Volume 33, Issue 159 (July & August 2025)                   J Adv Med Biomed Res 2025, 33(159): 299-308 | Back to browse issues page

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Jahandoust S, Farhangiyan P, Khalili M. LincRNA-p21 Downregulation: A Suppressor of Cell Cycle Dysregulation and A Promising Biomarker for Gastric Cancer. J Adv Med Biomed Res 2025; 33 (159) :299-308
URL: http://journal.zums.ac.ir/article-1-7589-en.html
LincRNA-p21 Downregulation: A Suppressor of Cell Cycle Dysregulation and A Promising Biomarker for Gastric Cancer
Somayeh Jahandoust1 , Pourandokht Farhangiyan1 , Mitra Khalili *2
1- Cancer Gene Therapy Research Center (CGRC), Zanjan University of Medical Sciences, Zanjan, Iran & Department of Medical Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
2- Cancer Gene Therapy Research Center (CGRC), Zanjan University of Medical Sciences, Zanjan, Iran & Department of Medical Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran , khalili.mitra@gmail.com
Abstract:   (144 Views)

Background & Objective:  Gastric cancer (GC) represents a major global health concern concern, often diagnosed at advanced stages with limited effective biomarkers for early detection. Long intergenic non-coding RNA p21 (lincRNA-p21) has been implicated in many cancers, yet its role in GC is not fully understood.
 Materials & Methods:  In the current case–control design, we analyzed long intergenic non-coding RNA p21 (lincRNA-p21)  gene expression in 40 matched tumor tissues along with their adjacent non-tumor counterparts , as well as in a panel of cancer and stem-like cell lines, including GC cell lines (AGS, MKN45), esophageal adenocarcinoma cell lines (FLO-1, OE-19), the human embryonal carcinoma cell line (NTERA2), human induced pluripotent stem cells (hiPSCs), and mesenchymal stem cells (MSCs). This approach was designed to explore whether lincRNA-p21 expression is linked to stemness and tumorigenic potential. RNA was extracted and processed for cDNA preparation, followed by quantitative PCR analysis. Additionally, public TCGA data were assessed via the UALCAN platform to evaluate the expression pattern of genes critical for cell cycle control (STAT3, CDK2, E2F) in gastric adenocarcinoma samples with differing p53 mutation statuses.
Results:  A significant reduction in lincRNA-p21 expression was identified in tumor tissues compared to non-tumor samples. (P = 0.01), and its reduced expression was consistent across various malignancy grades. Similarly, GC and stem-like cell lines exhibited lower lincRNA-p21 levels compared to normal controls, suggesting a role in suppressing stemness and tumor progression. TCGA analysis revealed elevated STAT3, CDK2, and E2F expression in both p53-mutated and wild-type gastric tumors, implicating dysregulation of the lincRNA-p21–P21–P53 axis in GC pathogenesis.
Conclusion:  The reduced levels of lincRNA-p21 and P21, along with elevated STAT3, CDK2, and E2F, indicate disrupted cell cycle control and tumorigenesis in GC. Consistent lincRNA-p21 downregulation across malignancy stages suggests its potential as an early prognostic biomarker for GC detection.

Keywords: Gastric Cancer, lincRNA-p21, Cancer Stem Cells, P21-P53 Axis, Biomarker
     
