Abstract
Objective The aim of the present work was to investigate the expression of nitric oxide synthase 2 (iNOS/ NOS2) in colorectal and gastric cancers and evaluate its association with patient’s prognosis by integrated bioinformatics analysis.
Methods The data for present study was obtained from the TCGA, GTEx, and STRING database. iNOS/NOS2 mRNA expression in normal tissue and colorectal, and gastric cancer tissuea were investigated through the GTEx and TCGA database. iNOS/NOS2 gene mutations and frequency were analyzed in the TCGA database using the cBioPortal online data analysis tool. The protein-protein interaction (PPI) network of iNOS/NOS2 was constructed by STRING database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of iNOS/NOS2 and relevant proteins involved in the PPI network were enriched and demonstrated by the bubble plot. Comparison of the overall survival(OS) and disease free survival(DFS) between samples expressing high and low levels of iNOS/NOS2 was analysis based on the TCGA databases through the GEPIA online data analysis tool.
Results For colon adenocarcinoma (COAD) and rectal adenocarcinoma(READ) iNOS/NOS2 mRNA expression levels in tumor tissue were significant higher than those of corresponding normal colorectal tissue (p<0.05). iNOS/NOS2 mutations were identified in both colorectal cancer and gastric cancer. Missense substitutions and synonymous substitution were the top two mutation types for colorectal and gastric cancer. The top positive and negative co-expressed genes correlated with iNOS/ NOS2 were TRIM40 (rpearson=0.56, p<0.05) and GDPD5 (rpearson=-0.41, p<0.05) in colorectal cancer respectively andCASP5 (rpearson=0.63,p<0.05) and PIAS3 (rpearson=-0.43,p<0.05) in gastric cancer. Twenty one proteins were included in the PPI network with 51 nodes and 345 edges which indicated the PPI enrichment wassignificant (p=1.0e-16). The KEGG of the included genes were mainly enriched in metabolic pathway and Jak-STAT signaling pathway. There was a significant difference indisease free survival (DFS) between samples expressing high and low iNOS/NOS2 (HR=0.37, p=0.044) in rectal cancer. The difference was not statistical between iNOS/NOS2 high and low expressing groups for overall survival(OS) or DFS in the colon cancer or gastric cancer(p>0.05).
Conclusions iNOS/NOS2 mRNA isup-regulated in tumor tissue compared to corresponding normal tissue in colorectal and gastric cancer which implement it in the development of colorectal and gastric cancers.
References
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020 Jan;70(1):7–30.10.3322/caac.21590Search in Google Scholar PubMed
2. Takii Y, Maruyama S, Nogami H. Can the prognosis of colorectal cancer be improved by surgery? World J Gastrointest Surg. 2016 Aug;8(8):574–7.10.4240/wjgs.v8.i8.574Search in Google Scholar PubMed PubMed Central
3. Li J. Gastric Cancer in Young Adults: A Different Clinical Entity from Carcinogenesis to Prognosis. Gastroenterol Res Pract. 2020 Mar;2020:9512707.10.1155/2020/9512707Search in Google Scholar PubMed PubMed Central
4. Sawaki K, Kanda M, Kodera Y. Review of recent efforts to discover biomarkers for early detection, monitoring, prognosis, and prediction of treatment responses of patients with gastric cancer. Expert Rev Gastroenterol Hepatol. 2018 Jul;12(7):657–70.10.1080/17474124.2018.1489233Search in Google Scholar PubMed
5. Johnson LA, June CH. Driving gene-engineered T cell immunotherapy of cancer. Cell Res. 2017 Jan;27(1):38–58.10.1038/cr.2016.154Search in Google Scholar PubMed PubMed Central
6. Chiang YT, Wang K, Fazli L, Qi RZ, Gleave ME, Collins CC, et al. GATA2 as a potential metastasis-driving gene in prostate cancer. Oncotarget. 2014 Jan;5(2):451–61.10.18632/oncotarget.1296Search in Google Scholar PubMed PubMed Central
