylation in smokers and never-smokers. Genomics Proteomics Bioinformatics. 2023; 21(5): 991-1013.

[68] Liu S, Chen X, Chen R, et al. Diagnostic role of Wnt pathway gene promoter methylation in non small cell lung cancer. Oncotarget. 2017; 8(22): 36354-36367.

[69] Sarne V, Huter S, Braunmueller S, et al. Promoter methylation of selected genes in non-small-cell lung cancer patients and cell lines. Int J Mol Sci. 2020; 21(13): 4595.

[70] Hua F, Fang N, Li X, Zhu S, Zhang W, Gu J. A meta-analysis of the relationship between RARβ gene promoter methylation and non-small cell lung cancer. PLoS One. 2014; 9(5): e96163.

[71] Mazieres J, He B, You L, Xu Z, Jablons DM. Wnt signaling in lung cancer. Cancer Lett. 2005; 222(1): 1-10.

[72] Kim MJ, Min Y, Jeong SK, et al. USP15 negatively regulates lung cancer progression through the TRAF6-BECN1 signaling axis for autophagy induction. Cell Death Dis. 2022; 13(4): 348.

[73] Young IC, Brabletz T, Lindley LE, et al. Multi-cancer analysis reveals universal association of oncogenic LBH expression with DNA hypomethylation and WNT-Integrin signaling pathways. Cancer Gene Ther. 2023; 30(9): 1234-1248.

[74] Wang X, Ju S, Chen Y, et al. Hypomethylation-activated cancer-testis gene SPANXC promotes cell metastasis in lung adenocarcinoma. J Cell Mol Med. 2019; 23(11): 7261-7267.

[75] Guo H, Vuille JA, Wittner BS, et al. DNA hypomethylation silences anti-tumor immune genes in early prostate cancer and CTCs. Cell. 2023; 186(13): 2765-2782.e2728.

[76] Sun Z, Zhang R, Zhang X, et al. LINE-1 promotes tumorigenicity and exacerbates tumor progression via stimulating metabolism reprogramming in non-small cell lung cancer. Mol Cancer. 2022; 21(1): 147.

[77] Vylegzhanina AV, Bespalov IA, Novototskaya-Vlasova KA, et al. Cancer relevance of circulating antibodies against LINE-1 antigens in humans. Cancer research communications. 2023; 3(11): 2256-2267.

[78] Bacolod MD, Barany F, Fisher PB. Can CpG methylation serve as surrogate markers for immune infiltration in cancer? Adv Cancer Res. 2019; 143: 351-384.

[79] Fei J, Xiao C, Yang M, Zhou X, Gong P. Inhibition of SNCG suppresses the proliferation of lung cancer cells induced by high glucose. Mol Med Rep. 2021; 23(2): 138.

[80] Zhang B, Ren Z, Zhao J, et al. Global analysis of HLA-A2 restricted MAGE-A3 tumor antigen epitopes and corresponding TCRs in non-small cell lung cancer. Theranostics. 2023; 13(13): 4449-4468.

[81] Zhou D, Zheng H, Liu Q, et al. Attenuated plasmodium sporozoite expressing MAGE-A3 induces antigen-specific CD8+ T cell response against lung cancer in mice. Cancer Biol Med. 2019; 16(2): 288-298.

[82] Tang R, Shuldiner EG, Kelly M, et al. Multiplexed screens identify RAS paralogues HRAS and NRAS as suppressors of KRAS-driven lung cancer growth. Nat Cell Biol. 2023; 25(1): 159-169.

[83] Park MK, Lee JC, Lee JW, Hwang SJ. Alu cell-free DNA concentration, Alu index, and LINE-1 hypomethylation as a cancer predictor. Clin Biochem. 2021; 94: 67-73.

[84] Liu L, Wang C, Li S, et al. ERO1L is a novel and potential biomarker in lung adenocarcinoma and shapes the immune-suppressive tumor microenvironment. Front Immunol. 2021; 12: 677169.

[85] Wang J, Zhao Y, Xu H, et al. Silencing NID2 by DNA hypermethylation promotes lung cancer. Pathol Oncol Res. 2020; 26(2): 801-811.

[86] Wang Y, Wei J, Feng L, et al. Aberrant m5C hypermethylation mediates intrinsic resistance to gefitinib through NSUN2/YBX1/QSOX1 axis in EGFR-mutant non-small-cell lung cancer. Mol Cancer. 2023; 22(1): 81.

[87] Wu J, He K, Zhang Y, et al. Inactivation of SMARCA2 by promoter hypermethylation drives lung cancer development. Gene. 2019; 687: 193-199.

[88] Kim JY, Choi JK, Jung H. Genome-wide methylation patterns predict clinical benefit of immunotherapy in lung cancer. Clin Epigenetics. 2020; 12(1): 119.

[89] Yoo SS, Choi JE, Lee WK, et al. Polymorphisms in the CASPASE genes and survival in patients with early-stage non-small-cell lung cancer. J Clin Oncol. 2009; 27(34): 5823-5829.

[90] Chen Z, Fan Y, Liu X, Shang X, Qi K, Zhang S. Clinicopathological significance of DAPK gene promoter hypermethylation in non-small cell lung cancer: A meta-analysis. Int J Biol Markers. 2022; 37(1): 47-57.

[91] Kang C, Wang D, Zhang X, Wang L, Wang F, Chen J. Construction and validation of a lung cancer diagnostic model based on 6-gene methylation frequency in blood, clinical features, and serum tumor markers. Comput Math Methods Med. 2021; 2021: 9987067.

[92] Li Y, Fan QX. [The role of lung cancer related gene methylation in the early diagnosis of lung cancer]. Zhonghua Zhong Liu Za Zhi. 2020; 42(8): 644-647.

