Investigation of MicroRNA-Target Gene Regulatory Networks in Oral Squamous Cell carcinoma

Authors

  • Jyotsna Choubey Department of Biotechnology, Raipur Institute of Technology, Raipur- 492001, Chhattisgarh, India
  • Tanushree Chatterjee Department of Biotechnology, Raipur Institute of Technology, Raipur- 492001, Chhattisgarh, India

Keywords:

Oral cancer, hub genes, transcription factor

Abstract

Oral squamous cell carcinoma (OSCC) is the seventh most common cancer worldwide. Despite improvement in its control, morbidity and mortality, rates have improved little in the past decades.  To find differential miRNA and gene expression, GSE98463 and GSE3524 expression profiles were acquired from the Gene Expression Omnibus (GEO) database. Screened DE-miRNAs' transcription factors and target genes were predicted. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to predict biological functions. Using Cytoscape software, protein–protein interaction (PPI) networks and hub genes were found in the miRNA-mRNA regulation network. Further hub gene expression and prognostic functions were examined.  We examined 34 DE-miRNAs, 23 upregulated and 11 downregulated. Most screened DE-miRNAs may be regulated by transcription factor SP1. 2190 and 1061 predicted target genes were obtained for upregulated and downregulated DE-miRNAs, respectively. Subsequently, 452 upregulated DEGs and 221 downregulated DEGs were identified. Then, 18 and 58 potential downregulated and upregulated genes commonly appeared in target genes of DE-miRNAs and DEGs were selected for GO annotation and KEGG pathway enrichment analysis. The candidate target genes were significantly enriched for the Protein digestion and absorption, Relaxin signalling pathway, and AGE-RAGE signalling pathway. Construction and analysis of PPI network showed that MMP9 and COL1A1were recognized as hub genes with the highest connectivity degrees. Expression analytic result of the top 10 hub genes in OSCC using GEPIA database was generally identical with previous differential expression analysis for TCGA data and its expression was significantly associated with patients’ overall survival. We constructed a putative oral cancer-related miRNA-mRNA regulation network in this study to better understand molecular mechanisms and find novel treatment targets for OSCC. Further trials are needed to confirm our findings.

References

Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018;68:394–424. doi: 10.3322/caac.21492. [PubMed] [CrossRef] [Google Scholar]

Dhanuthai K., Rojanawatsirivej S., Thosaporn W., Kintarak S., Subarnbhesaj A., Darling M., Kryshtalskyj E., Chiang C.P., Shin H.I., Choi S.Y., et al. Oral cancer: A multicenter study. Med. Oral Patol. Oral Cir. Bucal. 2018;23:e23–e29. doi: 10.4317/medoral.21999. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Rivera C., Venegas B. Histological and molecular aspects of oral squamous cell carcinoma (Review) Oncol. Lett. 2014;8:7–11. doi: 10.3892/ol.2014.2103. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Yanamoto S, Yamada S, Takahashi H, et al. Clinicopathological risk factors for local recurrence in oral squamous cell carcinoma. Int J Oral Maxillofac Surg 2012; 41; 1195-1200.

Murugan AK, Munirajan AK, Tsuchida N. Ras oncogenes in oral cancer: the past 20 years. Oral Oncol. 2012;48(5):383–92.

Murugan AK, Hong NT, Cuc TTK, Hung NC, Munirajan AK, Ikeda M-A, Tsuchida N. Detection of two novel mutations and relatively high incidence of H-RAS mutations in Vietnamese oral cancer. Oral Oncol. 2009;45(10):e161–6.

Arunkumar G, Anand S, Raksha P, Dhamodharan S, Rao HPS, Subbiah S, Murugan AK, Munirajan AK. LncRNA OIP5-AS1 is overexpressed in undifferentiated oral tumors and integrated analysis identifies AS a downstream effector of stemness-associated transcription factors. Sci Rep. 2018;8(1):7018.

Curry JM, Sprandio J, Cognetti D, Luginbuhl A, Bar-ad V, Pribitkin E, Tuluc M. Tumor microenvironment in head and neck squamous cell carcinoma. Semin Oncol. 2014;41(2):217–34.

Irimie A.I., Ciocan C., Gulei D., Mehterov N., Atanasov A.G., Dudea D., Berindan-Neagoe I. Current Insights into Oral Cancer Epigenetics. Int. J. Mol. Sci. 2018; 19:670. doi: 10.3390/ijms19030670.

Hema K.N., Smitha T., Sheethal H.S., Mirnalini S.A. Epigenetics in oral squamous cell carcinoma. J. Oral Maxillofac. Pathol. 2017; 21:252–259. doi: 10.4103/jomfp.JOMFP_150_17.