7. Fu HC, Chuang IC, Yang YC, Chuang PC, Lin H, Ou YC, et al. Low P16INK4A Expression Associated with High Expression of Cancer Stem Cell Markers Predicts Poor Prognosis in Cervical Cancer after Radiotherapy. Int J Mol Sci. 2018 Aug;19(9):19.10.3390/ijms19092541Search in Google Scholar PubMed PubMed Central
8. Macedo J, Silva E, Nogueira L, Coelho R, da Silva J, Dos Santos A, et al. Genomic profiling reveals the pivotal role of hrHPV driving copy number and gene expression alterations, including mRNA downregulation of TP53 and RB1 in penile cancer. Mol Carcinog. 2020 Jun;59(6):604–17.10.1002/mc.23185Search in Google Scholar PubMed
9. Aaltoma SH, Lipponen PK, Kosma VM. Inducible nitric oxide synthase (iNOS) expression and its prognostic value in prostate cancer. Anticancer Res. 2001 Jul-Aug;21 4B:3101–6.Search in Google Scholar
10. Jabłońska E, Puzewska W, Marcińczyk M, Grabowska Z, Jabłoński J. iNOS expression and NO production by neutrophils in cancer patients. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):175–9.Search in Google Scholar
11. Barani R, Motalleb G, Maghsoudi H. Evaluation of iNOS Expression in Esophageal Cancer Patients. Gastrointest Tumors. 2016 Sep;3(1):44–58.10.1159/000443976Search in Google Scholar PubMed PubMed Central
12. Li QT, Huang ZZ, Chen YB, Yao HY, Ke ZH, He XX, et al. Integrative Analysis of Siglec-15 mRNA in Human Cancers Based on Data Mining. J Cancer. 2020 Feb;11(9):2453–64.10.7150/jca.38747Search in Google Scholar PubMed PubMed Central
13. Vasaikar SV, Straub P, Wang J, Zhang B. LinkedOmics: analyzing multi-omics data within and across 32 cancer types. Nucleic Acids Res. 2018 Jan;46 D1:D956–63.10.1093/nar/gkx1090Search in Google Scholar PubMed PubMed Central
14. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019 Jan;47 D1:D607–13.10.1093/nar/gky1131Search in Google Scholar PubMed PubMed Central
15. Fortino V, Alenius H, Greco D. BACA: bubble chArt to compare annotations. BMC Bioinformatics. 2015 Feb;16(1):37.10.1186/s12859-015-0477-4Search in Google Scholar PubMed PubMed Central
16. Wang GY, Ji B, Wang X, Gu JH. Anti-cancer effect of iNOS inhibitor and its correlation with angiogenesis in gastric cancer. World J Gastroenterol. 2005 Jul;11(25):3830–3.10.3748/wjg.v11.i25.3830Search in Google Scholar PubMed PubMed Central
17. Song ZJ, Gong P, Wu YE. Relationship between the expression of iNOS,VEGF,tumor angiogenesis and gastric cancer. World J Gastroenterol. 2002 Aug;8(4):591–5.10.3748/wjg.v8.i4.591Search in Google Scholar PubMed PubMed Central
18. Rao CV. Nitric oxide signaling in colon cancer chemoprevention. Mutat Res. 2004 Nov;555(1-2):107–19.10.1016/j.mrfmmm.2004.05.022Search in Google Scholar PubMed
19. Padgett CM, Whorton AR. Cellular responses to nitric oxide: role of protein S-thiolation/dethiolation. Arch Biochem Biophys. 1998 Oct;358(2):232–42.10.1006/abbi.1998.0859Search in Google Scholar PubMed
20. Ziche M, Morbidelli L. Molecular regulation of tumour angiogenesis by nitric oxide. Eur Cytokine Netw. 2009 Dec;20(4):164–70.10.1684/ecn.2009.0169Search in Google Scholar PubMed
21. Chen L, Zeng X, Wang J, Briggs SS, O’Neill E, Li J, et al. Roles of tetrahydrobiopterin in promoting tumor angiogenesis. Am J Pathol. 2010 Nov;177(5):2671–80.10.2353/ajpath.2010.100025Search in Google Scholar PubMed PubMed Central
22. Schroecksnadel S, Sucher R, Kurz K, Fuchs D, Brandacher G. Influence of immunosuppressive agents on tryptophan degradation and neopterin production in human peripheral blood mononuclear cells. Transpl Immunol. 2011 Sep;25(2-3):119–23.10.1016/j.trim.2011.06.005Search in Google Scholar PubMed
23. Brandacher G, Maglione M, Schneeberger S, Obrist P, Thoeni G, Wrulich OA, et al. Tetrahydrobiopterin compounds prolong allograft survival independently of their effect on nitric oxide synthase activity. Transplantation. 2006 Feb;81(4):583–9.10.1097/01.tp.0000188949.03683.fdSearch in Google Scholar PubMed