[93] Porcel JM. Pleural mesothelioma. Med Clin (Barc). 2022; 159(5): 240-247.

[94] Li DM, Li GS, Li JD, et al. Clinical significance and prospective mechanism of increased CDKN2A expression in small cell lung cancer. Clin Transl Oncol. 2024; 26(6): 1519-1531.

[95] Reyes NS, Krasilnikov M, Allen NC, et al. Sentinel p16(INK4a+) cells in the basement membrane form a reparative niche in the lung. Science. 2022; 378(6616): 192-201.

[96] Mohammed F, Baydaa Abed Hussein A, Ahmed T. Evaluation of methylation panel in the promoter region of p16(INK4a), RASSF1A, and MGMT as a biomarker in sputum for lung cancer. Arch Razi Inst. 2022; 77(3): 1075-1081.

[97] Yehia L, Centomo ML, Pandolfi PP, Eng C. Two’s company, three’s a crowd: Rb1/Trp53/Pten trifecta and lung cancer molecular and histopathologic heterogeneity. J Thorac Oncol. 2023; 18(3): 260-261.

[98] Li J, Zhou S, Li H, Xu Y, Zhou N, Liu R. PTEN/AKT upregulation of TMSB10 contributes to lung cancer cell growth and predicts poor survival of the patients. Biosci Biotechnol Biochem. 2021; 85(4): 805-813.

[99] Chen B, Ying X, Bao L. MGMT gene promoter methylation in humoral tissue as biomarker for lung cancer diagnosis: An update meta-analysis. Thoracic cancer. 2021; 12(23): 3194-3200.

[100] Tsuboi M, Kondo K, Soejima S, et al. Chromate exposure induces DNA hypermethylation of the mismatch repair gene MLH1 in lung cancer. Mol Carcinog. 2020; 59(1): 24-31.

[101] Emam M, Machado JP, Antunes A. Evolutionary genomics of mammalian lung cancer genes reveals signatures of positive selection in APC, RB1 and TP53. Genomics. 2020; 112(6): 4722-4731.

[102] Liu F, Lu X, Zhou X, Huang H. APC gene promoter methylation as a potential biomarker for lung cancer diagnosis: a meta-analysis. Thoracic cancer. 2021; 12(21): 2907-2913.

[103] Ren K, Sun J, Liu L, et al. TP53-activated lncRNA GHRLOS regulates cell proliferation, invasion, and apoptosis of non-small cell lung cancer by modulating the miR-346/APC axis. Front Oncol. 2021; 11: 676202.

[104] Paschidis K, Zougros A, Chatziandreou I, et al. Methylation analysis of APC, AXIN2, DACT1, RASSF1A and MGMT gene promoters in non-small cell lung cancer. Pathol Res Pract. 2022; 234: 153899.

[105] Zhao JS, Shi S, Qu HY, et al. Glutamine synthetase licenses APC/C-mediated mitotic progression to drive cell growth. Nature metabolism. 2022; 4(2): 239-253.

[106] Zhang S, You X, Zheng Y, Shen Y, Xiong X, Sun Y. The UBE2C/CDH1/DEPTOR axis is an oncogene and tumor suppressor cascade in lung cancer cells. J Clin Invest. 2023; 133(4): e162434.

[107] Dong Y, Hu H, Zhang X, et al. Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis. Signal transduction and targeted therapy. 2023; 8(1): 95.

[108] Huang C, Ren S, Chen Y, et al. PD-L1 methylation restricts PD-L1/PD-1 interactions to control cancer immune surveillance. Sci Adv. 2023; 9(21): eade4186.

[109] Hong Y, Kim WJ. DNA methylation markers in lung cancer. Curr Genomics. 2021; 22(2): 79-87.

[110] Ptáková N, Martínek P, Holubec L, et al. Identification of tumors with NRG1 rearrangement, including a novel putative pathogenic UNC5D-NRG1 gene fusion in prostate cancer by data-drilling a de-identified tumor database. Genes Chromosomes Cancer. 2021; 60(7): 474-481.

[111] Xiao X, He W. Genetic polymorphisms in the TERT-CLPTM1L region and lung cancer susceptibility in Chinese males. Oncol Lett. 2017; 14(2): 1588-1594.

[112] Kang JU. Characterization of amplification patterns and target genes on the short arm of chromosome 7 in early-stage lung adenocarcinoma. Molecular medicine reports. 2013; 8(5): 1373-1378.

[113] Cheng S, Qian F, Huang Q, Wei L, Fu Y, Du Y. HOXA4, down-regulated in lung cancer, inhibits the growth, motility and invasion of lung cancer cells. Cell Death Dis. 2018; 9(5): 465.

[114] Qu H, Xu F, Bai Y, Si X, Yang A. Tumor suppressor in lung cancer 1 gene expression in epithelial ovarian cancer. Indian J Cancer. 2016; 53(1): 8-11.

[115] Wang Y, Huang P, Hu Y, et al. An oncolytic adenovirus delivering TSLC1 inhibits Wnt signaling pathway and tumor growth in SMMC-7721 xenograft mice model. Acta Biochim Biophy Sin. 2021; 53(6): 766-774.

[116] Sussan TE, Pletcher MT, Murakami Y, Reeves RH. Tumor suppressor in lung cancer 1 (TSLC1) alters tumorigenic growth properties and gene expression. Mol Cancer. 2005; 4: 28.

[117] Liu D, Feng X, Wu X, et al. Tumor suppressor in lung cancer 1 (TSLC1), a novel tumor suppressor gene, is implicated in the regulation of proliferation, invasion, cell cycle, apoptosis, and tumorigenicity in cutaneous squamous cell carcinoma. Tumour Biol. 2013; 34(6): 3773-3783.