Falzone L., Salemi R., Travali S., Scalisi A., McCubrey J.A., Candido S., Libra M. MMP-9 overexpression is associated with intragenic hypermethylation of MMP9 gene in melanoma. Aging (Albany NY) 2016;8:933–944. doi: 10.18632/aging.100951

Iorio MV and Croce CM. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med 2012; 4; 143-159.

13. Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature 2005; 435; 834-838.

Gomes CC, de Sousa SF, and Gomez RS. MicroRNAs: small molecules with a potentially role in oral squamous cell carcinoma. Curr Pharm Des 2013; 19; 1285-1291.

Yen YC, Shiah SG, Chu HC, et al. Reciprocal regulation of microRNA-99a and insulin-like growth factor I receptor signaling in oral squamous cell carcinoma cells. Mol Cancer 2014; 13; 6.

Chang KW, Liu CJ, Chu TH, et al. Association between high miR-211 microRNA expression and the poor prognosis of oral carcinoma. J Dent Res 2008; 87; 1063-1068.

Huang WC, Chan SH, Jang TH, et al. miRNA-491-5p and GIT1 serve as modulators and biomarkers for oral squamous cell carcinoma invasion and metastasis. Cancer Res 2014; 74; 751-764.

Sasahira T, Kurihara M, Bhawal UK, et al. Downregulation of miR-126 induces angiogenesis and lymphangiogenesis by activation of VEGF-A in oral cancer. Br J Cancer 2012; 107; 700-706.

Liu CJ, Tsai MM, Tu HF, et al. miR-196a overexpression and miR-196a2 gene polymorphism are prognostic predictors of oral carcinomas. Ann Surg Oncol 2013; 20 Suppl 3; S406-414.

Toruner GA, Ulger C, Alkan M, Galante AT et al. Association between gene expression profile and tumor invasion in oral squamous cell carcinoma. Cancer Genet Cytogenet 2004 Oct 1;154(1):27-35.

Chamorro-Petronacci C, Perez-Sayáns M, Padín-Iruegas ME, Marichalar-Mendia X, Gallas-Torreira M, García García A. Differential expression of snoRNAs in oral squamous cell carcinomas: new potential diagnostic markers. J Enzyme Inhib Med Chem. 2018 Dec;33(1):424-427. doi: 10.1080/14756366.2018.1426574.

Pathan, M., Keerthikumar, S., Chisanga, D., Alessandro, R., Ang, C. S., Askenase, P., et al. (2017). A novel community driven software for functional enrichment analysis of extracellular vesicles data. J. Extracell. Vesicles. 6:1321455. doi: 10.1080/20013078.2017.1321455

Fan, Y., Siklenka, K., Arora, S. K., Ribeiro, P., Kimmins, S., and Xia, J. (2016). miRNet - dissecting miRNA-target interactions and functional associations through network-based visual analysis. Nucleic Acids Res. 44, W135–W141. doi: 10.1093/nar/gkw288

Xiao, F., Zuo, Z., Cai, G., Kang, S., Gao, X., and Li, T. (2009). miRecords: an integrated resource for microRNA-target interactions. Nucleic Acids Res. 37, D105–D110.

Vlachos, I. S., Paraskevopoulou, M. D., Karagkouni, D., Georgakilas, G., Vergoulis, T., Kanellos, I., et al. (2015). DIANA-TarBase v7.0: indexing more than half a million experimentally supported miRNA:mRNA interactions. Nucleic Acids Res. 43, D153–D159.

Chou, C. H., Shrestha, S., Yang, C. D., Chang, N. W., Lin, Y. L., Liao, K. W., et al. (2018). miRTarBase update 2018: a resource for experimentally validated microRNA-target interactions. Nucleic Acids Res. 46, D296–D302.

Shannon, P. et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498–2504 (2003).

Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25(1):25–29.

Kanehisa M, Goto S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27–30.

Huang da W. Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009;4:44-57.

Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43:D447–D452.

Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–2504.

Tang, Z., Li, C., Kang, B., Gao, G., Li, C., and Zhang, Z. (2017). GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 45, W98–W102. doi: 10.1093/nar/gkx247

[34.] Hammond SM. An overview of microRNAs. Adv Drug Deliv Rev. 2015; 87:3–14. doi: 10.1016/j.addr.2015.05.001

[35] Tie J, Fan D. Big roles of microRNAs in tumorigenesis and tumor development. Histol Histopathol 2011; 26:1353e61.

[36 ]Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009; 136:215e33.

Downloads

Published

2023-12-28

Issue

Section

Articles

How to Cite

Investigation of MicroRNA-Target Gene Regulatory Networks in Oral Squamous Cell carcinoma. (2023). International Journal of Futuristic Innovation in Engineering, Science and Technology (IJFIEST), 2(3), 31-46. https://journal.inence.org/index.php/ijfiest/article/view/226