Abstract
In recent years, the mortality rate of lung adenocarcinoma (LUAD) is persistently increasing, which has already caused a huge impact on human living standards. Hence, there is an urgent need to probe the molecular mechanism of LUAD progression, so as to disclose prognostic and diagnostic markers for patients with LUAD. Methylation 450 K data and mRNA expression data of LUAD were obtained via bioinformatics analysis to screen methylation-driven genes. The expression of the target gene was detected through qRT-PCR, while the methylation level was evaluated via methylation-specific PCR (MSP). The impact of the gene on cell proliferation, migration, invasion, apoptosis and cell cycle was measured through CCK-8, wound healing, Transwell invasion assay, and flow cytometry. CFTR was defined by bioinformatics analysis as the target gene for this study. qRT-PCR revealed that CFTR was lowly expressed in LUAD cells. MSP displayed that the CFTR promoter region in LUAD cells was hypermethylated, and demethylation could pronouncedly increase the level of CFTR mRNA in LUAD cells. Cell biological functional experiments exhibited that CFTR hindered cell proliferation, migration, and invasion, fostered cell apoptosis of LUAD, and blocked the cell cycle in G2-M phase. CFTR was hypermethylated in LUAD, which mediated the low expression of CFTR in LUAD to stimulate the progression of LUAD.
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Data Availability
The data and materials in the current study are available from the corresponding author on reasonable request.
Change history
19 September 2021
The original online version of this article was revised: The email address of the author ‘Yue Wang’ has been changed.
References
Couzin-Frankel JG (2009) The promise of a cure: 20 years and counting. Science 324:1504–1507. https://doi.org/10.1126/science.324_1504
Gevaert O (2015) MethylMix: an R package for identifying DNA methylation-driven genes. Bioinformatics 31:1839–1841. https://doi.org/10.1093/bioinformatics/btv020
Greger V et al (1994) Frequency and parental origin of hypermethylated RB1 alleles in retinoblastoma. Hum Genet 94:491–496. https://doi.org/10.1007/BF00211013
Guo H et al (2014) The DNA methylation landscape of human early embryos. Nature 511:606–610. https://doi.org/10.1038/nature13544
Hanada M, Delia D, Aiello A, Stadtmauer E, Reed JC (1993) bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood 82:1820–1828
Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93:9821–9826. https://doi.org/10.1073/pnas.93.18.9821
Hoffmann F et al (2020) Prognostic and predictive value of PD-L2 DNA methylation and mRNA expression in melanoma. Clin Epigenet 12:94. https://doi.org/10.1186/s13148-020-00883-9
Kerschner JL, Gosalia N, Leir SH, Harris A (2014) Chromatin remodeling mediated by the FOXA1/A2 transcription factors activates CFTR expression in intestinal epithelial cells. Epigenetics 9:557–565. https://doi.org/10.4161/epi.27696
Li N et al (2016) miR-215 promotes malignant progression of gastric cancer by targeting RUNX1. Oncotarget 7:4817–4828. https://doi.org/10.18632/oncotarget.6736
Li W et al (2018) CFTR inhibits the invasion and growth of esophageal cancer cells by inhibiting the expression of NF-kappaB. Cell Biol Int 42:1680–1687. https://doi.org/10.1002/cbin.11069
Liu J et al (2016) CDH1 promoter methylation correlates with decreased gene expression and poor prognosis in patients with breast cancer. Oncol Lett 11:2635–2643. https://doi.org/10.3892/ol.2016.4274
Liu C, Song C, Li J, Sun Q (2020) CFTR functions as a tumor suppressor and is regulated by DNA methylation in colorectal cancer. Cancer Manag Res 12:4261–4270. https://doi.org/10.2147/CMAR.S248539
Ma K, Cao B, Guo M (2016) The detective, prognostic, and predictive value of DNA methylation in human esophageal squamous cell carcinoma. Clin Epigenet 8:43. https://doi.org/10.1186/s13148-016-0210-9
McGuinness C, Wesley UV (2008) Dipeptidyl peptidase IV (DPPIV), a candidate tumor suppressor gene in melanomas is silenced by promoter methylation. Front Biosci 13:2435–2443. https://doi.org/10.2741/2856
Moore LD, Le T, Fan G (2013) DNA methylation and its basic function. Neuropsychopharmacology 38:23–38. https://doi.org/10.1038/npp.2012.112
Mostafa AA, Morris DG (2014) Immunotherapy for lung cancer: has it finally arrived? Front Oncol 4:288. https://doi.org/10.3389/fonc.2014.00288
Nakamura H, Saji H (2014) Worldwide trend of increasing primary adenocarcinoma of the lung. Surg Today 44:1004–1012. https://doi.org/10.1007/s00595-013-0636-z