[118] Cai Y, Xiong S, Zheng Y, Luo F, Jiang P, Chu Y. Trichosanthin enhances anti-tumor immune response in a murine Lewis lung cancer model by boosting the interaction between TSLC1 and CRTAM. Cell Mol Immunol. 2011; 8(4): 359-367.

[119] Heller G, Fong KM, Girard L, et al. Expression and methylation pattern of TSLC1 cascade genes in lung carcinomas. Oncogene. 2006; 25(6): 959-968.

[120] Vo TTL, Nguyen TN, Nguyen TT, et al. SHOX2 methylation in Vietnamese patients with lung cancer. Mol Biol Rep. 2022; 49(5): 3413-3421.

[121] Li N, Zeng Y, Huang J. Signaling pathways and clinical application of RASSF1A and SHOX2 in lung cancer. J Cancer Res Clin Oncol. 2020; 146(6): 1379-1393.

[122] Liu J, Bian T, She B, et al. Evaluating the comprehensive diagnosis efficiency of lung cancer, including measurement of SHOX2 and RASSF1A gene methylation. BMC Cancer. 2024; 24(1): 282.

[123] Xie B, Dong W, He F, Peng F, Zhang H, Wang W. The combination of SHOX2 and RASSF1A DNA methylation had a diagnostic value in pulmonary nodules and early lung cancer. Oncology. 2024; 102(9): 759-774.

[124] Chen MC, Yang HS, Dong Z, et al. Immunogenomic features of radiologically distinctive nodules in multiple primary lung cancer. Cancer Immunol Immunother. 2024; 73(11): 217.

[125] Su H, Fan G, Huang J, Qiu X. YBX1 regulated by Runx3-miR-148a-3p axis facilitates non-small-cell lung cancer progression. Cell Signalling. 2021; 85: 110049.

[126] Li ZB, Chen X, Yi XJ. Tumor promoting effects of exosomal microRNA-210 derived from lung cancer cells on lung cancer through the RUNX3/PI3K/AKT signaling pathway axis. J Biol Regul Homeost Agents. 2021; 35(2): 473-484.

[127] Lee JY, Lee JW, Park TG, et al. Runx3 restoration regresses K-Ras-activated mouse lung cancers and inhibits recurrence. Cells. 2023; 12(20): 2438.

[128] Zhang J, Yang Y, Wei Y, Li L, Wang X, Ye Z. Hsa-miR-301a-3p inhibited the killing effect of natural killer cells on non-small cell lung cancer cells by regulating RUNX3. Cancer biomarkers: section A of Disease markers. 2023; 37(4): 249-259.

[129] Qin X, Wang XY, Fei JW, Li FH, Han J, Wang HX. MiR-20a promotes lung tumorigenesis by targeting RUNX3 via TGF-β signaling pathway. J Biol Regul Homeost Agents. 2020; 34(2).

[130] Ono T, Terada F, Okumura M, Chihara T, Hamao K. Impairment of cytokinesis by cancer-associated DAPK3 mutations. Biochem Biophys Res Commun. 2020; 533(4): 1095-1101.

[131] Li Y, Zhu M, Zhang X, Cheng D, Ma X. Clinical significance of DAPK promoter hypermethylation in lung cancer: a meta-analysis. Drug Des Dev Ther. 2015; 9: 1785-1796.

[132] Zhang Y, Wu J, Huang G, Xu S. Clinicopathological significance of DAPK promoter methylation in non-small-cell lung cancer: a systematic review and meta-analysis. Cancer Manag Res. 2018; 10: 6897-6904.

[133] Yu Q, Guo Q, Chen L, Liu S. Clinicopathological significance and potential drug targeting of CDH1 in lung cancer: a meta-analysis and literature review. Drug Des Dev Ther. 2015; 9: 2171-2178.

[134] Ye T, Li J, Sun Z, et al. Cdh1 functions as an oncogene by inducing self-renewal of lung cancer stem-like cells via oncogenic pathways. Int J Biol Sci. 2020; 16(3): 447-459.

[135] Liu R, Zhang Y, Ding Y, Zhang S, Pan L. Characteristics of TGFBR1-EGFR-CTNNB1-CDH1 signaling axis in wnt-regulated invasion and migration in lung cancer. Cell Transplant. 2020; 29: 963689720969167.

[136] Xu S, Zheng L, Kang L, Xu H, Gao L. microRNA-let-7e in serum-derived exosomes inhibits the metastasis of non-small-cell lung cancer in a SUV39H2/LSD1/CDH1-dependent manner. Cancer Gene Ther. 2021; 28(3-4): 250-264.

[137] Kim JS, Han J, Shim YM, Park J, Kim DH. Aberrant methylation of H-cadherin (CDH13) promoter is associated with tumor progression in primary nonsmall cell lung carcinoma. Cancer. 2005; 104(9): 1825-1833.

[138] Feng Q, Hawes SE, Stern JE, et al. DNA methylation in tumor and matched normal tissues from non-small cell lung cancer patients. Cancer Epidemiol Biomarkers Prev. 2008; 17(3): 645-654.

[139] Fan X, Tao S, Li Q, Deng B, Tan QY, Jin H. The miR-23a/27a/24-2 cluster promotes postoperative progression of early-stage non-small cell lung cancer. Molecular therapy oncolytics. 2022; 24: 205-217.

[140] Bradly DP, Gattuso P, Pool M, et al. CDKN2A (p16) promoter hypermethylation influences the outcome in young lung cancer patients. Diagnostic molecular pathology : the American journal of surgical pathology, part B. 2012; 21(4): 207-213.

