Volume 9, Issue 4 (Vol.9 No.4 Jan 2021)
rbmb.net 2021, 9(4): 478-489 |
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Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran. & Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran.
Abstract: (3151 Views)
Background: Gastric cancer is among the most common cancers worldwide that currently lacks effective diagnostic biomarkers and therapeutic targets. Next-generation RNA sequencing is a powerful tool that allows rapid and accurate transcriptome-wide profiling to detect differentially expressed transcripts involved in normal biological and pathological processes. Given the function of this technique, it has the potential to identify new molecular targets for the early diagnosis of disease, particularly in gastric adenocarcinoma.
Methods: In this study, whole-transcriptome analysis was performed with RNA sequencing on tumoral and non-tumoral tissue samples from patients with early-stage gastric cancer. Gene ontology and pathway enrichment analysis were used to determine the main function of the specific genes and pathways present in tissue samples.
Results: Analysis of the differentially expressed genes revealed 5 upregulated and 234 downregulated genes in gastric cancer tissues. Pathway enrichment analysis revealed significantly dysregulated signalling pathways, including those involved in gastric acid secretion, drug metabolism and transporters, molecular toxicology, O-linked glycosylation of mucins, immunotoxicity, metabolism of xenobiotics by cytochrome P450, and glycosylation. We also found novel downregulated non-coding RNAs present in gastric cancer tissues, including GATA6 antisense RNA 1, antisense to LYZ, antisense P4HB, overlapping ACER2, long intergenic non-protein coding RNA 2688 (LINC02688) and uncharacterized LOC25845 (PP7080).
Conclusions: The transcriptomic data found in this study illustrates the power of RNA-sequencing in discovering novel genes and tumorigenic pathways involved in human carcinogenesis. The anomalies present in these genes may serve as promising tools for the development of accurate diagnostic biomarkers for the detection of early-stage gastric cancer.
Methods: In this study, whole-transcriptome analysis was performed with RNA sequencing on tumoral and non-tumoral tissue samples from patients with early-stage gastric cancer. Gene ontology and pathway enrichment analysis were used to determine the main function of the specific genes and pathways present in tissue samples.
Results: Analysis of the differentially expressed genes revealed 5 upregulated and 234 downregulated genes in gastric cancer tissues. Pathway enrichment analysis revealed significantly dysregulated signalling pathways, including those involved in gastric acid secretion, drug metabolism and transporters, molecular toxicology, O-linked glycosylation of mucins, immunotoxicity, metabolism of xenobiotics by cytochrome P450, and glycosylation. We also found novel downregulated non-coding RNAs present in gastric cancer tissues, including GATA6 antisense RNA 1, antisense to LYZ, antisense P4HB, overlapping ACER2, long intergenic non-protein coding RNA 2688 (LINC02688) and uncharacterized LOC25845 (PP7080).
Conclusions: The transcriptomic data found in this study illustrates the power of RNA-sequencing in discovering novel genes and tumorigenic pathways involved in human carcinogenesis. The anomalies present in these genes may serve as promising tools for the development of accurate diagnostic biomarkers for the detection of early-stage gastric cancer.
Type of Article: Original Article |
Subject:
Cell Biology
Received: 2020/09/12 | Accepted: 2020/09/24 | Published: 2021/03/8
Received: 2020/09/12 | Accepted: 2020/09/24 | Published: 2021/03/8
References
1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. [DOI:10.3322/caac.21492] [PMID]
2. Samadani A A, Nikbakhsh N, Taheri H, et al. CDX1/2 and KLF5 Expression and Epigenetic Modulation of Sonic Hedgehog Signaling in Gastric Adenocarcinoma. Pathol Oncol Res. 2019;25(3):1215-1222. [DOI:10.1007/s12253-019-00594-4] [PMID]
3. Fattahi S, Kosari-Monfared M, Ghadami E, Golpour M, Khodadadi P, Ghasemiyan M, et al. Infection-associated epigenetic alterations in gastric cancer: New insight in cancer therapy. J Cell Physiol. 2018;233(12):9261-9270. [DOI:10.1002/jcp.27030] [PMID]
4. Kahtan Al-Bayaty M, Abdul-Rudha Abass S, Faraj Al-Marjani M. E-Cadherin Protein as a Potential Marker for Gastric Cancer and Its Association with Helicobacter Pylori- Induced Gastritis and Gastric Ulcer. Rep Biochem Mol Biol. 2019;8(3):269-277.