Type of Study: Original Research Article | Subject: Medical Biology
Received: 2025/02/11 | Accepted: 2025/08/31 | Published: 2025/09/29
References
1. Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet. 2020;396(10251):635-48. [DOI:10.1016/S0140-6736(20)31288-5] [PMID]
2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-49. [DOI:10.3322/caac.21660] [PMID]
3. Dykes IM, Emanueli C. Transcriptional and Post-transcriptional Gene Regulation by Long Non-coding RNA. Genom Proteom Bioinform. 2017;15(3):177-86. [DOI:10.1016/j.gpb.2016.12.005] [PMID] [PMCID]
4. Ciafrè SA, Russo M, Michienzi A, Galardi S. Long Noncoding RNAs and Cancer Stem Cells: Dangerous Liaisons Managing Cancer. Int J Mol Sci. 2023;24(3):1828. [DOI:10.3390/ijms24031828] [PMID] [PMCID]
5. Fischer M, Riege K, Hoffmann S. The landscape of human p53‐regulated long non‐coding RNAs reveals critical host gene co‐regulation. Mol Oncol. 2023;17(7):1263-79. [DOI:10.1002/1878-0261.13405] [PMID] [PMCID]
6. Bao X, Wu H, Zhu X, Guo X, Hutchins AP, Luo Z, et al. The p53-induced lincRNA-p21 derails somatic cell reprogramming by sustaining H3K9me3 and CpG methylation at pluripotency gene promoters. Cell Res. 2015;25(1):80-92. [DOI:10.1038/cr.2014.165] [PMID] [PMCID]
7. Huang Y, Yi Q, Feng J, Xie W, Sun W, Sun W. The role of lincRNA-p21 in regulating the biology of cancer cells. Hum Cell. 2022;35(6):1640-9. [DOI:10.1007/s13577-022-00768-4] [PMID]
8. Huarte M, Guttman M, Feldser D, Garber M, Koziol MJ, Kenzelmann-Broz D, et al. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell. 2010;142(3):409-19. [DOI:10.1016/j.cell.2010.06.040] [PMID] [PMCID]
9. Dimitrova N, Zamudio JR, Jong RM, Soukup D, Resnick R, Sarma K, et al. LincRNA-p21 activates p21 in cis to promote Polycomb target gene expression and to enforce the G1/S checkpoint. Mol Cell. 2014;54(5):777-90. [DOI:10.1016/j.molcel.2014.04.025] [PMID] [PMCID]
10. Jia M, Jiang L, Wang YD, Huang JZ, Yu M, Xue HZ. lincRNA-p21 inhibits invasion and metastasis of hepatocellular carcinoma through Notch signaling-induced epithelial-mesenchymal transition. Hepatol Res. 2016;46(11):1137-44. [DOI:10.1111/hepr.12659] [PMID]
11. Yu F, Guo Y, Chen B, Shi L, Dong P, Zhou M, et al. LincRNA-p21 Inhibits the Wnt/β-Catenin Pathway in Activated Hepatic Stellate Cells via Sponging MicroRNA-17-5p. Cell Physiol Biochem. 2017;41(5):1970-80. [DOI:10.1159/000472410] [PMID]
12. Chen S, Liang H, Yang H, Zhou K, Xu L, Liu J, et al. LincRNa-p21: function and mechanism in cancer. Med Oncol. 2017;34(5):98. [DOI:10.1007/s12032-017-0959-5] [PMID]
13. Khalili M, Vasei M, Khalili D, Alimoghaddam K, Sadeghizadeh M, Mowla SJ. Downregulation of the Genes Involved in Reprogramming (SOX2, c-MYC, miR-302, miR-145, and P21) in Gastric Adenocarcinoma. J Gastrointest Cancer. 2015;46(3):251-8. [DOI:10.1007/s12029-015-9695-2] [PMID]
14. Chandrashekar DS, Karthikeyan SK, Korla PK, Patel H, Shovon AR, Athar M, et al. UALCAN: An update to the integrated cancer data analysis platform. Neoplasia. 2022;25:18-27. [DOI:10.1016/j.neo.2022.01.001] [PMID] [PMCID]
15. Hall JR, Messenger ZJ, Tam HW, Phillips SL, Recio L, Smart RC. Long noncoding RNA lincRNA-p21 is the major mediator of UVB-induced and p53-dependent apoptosis in keratinocytes. Cell Death Dis. 2015;6(3):e1700. [DOI:10.1038/cddis.2015.67] [PMID] [PMCID]
16. Yang N, Fu Y, Zhang H, Sima H, Zhu N, Yang G. LincRNA-p21 activates endoplasmic reticulum stress and inhibits hepatocellular carcinoma. Oncotarget. 2015;6(29):28151-63. [DOI:10.18632/oncotarget.4661] [PMID] [PMCID]
17. Zhai H, Fesler A, Schee K, Fodstad O, Flatmark K, Ju J. Clinical significance of long intergenic noncoding RNA-p21 in colorectal cancer. Clin Colorectal Cancer. 2013;12(4):261-6. [DOI:10.1016/j.clcc.2013.06.003] [PMID]
18. Işın M, Uysaler E, Özgür E, Köseoğlu H, Şanlı Ö, Yücel Ö B, et al. Exosomal lncRNA-p21 levels may help to distinguish prostate cancer from benign disease. Front Genet. 2015;6:168. [DOI:10.3389/fgene.2015.00168] [PMID] [PMCID]
19. Wang X, Ruan Y, Wang X, Zhao W, Jiang Q, Jiang C, et al. Long intragenic non-coding RNA lincRNA-p21 suppresses development of human prostate cancer. Cell Prolif. 2017;50(2):e12318. [DOI:10.1111/cpr.12318] [PMID] [PMCID]
20. Isin M, Ozgur E, Cetin G, Erten N, Aktan M, Gezer U, et al. Investigation of circulating lncRNAs in B-cell neoplasms. Clin Chim Acta. 2014;431:255-9. [DOI:10.1016/j.cca.2014.02.010] [PMID]
21. Yang F, Zhang H, Mei Y, Wu M. Reciprocal regulation of HIF-1α and lincRNA-p21 modulates the Warburg effect. Mol Cell. 2014;53(1):88-100. [DOI:10.1016/j.molcel.2013.11.004] [PMID]
22. Chen L, Yuan D, Yang Y, Ren M. LincRNA-p21 enhances the sensitivity of radiotherapy for gastric cancer by targeting the β-catenin signaling pathway. J Cell Biochem. 2019;120(4):6178-87. [DOI:10.1002/jcb.27905] [PMID]
23. Shao S, Zhao X, Zhang X, Luo M, Zuo X, Huang S, et al. Notch1 signaling regulates the epithelial-mesenchymal transition and invasion of breast cancer in a Slug-dependent manner. Mol Cancer. 2015;14(1):28. [DOI:10.1186/s12943-015-0295-3] [PMID] [PMCID]
24. Kawamura T, Suzuki J, Wang YV, Menendez S, Morera LB, Raya A, et al. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature. 2009;460(7259):1140-4. [DOI:10.1038/nature08311] [PMID] [PMCID]
25. Ma X, Yan W, Xu P, Ma L, Zan Y, Huang L, et al. LncRNA-p21 suppresses cell proliferation and induces apoptosis in gastric cancer by sponging miR-514b-3p and up-regulating ARHGEF9 expression. Biol Chem. 2022;403(10):945-58. [DOI:10.1515/hsz-2022-0153] [PMID]
26. Chen Y, Wei G, Xia H, Yu H, Tang Q, Bi F. Down regulation of lincRNA-p21 contributes to gastric cancer development through Hippo-independent activation of YAP. Oncotarget. 2017;8(38):63813-24. [DOI:10.18632/oncotarget.19130] [PMID] [PMCID]
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