[141] Hamad SH, Montgomery SA, Simon JM, et al. TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure-and combined-small cell lung cancer in mice. Oncogene. 2022; 41(25): 3423-3432.

[142] Suzuki T, Sakai S, Ota K, et al. Expression of tumor suppressor FHIT is regulated by the LINC00173-SNAIL axis in human lung adenocarcinoma. Int J Mol Sci. 2023; 24(23).

[143] Jiao Y, Kang G, Pan P, et al. Acetylcholine promotes chronic stress-induced lung adenocarcinoma progression via α5-nAChR/FHIT pathway. Cellular and molecular life sciences : CMLS. 2023; 80(5): 119.

[144] Li R, Todd NW, Qiu Q, et al. Genetic deletions in sputum as diagnostic markers for early detection of stage I non-small cell lung cancer. Clin Cancer Res. 2007; 13(2 Pt 1): 482-487.

[145] Minina VI, Soboleva OA, Glushkov AN, et al. Polymorphisms of GSTM1, GSTT1, GSTP1 genes and chromosomal aberrations in lung cancer patients. J Cancer Res Clin Oncol. 2017; 143(11): 2235-2243.

[146] Haroun RA, Zakhary NI, Mohamed MR, Abdelrahman AM, Kandil EI, Shalaby KA. Assessment of the prognostic value of methylation status and expression levels of FHIT, GSTP1 and p16 in non-small cell lung cancer in Egyptian patients. Asian Pac J Cancer Prev. 2014; 15(10): 4281-4287.

[147] Xiao J, Wang Y, Wang Z, et al. The relevance analysis of GSTP1 rs1695 and lung cancer in the Chinese Han population. Int J Biol Markers. 2021; 36(3): 48-54.

[148] Borg M, Wen SWC, Andersen RF, Timm S, Hansen TF, Hilberg O. Methylated circulating tumor DNA in blood as a tool for diagnosing lung cancer: a systematic review and meta-analysis. Cancers. 2023; 15(15).

[149] Gao H, Yang J, He L, et al. The diagnostic potential of SHOX2 and RASSF1A DNA methylation in early lung adenocarcinoma. Front Oncol. 2022; 12: 849024.

[150] Du C, Tan L, Xiao X, et al. Detection of the DNA methylation of seven genes contribute to the early diagnosis of lung cancer. J Cancer Res Clin Oncol. 2024; 150(2): 77.

[151] Jin Y, Lu R, Liu F, Jiang G, Wang R, Zheng M. DNA methylation analysis in plasma for early diagnosis in lung adenocarcinoma. Medicine (Baltimore). 2024; 103(28): e38867.

[152] Ji XY, Li H, Chen HH, Lin J. Diagnostic performance of RASSF1A and SHOX2 methylation combined with EGFR mutations for differentiation between small pulmonary nodules. J Cancer Res Clin Oncol. 2023; 149(11): 8557-8571.

[153] Jiang M, Jia K, Wang L, et al. Alterations of DNA damage response pathway: biomarker and therapeutic strategy for cancer immunotherapy. Acta pharmaceutica Sinica B. 2021; 11(10): 2983-2994.

[154] Pongor LS, Tlemsani C, Elloumi F, et al. Integrative epigenomic analyses of small cell lung cancer cells demonstrates the clinical translational relevance of gene body methylation. iScience. 2022; 25(11): 105338.

[155] Tong L, Sun J, Zhang X, et al. Development of an autoantibody panel for early detection of lung cancer in the Chinese population. Frontiers in medicine. 2023; 10: 1209747.

[156] Chen P, Lu W, Chen T. Seven tumor-associated autoantibodies as a serum biomarker for primary screening of early-stage non-small cell lung cancer. J Clin Lab Anal. 2021; 35(11): e24020.

[157] Luo B, Mao G, Ma H, Chen S. The role of seven autoantibodies in lung cancer diagnosis. J Thorac Dis. 2021; 13(6): 3660-3668.

[158] Wang Z, Xie K, Zhu G, et al. Early detection and stratification of lung cancer aided by a cost-effective assay targeting circulating tumor DNA (ctDNA) methylation. Respir Res. 2023; 24(1): 163.

[159] Bajbouj K, Al-Ali A, Ramakrishnan RK, Saber-Ayad M, Hamid Q. Histone modification in NSCLC: molecular mechanisms and therapeutic targets. Int J Mol Sci. 2021; 22(21).

[160] Chen Y, Liu X, Li Y, Quan C, Zheng L, Huang K. Lung cancer therapy targeting histone methylation: opportunities and challenges. Comput Struct Biotechnol J. 2018; 16: 211-223.

[161] Chang S, Yim S, Park H. The cancer driver genes IDH1/2, JARID1C/KDM5C, and UTX/KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism. Exp Mol Med. 2019; 51(6): 1-17.

[162] Guo Y, Wen H, Chen Z, et al. Conjoint analysis of succinylome and phosphorylome reveals imbalanced HDAC phosphorylation-driven succinylayion dynamic contibutes to lung cancer. Briefings Bioinf. 2024; 25(5): bbae415.

[163] Zhou S, Cai Y, Liu X, et al. Role of H2B mono-ubiquitination in the initiation and progression of cancer. Bull Cancer. 2021; 108(4): 385-398.

[164] Khan P, Siddiqui JA, Maurya SK, et al. Epigenetic landscape of small cell lung cancer: small image of a giant recalcitrant disease. Semin Cancer Biol. 2022; 83: 57-76.

[165] Martinez-Useros J, Martin-Galan M, Florez-Cespedes M, Garcia-Foncillas J. Epigenetics of most aggressive solid tumors: pathways, targets and treatments. Cancers. 2021; 13(13): 3209.

