Promoter methylation of Wrap53α, an antisense transcript of p53, is associated with the poor prognosis of patients with non‑small cell lung cancer

Kim,Dong  Sun; Lee,Won  Kee; Park,Jae  Yong

doi:10.3892/ol.2018.9404

Promoter methylation of Wrap53α, an antisense transcript of p53, is associated with the poor prognosis of patients with non‑small cell lung cancer

Authors:
- Dong Sun Kim
- Won Kee Lee
- Jae Yong Park
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Affiliations: Department of Anatomy, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu 702‑422, Republic of Korea, Department of Preventive Medicine, School of Medicine, Kyungpook National University, Daegu 702‑422, Republic of Korea, Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu 702‑422, Republic of Korea
Published online on: September 5, 2018 https://doi.org/10.3892/ol.2018.9404
Pages: 5823-5828
Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Lung cancer, of which non‑small cell lung cancer (NSCLC) accounts for ~85% of cases, remains a leading cause of cancer‑associated mortality and morbidity worldwide. Tumor suppressor p53 is a master regulator of diverse cellular processes and is a therapeutic target in cancer. However, many aspects of its transcriptional regulation are still not well defined. WD repeat containing antisense to TP53α (Wrap53α) a newly identified natural antisense transcript of p53, can regulate p53 expression following DNA damage. The present study determined the methylation status of the Wrap53α promoter in primary lung tissues using methylation‑specific polymerase chain reaction and evaluated its associations with clinicopathological features and survival in patients with NSCLC. The Wrap53α promoter was methylated in 12 (8.2%) of 146 malignant tissues. Its methylation was associated with the downregulation of its transcription and was frequently detected in patients with stages II‑IIIA (P=0.03), and p53 mutation‑negative cases (P=0.08). Methylation of Wrap53α promoter was associated with worse overall survival of total patients with a borderline significance [adjusted Hazard Ratio (HR)=2.44, 95% Confidence Interval (CI)=0.98‑6.04, P=0.05]. Notably, Wrap53α promoter methylation significantly associated with poor overall survival in p53 mutation‑negative patients (log‑rank P=0.01, adjusted HR=2.92, 95% CI=1.00‑8.60, P=0.05), but not in patients with p53 mutations. The results of the present study suggest that Wrap53α may serve a role in the pathogenesis of a subset of lung cancer, and its methylation may be considered to be a prognostic marker for surgically resected NSCLC patients. However, further studies with a larger sample size are required to confirm this finding.