5. Dassen A E, Lemmens V E, Van De Poll-Franse L V, Creemers J, Brenninkmeijer S J, Lips D J, et al. Trends in incidence, treatment and survival of gastric adenocarcinoma between 1990 and 2007: a population-based study in the Netherlands. Eur J Cancer. 2010;46(6):1101-10. [DOI:10.1016/j.ejca.2010.02.013] [PMID]
6. Liu G, Xu M, Gao T, Xu L, Zeng P, Bo H, et al. Surgical Compliance and Outcomes in Gastric Cancer: a population-based cohort study. J Cancer. 2019;10(4):779-788. [DOI:10.7150/jca.29073] [PMID] [PMCID]
7. Zhang J, Gan L, Wu Z, Yan S, Liu X, Guo W. The influence of marital status on the stage at diagnosis, treatment, and survival of adult patients with gastric cancer: a population-based study. Oncotarget. 2017;8(14):22385-22405. [DOI:10.18632/oncotarget.7399] [PMID] [PMCID]
8. Vishnubalaji R, Sasidharan Nair V, Ouararhni K, Elkord E, Alajez NM. Integrated Transcriptome and Pathway Analyses Revealed Multiple Activated Pathways in Breast Cancer. Front Oncol. 2019;9:910. [DOI:10.3389/fonc.2019.00910] [PMID] [PMCID]
9. Sun H. Identification of key genes associated with gastric cancer based on DNA microarray data. Oncol Lett. 2016;11(1):525-530. [DOI:10.3892/ol.2015.3929] [PMID] [PMCID]
10. Valdes-Mora F, Handler K, Law A M K, Salomon R, Oakes S R, Ormandy CJ, et al. Single-Cell Transcriptomics in Cancer Immunobiology: The Future of Precision Oncology. Front Immunol. 2018;9:2582. [DOI:10.3389/fimmu.2018.02582] [PMID] [PMCID]
11. Deng Z, Wang H, Guo G, Li X, Cai Y, Tang Y, et al. Next-Generation Sequencing Analysis of mRNA Profile in Cisplatin-Resistant Gastric Cancer Cell Line SGC7901. Med Sci Monit. 2019;25:2386-2396. [DOI:10.12659/MSM.915866] [PMID] [PMCID]
12. Li D, Yang W, Arthur C, Liu J S, Cruz-Niera C, Qu Yan M. Systems biology analysis reveals new insights into invasive lung cancer. BMC Syst Biol. 2018;12(Suppl 7):117. [DOI:10.1186/s12918-018-0637-z] [PMID] [PMCID]
13. Elchuri S V, Rajasekaran S, Miles W O. RNA-Sequencing of Primary Retinoblastoma Tumors Provides New Insights and Challenges Into Tumor Development. Front Genet. 2018;9:170. [DOI:10.3389/fgene.2018.00170] [PMID] [PMCID]
14. Yin H, Wang S, Zhang Y, Cai Y, Liu H. Analysis of Important Gene Ontology Terms and Biological Pathways Related to Pancreatic Cancer. BioMed Research International. 2016;2016:7861274. [DOI:10.1155/2016/7861274] [PMID] [PMCID]
15. Chen L, Zhang Y H, Lu G, Huang T, Cai Y-D. Analysis of cancer-related lncRNAs using gene ontology and KEGG pathways. Artif Intell Med. 2017;76:27-36. [DOI:10.1016/j.artmed.2017.02.001] [PMID]
16. Fattahi S, Kosari-Monfared M, Golpour M, Emami Z, Ghasemiyan M, Nouri M, et al. LncRNAs as potential diagnostic and prognostic biomarkers in gastric cancer: A novel approach to personalized medicine. J Cell Physiol. 2020;235(4):3189-3206. [DOI:10.1002/jcp.29260] [PMID]
17. Yamada A, Yu P, Lin W, Okugawa Y, Boland CR, Goel A. A RNA-Sequencing approach for the identification of novel long non-coding RNA biomarkers in colorectal cancer. Sci Rep. 2018;8(1):575. [DOI:10.1038/s41598-017-18407-6] [PMID] [PMCID]
18. Juan L, Tong H-L, Zhang P, Guo G, Wang Zi, Wen X, et al. Identification and characterization of novel serum microRNA candidates from deep sequencing in cervical cancer patients. Sci Rep. 2014;4:6277. [DOI:10.1038/srep06277] [PMID] [PMCID]