[166] Sumimoto H, Takano A, Igarashi T, Hanaoka J, Teramoto K, Daigo Y. Oncogenic epidermal growth factor receptor signal-induced histone deacetylation suppresses chemokine gene expression in human lung adenocarcinoma. Sci Rep. 2023; 13(1): 5087.

[167] Yun HS, Lee J, Kim JY, et al. A novel function of HRP-3 in regulating cell cycle progression via the HDAC-E2F1-Cyclin E pathway in lung cancer. Cancer Sci. 2022; 113(1): 145-155.

[168] Klein BJ, Wang X, Cui G, et al. PHF20 Readers Link Methylation of Histone H3K4 and p53 with H4K16 Acetylation. Cell Rep. 2016; 17(4): 1158-1170.

[169] Ganai SA, Shah BA, Yatoo MA. Histone deacetylase inhibitors as sanguine epitherapeutics against the deadliest lung cancer. Adv Cancer Res. 2023; 158: 163-198.

[170] Mi W, Guan H, Lyu J, et al. YEATS2 links histone acetylation to tumorigenesis of non-small cell lung cancer. Nat Commun. 2017; 8(1): 1088.

[171] Sha T, Li J, Sun S, et al. YEATS domain-containing 2 (YEATS2), targeted by microRNA miR-378a-5p, regulates growth and metastasis in head and neck squamous cell carcinoma. Bioengineered. 2021; 12(1): 7286-7296.

[172] Wang H, Lu X, Chen J. Construction and experimental validation of an acetylation-related gene signature to evaluate the recurrence and immunotherapeutic response in early-stage lung adenocarcinoma. BMC Med Genet. 2022; 15(1): 254.

[173] Jeon T, Oh UJ, Min J, Kim C. Gene-level dissection of chromosome 3q locus amplification in squamous cell carcinoma of the lung using the nCounter assay. Thoracic cancer. 2023; 14(26): 2635-2641.

[174] Chen F, Qi S, Zhang X, Wu J, Yang X, Wang R. lncRNA PLAC2 activated by H3K27 acetylation promotes cell proliferation and invasion via the activation of Wnt/β-catenin pathway in oral squamous cell carcinoma. Int J Oncol. 2019; 54(4): 1183-1194.

[175] Li YF, Zhang J, Yu L. Circular RNAs regulate cancer onset and progression via Wnt/β-catenin signaling pathway. Yonsei Med J. 2019; 60(12): 1117-1128.

[176] Lin S, Zhen Y, Guan Y, Yi H. Roles of Wnt/β-catenin signaling pathway regulatory long non-coding RNAs in the pathogenesis of non-small cell lung cancer. Cancer Manag Res. 2020; 12: 4181-4191.

[177] Yang Q, Wang M, Xu J, et al. LINC02159 promotes non-small cell lung cancer progression via ALYREF/YAP1 signaling. Mol Cancer. 2023; 22(1): 122.

[178] Shang B, Lu F, Jiang S, et al. ALDOC promotes non-small cell lung cancer through affecting MYC-mediated UBE2N transcription and regulating Wnt/β-catenin pathway. Aging. 2023; 15(18): 9614-9632.

[179] Li J, Xie G, Tian Y, et al. RNA m(6)A methylation regulates dissemination of cancer cells by modulating expression and membrane localization of β-catenin. Mol Ther. 2022; 30(4): 1578-1596.

[180] Yu W, Hua Y, Qiu H, et al. PD-L1 promotes tumor growth and progression by activating WIP and β-catenin signaling pathways and predicts poor prognosis in lung cancer. Cell Death Dis. 2020; 11(7): 506.

[181] Iksen, Pothongsrisit S, Pongrakhananon V. Targeting the PI3K/AKT/mTOR signaling pathway in lung cancer: an update regarding potential drugs and natural products. Molecules. 2021; 26(13): 4100.

[182] Fumarola C, Bonelli MA, Petronini PG, Alfieri RR. Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer. Biochem Pharmacol. 2014; 90(3): 197-207.

[183] Yu X, Li Y, Jiang G, et al. FGF21 promotes non-small cell lung cancer progression by SIRT1/PI3K/AKT signaling. Life Sci. 2021; 269: 118875.

[184] Faltus C, Lahnsteiner A, Barrdahl M, et al. Identification of NHLRC1 as a Novel AKT Activator from a Lung Cancer Epigenome-Wide Association Study (EWAS). Int J Mol Sci. 2022; 23(18).

[185] Larson MH, Pan W, Kim HJ, et al. A comprehensive characterization of the cell-free transcriptome reveals tissue-and subtype-specific biomarkers for cancer detection. Nat Commun. 2021; 12(1): 2357.

[186] Zu L, He J, Zhou N, Tang Q, Liang M, Xu S. Identification of multiple organ metastasis-associated hub mRNA/miRNA signatures in non-small cell lung cancer. Cell Death Dis. 2023; 14(12): 798.

[187] Alahdal M, Elkord E. Non-coding RNAs in cancer immunotherapy: Predictive biomarkers and targets. Clin Transl Med. 2023; 13(9): e1425.

[188] Gilyazova I, Gimalova G, Nizamova A, et al. Non-coding RNAs as key regulators in lung cancer. Int J Mol Sci. 2023; 25(1): 560.

[189] Kawami M, Takenaka S, Akai M, Yumoto R, Takano M. Characterization of miR-34a-induced epithelial-mesenchymal transition in non-small lung cancer cells focusing on p53. Biomolecules. 2021; 11(12): 1853.