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1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	McIntyre A and Ganti AK: Lung cancer-A global perspective. J Surg Oncol. 115:550–554. 2017. View Article : Google Scholar : PubMed/NCBI
3	Kerr KM, Galler JS, Hagen JA, Laird PW and Laird-Offringa IA: The role of DNA methylation in the development and progression of lung adenocarcinoma. Dis Markers. 23:5–30. 2007. View Article : Google Scholar : PubMed/NCBI
4	Brzeziańska E, Dutkowska A and Antczak A: The significance of epigenetic alterations in lung carcinogenesis. Mol Biol Rep. 40:309–325. 2013. View Article : Google Scholar : PubMed/NCBI
5	Green DR and Kroemer G: Cytoplasmic functions of the tumour suppressor p53. Nature. 458:1127–1130. 2009. View Article : Google Scholar : PubMed/NCBI
6	Gibbons DL, Byers LA and Kurie JM: Smoking, p53 mutation, and lung cancer. Mol Cancer Res. 12:3–13. 2014. View Article : Google Scholar : PubMed/NCBI
7	Saldaña-Meyer R and Recillas-Targa F: Transcriptional and epigenetic regulation of the p53 tumor suppressor gene. Epigenetics. 6:1068–1077. 2011. View Article : Google Scholar : PubMed/NCBI
8	Mahmoudi S, Henriksson S, Corcoran M, Méndez-Vidal C, Wiman KG and Farnebo M: Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage. Mol Cell. 33:462–471. 2009. View Article : Google Scholar : PubMed/NCBI
9	Bug M and Dobbelstein M: Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanism. Oncogene. 30:3612–3624. 2011. View Article : Google Scholar : PubMed/NCBI
10	Yuan JM, Li XD, Liu ZY, Hou GQ, Kang JH, Huang DY and Du SX: Cisplatin induces apoptosis via upregulating Wrap53 in U-2OS osteosarcoma cells. Asian Pac J Cancer Prev. 12:3465–3469. 2011.PubMed/NCBI
11	Pouladi N, Kouhsari SM, Feizi MH, Gavgani RR and Azarfam P: Overlapping region of p53/wrap53 transcripts: Mutational analysis and sequence similarity with microRNA-4732-5p. Asian Pac J Cancer Prev. 14:3503–3507. 2013. View Article : Google Scholar : PubMed/NCBI
12	Mahmoudi S, Henriksson S, Farnebo L, Roberg K and Farnebo M: WRAP53 promotes cancer cell survival and is a potential target for cancer therapy. Cell Death Dis. 2:e1142011. View Article : Google Scholar : PubMed/NCBI
13	Zhang H, Wang DW, Adell G and Sun XF: WRAP53 is an independent prognostic factor in rectal cancer-a study of Swedish clinical trial of preoperative radiotherapy in rectal cancer patients. BMC Cancer. 12:2942012. View Article : Google Scholar : PubMed/NCBI
14	Rao X and Huang D, Sui X, Liu G, Song X, Xie J and Huang D: Overexpression of WRAP53 is associated with development and progression of esophageal squamous cell carcinoma. PLoS One. 9:e916702014. View Article : Google Scholar : PubMed/NCBI
15	Yuan XS, Cao LX, Hu YJ, Bao FC, Wang ZT, Cao JL, Yuan P, Lv W and Hu J: Clinical, cellular, and bioinformatic analyses reveal involvement of WRAP53 overexpression in carcinogenesis of lung adenocarcinoma. Tumor Biol. 39:10104283176943092017. View Article : Google Scholar
16	Lee EB, Jin G, Lee SY, Park JY, Kim MJ, Choi JE, Jeon HS, Cha SI, Cho S, Kim CH, et al: TP53 mutations in Korean patients with non-small cell lung cancer. J Korean Med Sci. 25:698–705. 2010. View Article : Google Scholar : PubMed/NCBI
17	Swiatkowska A, Zydowicz P, Sroka J and Ciesiołka J: The role of the 5′ terminal region of p53 mRNA in the p53 gene expression. Acta Biochim Pol. 63:645–651. 2016. View Article : Google Scholar : PubMed/NCBI
18	Alonso S, Izarirre N, López S, Smith-Zubiaga I, Hervella M, Boyano MD, Arroyo-Berdugo Y, Gardeazabal J, Díaz-Ramón JL, Sánchez Díez A, et al: The diversity profile of TP53 is influenced by positive selection on the immediately upstream locus WDR79. Hum Hered. 69:34–44. 2010. View Article : Google Scholar : PubMed/NCBI
19	Nie L, Wu HJ, Hsu JM, Chang SS, Labaff AM, Li CW, Wang Y, Hsu JL and Hung MC: Long non-coding RNAs: Versatile master regulators of gene expression and crucial players in cancer. Am J Transl Res. 4:127–150. 2012.PubMed/NCBI
20	Su WY, Xing H and Fang JY: Natural antisense transcripts regulate gene expression in an epigenetic manner. Biochem Biophys Res Commun. 396:177–181. 2010. View Article : Google Scholar : PubMed/NCBI
21	Kanai Y: Alterations of DNA methylation and clinicopathological diversity of human cancers. Pathol Int. 58:544–558. 2008. View Article : Google Scholar : PubMed/NCBI
22	Wu Q and Ni X: ROS-mediated DNA methylation pattern alterations in carcinogenesis. Curr Drug Targets. 16:13–19. 2015. View Article : Google Scholar : PubMed/NCBI
23	Lin RK and Wang YC: Dysregulated transcriptional and post-translational control of DNA methyltransferases in cancer. Cell Biosci. 4:462014. View Article : Google Scholar : PubMed/NCBI
24	Jin T, Hao J and Fan D: Nicotine induces aberrant hypermethylation of tumor suppressor genes in pancreatic epithelial ductal cells. Biochem Biophys Res Commun. 499:934–940. 2018. View Article : Google Scholar : PubMed/NCBI
25	Lin RK, Wu CY, Chang JW, Juan LJ, Hsu HS, Chen CY, Lu YY, Tang YA, Yang YC, Yang PC and Wang YC: Dysregulation of p53/Sp1 control leads to DNA methyltransferase-1 overexpression in lung cancer. Cancer Res. 70:5807–5817. 2010. View Article : Google Scholar : PubMed/NCBI
26	Tang YA, Tsai YT, Lin RK, Hsu HS, Chen CY and Wang YC: Dysregulation of p53 and RB transcriptional control leads to overexperssion of DNA methyltransferase in lung cancer. J Cancer Res Pract. 1:14–27. 2014. View Article : Google Scholar
27	Yue X, Zhao Y, Xu Y, Zheng M, Feng Z and Hu W: Mutant p53 in cancer: Accumulation, gain-of-function, and therapy. J Mol Biol. 429:1595–1606. 2017. View Article : Google Scholar : PubMed/NCBI
28	Yeang CH, McComick F and Levine A: Combinatorial patterns of somatic gene mutations in cancer. FASEB J. 22:2605–2622. 2008. View Article : Google Scholar : PubMed/NCBI