19. Zhang Y, Han T, Feng D, Li J, Wu M, Peng X, et al. Screening of non-invasive miRNA biomarker candidates for metastasis of gastric cancer by small RNA sequencing of plasma exosomes. Carcinogenesis. 2019;41(5):582-590. [DOI:10.1093/carcin/bgz186] [PMID]
20. Morash M, Mitchell H, Beltran H, Elemento O, Pathak J. The Role of Next-Generation Sequencing in Precision Medicine: A Review of Outcomes in Oncology. J Pers Med. 2018;8(3):30. [DOI:10.3390/jpm8030030] [PMID] [PMCID]
21. Suwinski P, Ong C, Ling M H T, Ming Poh Y, Khan A M, San Ong H. Advancing Personalized Medicine Through the Application of Whole Exome Sequencing and Big Data Analytics. Front Genet. 2019;10:49. [DOI:10.3389/fgene.2019.00049] [PMID] [PMCID]
22. Yao X, Smolka A J. Gastric Parietal Cell Physiology and Helicobacter pylori-Induced Disease. Gastroenterology. 2019;156(8):2158-2173. [DOI:10.1053/j.gastro.2019.02.036] [PMID] [PMCID]
23. Coronel-Castillo C E, Contreras-Carmona J, Méndez-Sánchez N. The proton pump inhibitors use and gastric cancer development: is it a real association?. AMJ. 2018. [DOI:10.21037/amj.2018.08.05]
24. Cheung K S, Chan E W, Wong A Y S, Chen L, Wong I C K, Keung Leung W. Long-term proton pump inhibitors and risk of gastric cancer development after treatment for Helicobacter pylori: a population-based study. Gut. 2018;67(1):28-35. [DOI:10.1136/gutjnl-2017-314605] [PMID]
25. Joo M K, Park J-J, Chun H J. Proton pump inhibitor: The dual role in gastric cancer. World J Gastroenterol. 2019;25(17):2058-2070. [DOI:10.3748/wjg.v25.i17.2058] [PMID] [PMCID]
26. Ahn J S, Eom C-S, Jeon C Y, Min Park S. Acid suppressive drugs and gastric cancer: a meta-analysis of observational studies. World J Gastroenterol. 2013;19(16):2560-8. [DOI:10.3748/wjg.v19.i16.2560] [PMID] [PMCID]
27. Zavros Y, Eaton K A, Kang W, Rathinavelu S, Katukuri V, Kao JY, et al. Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma. Oncogene. 2005;24(14):2354-66. [DOI:10.1038/sj.onc.1208407] [PMID]
28. Dokhaee F, Mazhari S, Galehdari M, Bahadori Monfared A, Baghaei K. Evaluation of GKN1 and GKN2 gene expression as a biomarker of gastric cancer. Gastroenterology and hepatology from bed to bench. 2018;11(Suppl 1):S140-S145.
29. Koper-Lenkiewicz O M, Kaminska J, Gawronska B, Matowicka-Karna J. The role and diagnostic potential of gastrokine 1 in gastric cancer. Cancer Manag Res. 2019;11:1921-1931. [DOI:10.2147/CMAR.S194949] [PMID] [PMCID]
30. Zhang Z, Xue H, Dong Y, Zhang J, Pan Y, Shi L, et al. GKN2 promotes oxidative stress-induced gastric cancer cell apoptosis via the Hsc70 pathway. J Exp Clin Cancer Res. 2019;38(1):338. [DOI:10.1186/s13046-019-1336-3] [PMID] [PMCID]
31. Yoon J H, Ham I-H, Kim O, Ashktorab H, Smoot DT, Nam SW, et al. Gastrokine 1 protein is a potential theragnostic target for gastric cancer. Gastric Cancer. 2018;21(6):956-967. [DOI:10.1007/s10120-018-0828-8] [PMID]
32. Shi L-S, Wang H, Wang F, FENG M, WANG M, GUAN W. Effects of gastrokine‑2 expression on gastric cancer cell apoptosis by activation of extrinsic apoptotic pathways. Mol Med Rep. 2014;10(6):2898-2904. [DOI:10.3892/mmr.2014.2603] [PMID] [PMCID]
33. Kong Y, Zheng Y, Jia Y, Li P, Wang Y. Decreased LIPF expression is correlated with DGKA and predicts poor outcome of gastric cancer. Oncol Rep. 2016;36(4):1852-60. [DOI:10.3892/or.2016.4989] [PMID] [PMCID]
34. Kim B, Bang S, Lee S, Kim S, Jung Y, Lee C, et al. Expression profiling and subtype-specific expression of stomach cancer. Cancer Res. 2003;63(23):8248-55.