[190] Hu H, Cheng R, Wang Y, et al. Oncogenic KRAS signaling drives evasion of innate immune surveillance in lung adenocarcinoma by activating CD47. J Clin Invest. 2023; 133(2): e153470.

[191] Gardner EE, Lok BH, Schneeberger VE, et al. Chemosensitive relapse in small cell lung cancer proceeds through an EZH2-SLFN11 axis. Cancer Cell. 2017; 31(2): 286-299.

[192] Li C, Lv Y, Shao C, et al. Tumor-derived exosomal lncRNA GAS5 as a biomarker for early-stage non-small-cell lung cancer diagnosis. J Cell Physiol. 2019; 234(11): 20721-20727.

[193] Tan Q, Zuo J, Qiu S, et al. Identification of circulating long non-coding RNA GAS5 as a potential biomarker for non-small cell lung cancer diagnosisnon-small cell lung cancer, long non-coding RNA, plasma, GAS5, biomarker. Int J Oncol. 2017; 50(5): 1729-1738.

[194] Chen Y, Li Z, Chen X, Zhang S. Long non-coding RNAs: from disease code to drug role. Acta pharmaceutica Sinica B. 2021; 11(2): 340-354.

[195] Liu T, Han C, Fang P, et al. Long non-coding RNAs in lung cancer: implications for lineage plasticity-mediated TKI resistance. Cell Mol Life Sci. 2021; 78(5): 1983-2000.

[196] Wang Q, Wu J, Huang H, et al. lncRNA LIFR-AS1 suppresses invasion and metastasis of non-small cell lung cancer via the miR-942-5p/ZNF471 axis. Cancer Cell Int. 2020; 20: 180.

[197] Wei K, Ma Z, Yang F, et al. M2 macrophage-derived exosomes promote lung adenocarcinoma progression by delivering miR-942. Cancer Lett. 2022; 526: 205-216.

[198] El-Aal AEA, Elshafei A, Ismail MY, El-Shafey MM. Identification of miR-106b-5p, miR-601, and miR-760 expression and their clinical values in non-small cell lung cancer (NSCLC) patients’ serum. Pathol Res Pract. 2023; 248: 154663.

[199] Davenport ML, Echols JB, Silva AD, et al. miR-31 displays subtype specificity in lung cancer. Cancer Res. 2021; 81(8): 1942-1953.

[200] Edmonds MD, Boyd KL, Moyo T, et al. MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer. J Clin Invest. 2016; 126(1): 349-364.

[201] Simiene J, Dabkeviciene D, Stanciute D, et al. Potential of miR-181a-5p and miR-630 as clinical biomarkers in NSCLC. BMC Cancer. 2023; 23(1): 857.

[202] Chen Y, Zhang Y. CircDLG1 promotes malignant development of non-small cell lung cancer through regulation of the miR-630/CENPF axis. Strahlenther Onkol. 2023; 199(2): 169-181.

[203] Lv H, Yu J, Zhang H, et al. MicroRNA-631 deriving from bone marrow mesenchymal stem cell exosomes facilitates the malignant behavior of non-small cell lung cancer via modulating the E2F family of transcription factor 2/phosphatidylinositol 3-kinase/Akt signaling pathway. Bioengineered. 2022; 13(4): 8382-8395.

[204] Zhang ZW, An Y, Teng CB. [The roles of miR-17-92 cluster in mammal development and tumorigenesis]. Yi chuan = Hereditas. 2009; 31(11): 1094-1100.

[205] Zhu L, Sun L, Xu G, et al. The diagnostic value of has_circ_0006423 in non-small cell lung cancer and its role as a tumor suppressor gene that sponges miR-492. Sci Rep. 2022; 12(1): 13722.

[206] Zhu SY, Zhang ZX, Gu L, et al. CircFBXW7 inhibits proliferation, migration, and invasion of nonsmall cell lung cancer cells by regulating miR-492. J Oncol. 2022; 2022: 8699359.

[207] Duan X, Qiao S, Li D, et al. Circulating miRNAs in serum as biomarkers for early diagnosis of non-small cell lung cancer. Front Genet. 2021; 12: 673926.

[208] Lai XN, Li J, Tang LB, Chen WT, Zhang L, Xiong LX. MiRNAs and LncRNAs: dual roles in TGF-β signaling-regulated metastasis in lung cancer. Int J Mol Sci. 2020; 21(4): 1193.

[209] Goyal B, Yadav SRM, Awasthee N, Gupta S, Kunnumakkara AB, Gupta SC. Diagnostic, prognostic, and therapeutic significance of long non-coding RNA MALAT1 in cancer. Biochimica et biophysica acta Reviews on cancer. 2021; 1875(2): 188502.

[210] Esfandi F, Taheri M, Omrani MD, et al. Expression of long non-coding RNAs (lncRNAs) has been dysregulated in non-small cell lung cancer tissues. BMC Cancer. 2019; 19(1): 222.

[211] Wang C, Tan S, Li J, Liu WR, Peng Y, Li W. CircRNAs in lung cancer - biogenesis, function and clinical implication. Cancer Lett. 2020; 492: 106-115.

[212] Su C, Han Y, Zhang H, et al. CiRS-7 targeting miR-7 modulates the progression of non-small cell lung cancer in a manner dependent on NF-κB signalling. J Cell Mol Med. 2018; 22(6): 3097-3107.

[213] Li J, Zhang Q, Jiang D, Shao J, Li W, Wang C. CircRNAs in lung cancer-role and clinical application. Cancer Lett. 2022; 544: 215810.

[214] Saliminejad K, Khorram Khorshid HR, Soleymani Fard S, Ghaffari SH. An overview of microRNAs: Biology, functions, therapeutics, and analysis methods. J Cell Physiol. 2019; 234(5): 5451-5465.