24. Guo G, Bhat NR. Hypoxia/reoxygenation differentially modulates NF-kappaB activation and iNOS expression in astrocytes and microglia. Antioxid Redox Signal. 2006 May-Jun;8(5-6):911–8.10.1089/ars.2006.8.911Search in Google Scholar PubMed
25. Akhavan-Sigari R, Gaab MR, Rohde V, Brandis A, Tezval H, Abili M, et al. Expression of vascular endothelial growth factor receptor 2 (VEGFR-2), inducible nitric oxide synthase (iNOS), and Ki-M1P in skull base chordoma: a series of 145 tumors. Neurosurg Rev. 2014 Jan;37(1):79–88.10.1007/s10143-013-0495-5Search in Google Scholar PubMed
26. MacKenzie A, Wadsworth RM. Extracellular L-arginine is required for optimal NO synthesis by eNOS and iNOS in the rat mesenteric artery wall. Br J Pharmacol. 2003 Aug;139(8):1487–97.10.1038/sj.bjp.0705380Search in Google Scholar PubMed PubMed Central
27. Briones AM, Alonso MJ, Marín J, Salaices M. Role of iNOS in the vasodilator responses induced by L-arginine in the middle cerebral artery from normotensive and hypertensive rats. Br J Pharmacol. 1999 Jan;126(1):111–20.10.1038/sj.bjp.0702281Search in Google Scholar PubMed PubMed Central
28. Sanhueza C, Araos J, Naranjo L, Barros E, Subiabre M, Toledo F, et al. Nitric oxide and pH modulation in gynaecological cancer. J Cell Mol Med. 2016 Dec;20(12):2223–30.10.1111/jcmm.12921Search in Google Scholar PubMed PubMed Central
29. Huang Z, Fu J, Zhang Y. Nitric Oxide Donor-Based Cancer Therapy: advances and Prospects. J Med Chem. 2017 Sep;60(18):7617–35.10.1021/acs.jmedchem.6b01672Search in Google Scholar PubMed
30. Oleson BJ, Corbett JA. Dual Role of Nitric Oxide in Regulating the Response of β Cells to DNA Damage. Antioxid Redox Signal. 2018 Nov;29(14):1432–45.10.1089/ars.2017.7351Search in Google Scholar PubMed PubMed Central
31. Tamir S, Burney S, Tannenbaum SR. DNA damage by nitric oxide. Chem Res Toxicol. 1996 Jul-Aug;9(5):821–7.10.1021/tx9600311Search in Google Scholar PubMed
32. Keefer LK, Wink DA. DNA damage and nitric oxide. Adv Exp Med Biol. 1996;387:177–85.10.1007/978-1-4757-9480-9_24Search in Google Scholar PubMed
33. Ambs S, Hussain SP, Harris CC. Interactive effects of nitric oxide and the p53 tumor suppressor gene in carcinogenesis and tumor progression. FASEB J. 1997 May;11(6):443–8.10.1096/fasebj.11.6.9194524Search in Google Scholar PubMed
34. Anadol E, Yar Saglam AS, Gultiken N, Karakas K, Alcigir E, Alkan H, et al. Expression of iNOS, COX-2 and VEGF in canine mammary tumours and non-neoplastic mammary glands: association with clinicopathological features and tumour grade. Acta Vet Hung. 2017 Sep;65(3):382–93.10.1556/004.2017.036Search in Google Scholar PubMed
35. Sappayatosok K, Maneerat Y, Swasdison S, Viriyavejakul P, Dhanuthai K, Zwang J, et al. Expression of pro-inflammatory protein, iNOS, VEGF and COX-2 in oral squamous cell carcinoma (OSCC), relationship with angiogenesis and their clinico-pathological correlation. Med Oral Patol Oral Cir Bucal. 2009 Jul;14(7):E319–24.Search in Google Scholar
36. Huerta S, Chilka S, Bonavida B. Nitric oxide donors: novel cancer therapeutics (review) [review]. Int J Oncol. 2008 Nov;33(5):909–27.Search in Google Scholar
37. Wink DA, Ridnour LA, Hussain SP, Harris CC. The reemergence of nitric oxide and cancer. Nitric Oxide. 2008 Sep;19(2):65–7.10.1016/j.niox.2008.05.003Search in Google Scholar PubMed PubMed Central
38. Moochhala S, Rajnakova A. Role of nitric oxide in cancer biology. Free Radic Res. 1999 Dec;31(6):671–9.10.1080/10715769900301231ASearch in Google Scholar
39. Xu W, Liu LZ, Loizidou M, Ahmed M, Charles IG. The role of nitric oxide in cancer. Cell Res. 2002 Dec;12(5-6):311–20.10.1038/sj.cr.7290133Search in Google Scholar PubMed
© 2020 Mingbei Lu et al., published by De Gruyter
This work is licensed under the Creative Commons Attribution 4.0 International License.