35. Aihara E, Engevik K A, Montrose M H. Trefoil Factor Peptides and Gastrointestinal Function. Annu Rev Physiol. 2017;79:357-380. [DOI:10.1146/annurev-physiol-021115-105447] [PMID] [PMCID]
36. Song J-Y, Kim B-W, Lee A-W, Lee K-Y, Chung I-S, Lee B-I, et al. Expression of MUC5AC and Trefoil Peptide 1 (TFF1) in the Subtypes of Intestinal Metaplasia. Clin Endosc. 2012;45(2):151-154. [DOI:10.5946/ce.2012.45.2.151] [PMID] [PMCID]
37. Chen C-H. Genetic Variations and Polymorphisms of Metabolic Enzymes, in Xenobiotic Metabolic Enzymes: Bioactivation and Antioxidant Defense. 2020, Springer International Publishing. 155-68. [DOI:10.1007/978-3-030-41679-9_14]
38. He X, Feng S. Role of Metabolic Enzymes P450 (CYP) on Activating Procarcinogen and their Polymorphisms on the Risk of Cancers. Curr Drug Metab. 2015;16(10):850-63. [DOI:10.2174/138920021610151210164501] [PMID]
39. Zanger U M, Schwab M. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103-41. [DOI:10.1016/j.pharmthera.2012.12.007] [PMID]
40. Zhang G H, Chen M M, Kai J Y, Ma Q, Ling Zhong A, Hong Xie S, et al. Molecular profiling of mucinous epithelial ovarian cancer by weighted gene co-expression network analysis. Gene. 2019;709:56-64. [DOI:10.1016/j.gene.2019.05.034] [PMID]
41. Mcfadyen M C, Melvin W T, Murray G I. Cytochrome P450 CYP1B1 activity in renal cell carcinoma. Br J Cancer. 2004;91(5):966-971. [DOI:10.1038/sj.bjc.6602053] [PMID] [PMCID]
42. Rodriguez-Antona C, Ingelman-Sundberg M. Cytochrome P450 pharmacogenetics and cancer. Oncogene. 2006;25(11):1679-91. [DOI:10.1038/sj.onc.1209377] [PMID]
43. Murray G I, Taylor M C, Burke M D, Melvin WT. Enhanced expression of cytochrome P450 in stomach cancer. Br J Cancer. 1998;77(7):1040-1044. [DOI:10.1038/bjc.1998.173] [PMID] [PMCID]
44. Chugh S, Gnanapragassam V S, Jain M, Rachagani S, Ponnusamy MP, Batra SK. Pathobiological implications of mucin glycans in cancer: Sweet poison and novel targets. Biochim Biophys Acta. 2015;1856:211-25. [DOI:10.1016/j.bbcan.2015.08.003] [PMID] [PMCID]
45. Tuccillo F M, De Laurentiis A, Palmieri C, Fiume G, Bonelli P, Borrelli A. Aberrant glycosylation as biomarker for cancer: focus on CD43. Biomed Res Int. 2014;2014:742831. [DOI:10.1155/2014/742831] [PMID] [PMCID]
46. Duarte H O, Freitas D, Gomes C, Gomes J, Magalhães A, Reis CA. Mucin-Type O-Glycosylation in Gastric Carcinogenesis. Biomolecules. 2016;6(3):33. [DOI:10.3390/biom6030033] [PMID] [PMCID]
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