[215] Li B, Cao Y, Sun M, Feng H. Expression, regulation, and function of exosome-derived miRNAs in cancer progression and therapy. FASEB J. 2021; 35(10): e21916.

[216] Kim JS, Kim EJ, Lee S, et al. MiR-34a and miR-34b/c have distinct effects on the suppression of lung adenocarcinomas. Exp Mol Med. 2019; 51(1): 1-10.

[217] Dezfuli NK, Alipoor SD, Dalil Roofchayee N, et al. Evaluation expression of miR-146a and miR-155 in Non-Small-Cell Lung Cancer Patients. Front Oncol. 2021; 11: 715677.

[218] Wu J, Shen Z. Exosomal miRNAs as biomarkers for diagnostic and prognostic in lung cancer. Cancer Med. 2020; 9(19): 6909-6922.

[219] Ulivi P, Zoli W. miRNAs as non-invasive biomarkers for lung cancer diagnosis. Molecules. 2014; 19(6): 8220-8237.

[220] O’Farrell HE, Bowman RV, Fong KM, Yang IA. Plasma extracellular vesicle miRNAs can identify lung cancer, current smoking status, and stable COPD. Int J Mol Sci. 2021; 22(11): 5803.

[221] Zhou C, Chen Z, Zhao L, et al. A novel circulating miRNA-based signature for the early diagnosis and prognosis prediction of non-small-cell lung cancer. J Clin Lab Anal. 2020; 34(11): e23505.

[222] Li K, Gong Q, Xiang XD, et al. HNRNPA2B1-mediated m(6)A modification of lncRNA MEG3 facilitates tumorigenesis and metastasis of non-small cell lung cancer by regulating miR-21-5p/PTEN axis. J Transl Med. 2023; 21(1): 382.

[223] Qian S, Liu J, Liao W, Wang F. METTL3 promotes non-small-cell lung cancer growth and metastasis by inhibiting FDX1 through copper death-associated pri-miR-21-5p maturation. Epigenomics. 2023; 15(23): 1237-1255.

[224] Sultana A, Alam MS, Liu X, et al. Single-cell RNA-seq analysis to identify potential biomarkers for diagnosis, and prognosis of non-small cell lung cancer by using comprehensive bioinformatics approaches. Transl Oncol. 2023; 27: 101571.

[225] Li J, Zhong X, Zhao Y, Shen J, Xiao Z, Pilapong C. Acacetin inhibited non-small-cell lung cancer (NSCLC) cell growth via upregulating miR-34a in vitro and in vivo. Sci Rep. 2024; 14(1): 2348.

[226] Yang J, Xu J, Wang W, Zhang B, Yu X, Shi S. Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets. Signal transduction and targeted therapy. 2023; 8(1): 210.

[227] Dai E, Zhu Z, Wahed S, Qu Z, Storkus WJ, Guo ZS. Epigenetic modulation of antitumor immunity for improved cancer immunotherapy. Mol Cancer. 2021; 20(1): 171.

[228] Chen H, Yao J, Bao R, et al. Cross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer. Mol Cancer. 2021; 20(1): 29.

[229] Zhang J, Gao J, Hu M, et al. Integrated investigation of the clinical implications and targeted landscape for RNA methylation modifications in hepatocellular carcinoma. Eur J Med Res. 2023; 28(1): 46.

[230] Fernández-Barrena MG, Arechederra M, Colyn L, Berasain C, Avila MA. Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg. JHEP reports : innovation in hepatology. 2020; 2(6): 100167.

[231] Li X, Peng X, Zhang C, et al. Bladder cancer-derived small extracellular vesicles promote tumor angiogenesis by inducing hbp-related metabolic reprogramming and SerRS O-GlcNAcylation in endothelial cells. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2022; 9(30): e2202993.

[232] Park M, Kim D, Ko S, Kim A, Mo K, Yoon H. Breast cancer metastasis: mechanisms and therapeutic implications. Int J Mol Sci. 2022; 23(12): 6806.

[233] Qian Y, Gong Y, Fan Z, et al. Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma. J Hematol Oncol. 2020; 13(1): 130.

[234] Kochumon S, Al-Sayyar A, Jacob T, et al. TGF-β and TNF-α interaction promotes the expression of MMP-9 through H3K36 dimethylation: implications in breast cancer metastasis. Front Immunol. 2024; 15: 1430187.

[235] Chatterjee B, Saha P, Bose S, et al. MicroRNAs: as critical regulators of tumor-associated macrophages. Int J Mol Sci. 2020; 21(19): 7117.

[236] Najem A, Soumoy L, Sabbah M, et al. Understanding molecular mechanisms of phenotype switching and crosstalk with TME to reveal new vulnerabilities of melanoma. Cells. 2022; 11(7): 1157.

[237] Alipoor SD, Chang H. Exosomal miRNAs in the tumor microenvironment of multiple myeloma. Cells. 2023; 12(7): 1030.

[238] Lambrechts D, Wauters E, Boeckx B, et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat Med. 2018; 24(8): 1277-1289.

[239] Schamschula E, Lahnsteiner A, Assenov Y, et al. Disease-related blood-based differential methylation in cystic fibrosis and its representation in lung cancer revealed a regulatory locus in PKP3 in lung epithelial cells. Epigenetics. 2022; 17(8): 837-860.

[240] O’Leary K, Shia A, Schmid P. Epigenetic regulation of EMT in non-small cell lung cancer. Curr Cancer Drug Targets. 2018; 18(1): 89-96.

[241] Nicorescu I, Dallinga GM, de Winther MPJ, Stroes ESG, Bahjat M. Potential epigenetic therapeutics for atherosclerosis treatment. Atherosclerosis. 2019; 281: 189-197.