Pearson H (2009) Human genetics: one gene, twenty years. Nature 460:164–169. https://doi.org/10.1038/460164a
Relli V, Trerotola M, Guerra E, Alberti S (2018) Distinct lung cancer subtypes associate to distinct drivers of tumor progression. Oncotarget 9:35528–35540. https://doi.org/10.18632/oncotarget.26217
Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6:597–610. https://doi.org/10.1038/nrg1655
Sakai T et al (1991) Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. Am J Hum Genet 48:880–888
Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67:7–30. https://doi.org/10.3322/caac.21387
Son JW et al (2011) Promoter hypermethylation of the CFTR gene and clinical/pathological features associated with non-small cell lung cancer. Respirology 16:1203–1209. https://doi.org/10.1111/j.1440-1843.2011.01994.x
Song X et al (2018) High PITX1 expression in lung adenocarcinoma patients is associated with DNA methylation and poor prognosis. Pathol Res Pract 214:2046–2053. https://doi.org/10.1016/j.prp.2018.09.025
Wang Y et al (2017) Methylation of ZNF331 is an independent prognostic marker of colorectal cancer and promotes colorectal cancer growth. Clin Epigenet 9:115. https://doi.org/10.1186/s13148-017-0417-4
Wang X et al (2018) Overexpression of geranylgeranyl diphosphate synthase contributes to tumour metastasis and correlates with poor prognosis of lung adenocarcinoma. J Cell Mol Med 22:2177–2189. https://doi.org/10.1111/jcmm.13493
Wu Z, Li J, Zhang Y, Hu L, Peng X (2020) CFTR regulates the proliferation, migration and invasion of cervical cancer cells by inhibiting the NF-kappaB signalling pathway. Cancer Manag Res 12:4685–4697. https://doi.org/10.2147/CMAR.S252296
Xia X, Wang J, Liu Y, Yue M (2017) Lower cystic fibrosis transmembrane conductance regulator (CFTR) promotes the proliferation and migration of endometrial carcinoma. Med Sci Monit 23:966–974. https://doi.org/10.12659/msm.899341
Xie C et al (2013) CFTR suppresses tumor progression through miR-193b targeting urokinase plasminogen activator (uPA) in prostate cancer. Oncogene. https://doi.org/10.1038/onc.2012.251
Xu X (2015) DNA methylation and cognitive aging. Oncotarget 6:13922–13932. https://doi.org/10.18632/oncotarget.4215
Xu J et al (2015) High level of CFTR expression is associated with tumor aggression and knockdown of CFTR suppresses proliferation of ovarian cancer in vitro and in vivo. Oncol Rep 33:2227–2234. https://doi.org/10.3892/or.2015.3829
Yang A et al (2018) Homocysteine activates autophagy by inhibition of CFTR expression via interaction between DNA methylation and H3K27me3 in mouse liver. Cell Death Dis 9:169. https://doi.org/10.1038/s41419-017-0216-z
Yang M et al (2020) Methylation-induced silencing of ALDH2 facilitates lung adenocarcinoma bone metastasis by activating the MAPK pathway. Front Oncol 10:1141. https://doi.org/10.3389/fonc.2020.01141
Young B et al (2008) First large, multicenter, open-label study utilizing HLA-B*5701 screening for abacavir hypersensitivity in North America. AIDS 22:1673–1675. https://doi.org/10.1097/QAD.0b013e32830719aa
Zhang JT et al (1833) Downregulation of CFTR promotes epithelial-to-mesenchymal transition and is associated with poor prognosis of breast cancer. Biochim Biophys Acta 2961–2969:2013. https://doi.org/10.1016/j.bbamcr.2013.07.021
Zheng R et al (2017) Methylation of DIRAS1 promotes colorectal cancer progression and may serve as a marker for poor prognosis. Clin Epigenet 9:50. https://doi.org/10.1186/s13148-017-0348-0
Ziakas PD, Poulou LS, Zintzaras E (2016) FcgammaRIIa-H131R variant is associated with inferior response in diffuse large B cell lymphoma: a meta-analysis of genetic risk. J BUON 21:1454–1458
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This study was supported by the funds from the 13th 5-Year Plan Industrialization Project of Jilin Provincial Department of Education (JJKH20201060KJ).
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LT contributed to the study design. LL conducted the literature search. PY acquired the data. SX wrote the article. YW performed data analysis. LX drafted and revised the article. ZX gave the final approval of the version to be submitted.
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Wang, Y., Tang, L., Yang, L. et al. DNA Methylation-Mediated Low Expression of CFTR Stimulates the Progression of Lung Adenocarcinoma. Biochem Genet 60, 807–821 (2022). https://doi.org/10.1007/s10528-021-10128-w
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DOI: https://doi.org/10.1007/s10528-021-10128-w