[242] Franco F, Jaccard A, Romero P, Yu YR, Ho PC. Metabolic and epigenetic regulation of T-cell exhaustion. Nature metabolism. 2020; 2(10): 1001-1012.

[243] Su S, Chen J, Yao H, et al. CD10(+)GPR77(+) cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell. 2018; 172(4): 841-856.e816.

[244] Chen Y, Zhu WG. Biological function and regulation of histone and non-histone lysine methylation in response to DNA damage. Acta Biochim Biophy Sin. 2016; 48(7): 603-616.

[245] Xia M, Wang B, Wang Z, Zhang X, Wang X. Epigenetic regulation of NK cell-mediated antitumor immunity. Front Immunol. 2021; 12: 672328.

[246] Zhang Y, Good-Jacobson KL. Epigenetic regulation of B cell fate and function during an immune response. Immunol Rev. 2019; 288(1): 75-84.

[247] Weber R, Fleming V, Hu X, et al. Myeloid-derived suppressor cells hinder the anti-cancer activity of immune checkpoint inhibitors. Front Immunol. 2018; 9: 1310.

[248] Lo YMD, Han DSC, Jiang P, Chiu RWK. Epigenetics, fragmentomics, and topology of cell-free DNA in liquid biopsies. Science. 2021; 372(6538): eaaw3616.

[249] Jin S, Zhu D, Shao F, et al. Efficient detection and post-surgical monitoring of colon cancer with a multi-marker DNA methylation liquid biopsy. Proc Nat Acad Sci USA. 2021; 118(5): e2017421118.

[250] Li Y, Seto E. HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb Perspect Med. 2016; 6(10): a026831.

[251] Casagrande GMS, Silva MO, Reis RM, Leal LF. Liquid biopsy for lung cancer: up-to-date and perspectives for screening programs. Int J Mol Sci. 2023; 24(3): 2505.

[252] Xu RH, Wei W, Krawczyk M, et al. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma. Nat Mater. 2017; 16(11): 1155-1161.

[253] Dietrich D, Weider S, de Vos L, et al. Circulating cell-free SEPT9 DNA methylation in blood is a biomarker for minimal residual disease detection in head and neck squamous cell carcinoma patients. Clin Chem. 2023; 69(9): 1050-1061.

[254] Moqri M, Herzog C, Poganik JR, et al. Biomarkers of aging for the identification and evaluation of longevity interventions. Cell. 2023; 186(18): 3758-3775.

[255] García-Giménez JL, Mena-Mollá S, Beltrán-García J, Sanchis-Gomar F. Challenges in the analysis of epigenetic biomarkers in clinical samples. Clin Chem Lab Med. 2017; 55(10): 1474-1477.

[256] Giri AK, Aittokallio T. DNMT inhibitors increase methylation in the cancer genome. Front Pharmacol. 2019; 10: 385.

[257] Tellez CS, Picchi MA, Juri D, et al. Chromatin remodeling by the histone methyltransferase EZH2 drives lung pre-malignancy and is a target for cancer prevention. Clinical epigenetics. 2021; 13(1): 44.

[258] Reggiani F, Talarico G, Gobbi G, et al. BET inhibitors drive Natural Killer activation in non-small cell lung cancer via BRD4 and SMAD3. Nat Commun. 2024; 15(1): 2567.

[259] Duan L, Tadi MJ, Maki CG. CSE1L is a negative regulator of the RB-DREAM pathway in p53 wild-type NSCLC and can be targeted using an HDAC1/2 inhibitor. Sci Rep. 2023; 13(1): 16271.

[260] Gaździcka J, Świętek A, Hudy D, et al. Concentration of secreted frizzled-related proteins (SFRPs) in non-small cell lung carcinoma subtypes—a preliminary study. Current oncology (Toronto, Ont). 2023; 30(11): 9968-9980.

[261] Pawlak A, Chybicka K, Zioło E, Strządała L, Kałas W. The contrasting delayed effects of transient exposure of colorectal cancer cells to decitabine or azacitidine. Cancers. 2022; 14(6): 1530.

[262] Sunaga N, Kaira K, Shimizu K, et al. The oncogenic role of LGR6 overexpression induced by aberrant Wnt/β-catenin signaling in lung cancer. Thoracic cancer. 2024; 15(2): 131-141.

[263] He T, Gao Y, Fang Y, et al. The HDAC inhibitor GCJ-490A suppresses c-Met expression through IKKα and overcomes gefitinib resistance in non-small cell lung cancer. Cancer Biol Med. 2022; 19(8): 1172-1192.

[264] Yang L, Jin M, Jeong KW. Histone H3K4 methyltransferases as targets for drug-resistant cancers. Biology. 2021; 10(7): 581.

[265] Li Y, Li M, Jin F, Liu J, Chen M, Yin J. DNAJC12 promotes lung cancer growth by regulating the activation of β-catenin. Int J Mol Med. 2021; 47(6): 105.

[266] Hao A, Wang Y, Stovall DB, Wang Y, Sui G. Emerging roles of LncRNAs in the EZH2-regulated oncogenic network. Int J Biol Sci. 2021; 17(13): 3268-3280.

[267] Zhang J, Liu L, Wei X, et al. Pan-cancer characterization of ncRNA synergistic competition uncovers potential carcinogenic biomarkers. PLoS Comput Biol. 2023; 19(10): e1011308.

[268] Khan FB, Uddin S, Elderdery AY, et al. Illuminating the molecular intricacies of exosomes and ncRNAs in cardiovascular diseases: prospective therapeutic and biomarker potential. Cells. 2022; 11(22): 3664.

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