Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

SOX9 and IL1A as the Potential Gene Biomarkers of the Oral Cancer

Author(s): Tianke Li, Dongmei Cheng, Jie Guo, He Chen, Suxin Zhang and Yang Bao*

Volume 26, Issue 8, 2023

Published on: 17 October, 2022

Page: [1461 - 1479] Pages: 19

DOI: 10.2174/1386207325666220628091041

Price: $65

conference banner
Abstract

Objective: Oral cancer is one of the most common malignant tumors in the head and neck. It is easy to relapse, and the prognosis is poor. However, the molecular mechanism in the development of oral cancer is still unclear.

Methods: A total of 30 normal individuals and 30 patients with head and neck cancer who underwent surgery were recruited in the Fourth Hospital of Hebei Medical University between February 2019 and November 2021. Furthermore, Human Protein Atlas (HPA) analysis, RT-qPCR, and immunofluorescence were used to verify the expression of SOX9 and IL1A. The GSE69002 dataset was downloaded from the Gene Expression Omnibus (GEO) database. GEO2R was used to identify the differentially expressed genes (DEGs). The Protein-Protein Interaction (PPI) network was constructed by using the STRING, and Cytoscape software was performed for visualization. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for enrichment analysis were made via the DAVID, Metascape, Gene Set Enrichment Analysis (GSEA), and Bin Gene Ontology (BINGO) analysis. Gene Expression Profiling Interactive Analysis (GEPIA) analysis was used to analyze the expression level of hub genes and pathological stage. The cBioPortal can be used for mutation analysis and pathway prediction of hub genes. Kaplan Meier Plotter was used for survival analysis of hub genes.

Results: The relative expression level of SOX9 (P=0.021, t=4.332) and IL1A (P=0.011, t= -4.213) in oral cancer was significantly higher than that in the standard group (P<0.05). The DEGs are mainly enriched in cell division, inflammation, interleukin-12 beta-subunit binding, and interleukin- 10 receptor binding. All the differentially expressed gene pathways eventually converge in cell growth and apoptosis. No relationship between the pathologic stage and the expression of hub genes. The poor overall survival of patients with the high expression of SOX9 (Hazard Ratio (HR) = 1.46, P = 0.009) and IL1A (HR = 1.49, P = 0.008). There were strong correlations between the hub genes and the head and neck neoplasms via the Comparative Toxicogenomics Database (CTD). The immunofluorescence and PCR results showed that the level of SOX9 (P<0.001, t = -23.368) in the cancer group was significantly higher than that in the normal group; The level of IL1A in the cancer group was significantly higher than that in the normal group (P<0.001, t = -11.960).

Conclusion: SOX9 and IL1A genes are highly expressed in oral cancer and might be potential therapeutic targets for oral cancer. The poor overall survival of patients with the high expression of SOX9 and IL1A.

Keywords: SOX9, IL1A, potential gene, biomarkers, oral cancer, bioinformatics.

Graphical Abstract
[1]
Valdez, J.A.; Brennan, M.T. Impact of oral cancer on quality of life. Dent. Clin. North Am., 2018, 62(1), 143-154.
[http://dx.doi.org/10.1016/j.cden.2017.09.001] [PMID: 29126491]
[2]
Wong, T.; Wiesenfeld, D. Oral cancer. Australian Dent. J., 2018, 63(1), 91-99.
[http://dx.doi.org/10.1111/adj.12594]
[3]
Salomão, R.; Ferreira, B.L.; Salomão, M.C.; Santos, S.S.; Azevedo, L.; Brunialti, M. Sepsis: Evolving concepts and challenges. Rev. Bras. Pesqui. Med. Biol., 2019, 52(4), e8595.
[4]
Dhanuthai, K.; Rojanawatsirivej, S.; Thosaporn, W.; Kintarak, S.; Subarnbhesaj, A.; Darling, M.; Kryshtalskyj, E.; Chiang, C.P.; Shin, H.I.; Choi, S.Y.; Lee, S.S.; Aminishakib, P. Oral cancer: A multicenter study. Med. Oral Patol. Oral Cir. Bucal, 2018, 23(1), e23-e29.
[PMID: 29274153]
[5]
Montero, P.H.; Patel, S.G. Cancer of the oral cavity. Surg. Oncol. Clin. N. Am., 2015, 24(3), 491-508.
[http://dx.doi.org/10.1016/j.soc.2015.03.006] [PMID: 25979396]
[6]
Sarode, G.; Maniyar, N.; Sarode, S.C.; Jafer, M.; Patil, S.; Awan, K.H. Epidemiologic aspects of oral cancer. Dis. Mon., 2020, 66(12), 100988.
[http://dx.doi.org/10.1016/j.disamonth.2020.100988] [PMID: 32605720]
[7]
Paré, A.; Joly, A. Oral cancer: Risk factors and management. Presse Med., 2017, 46(3), 320-330.
[PMID: 28233703]
[8]
Chattopadhyay, I.; Verma, M.; Panda, M. Role of oral microbiome signatures in diagnosis and prognosis of oral cancer. Technol. Cancer Res. Treat., 2019, 18, 1533033819867354.
[http://dx.doi.org/10.1177/1533033819867354] [PMID: 31370775]
[9]
D'souza, S.; Addepalli, V. Preventive measures in oral cancer: An overview. Biomed. Pharmacother., 2018, 107(72-80)2018. , 107-72-80.
[http://dx.doi.org/10.1016/j.biopha.2018.07.114]
[10]
Gauthier, J.; Vincent, A.T.; Charette, S.J.; Derome, N. A brief history of bioinformatics. Brief. Bioinform., 2019, 20(6), 1981-1996.
[http://dx.doi.org/10.1093/bib/bby063] [PMID: 30084940]
[11]
Lebo, M.S.; Hao, L.; Lin, C.F.; Singh, A. Bioinformatics in clinical genomic sequencing. Clin. Lab. Med., 2020, 40(2), 163-187.
[http://dx.doi.org/10.1016/j.cll.2020.02.003] [PMID: 32439067]
[12]
Tao, Z.; Shi, A.; Li, R.; Wang, Y.; Wang, X.; Zhao, J. Microarray bioinformatics in cancer- A review. J. BUON, 2017, 22(4), 838-843.
[13]
Canzoneri, R.; Lacunza, E.; Abba, M.C. Genomics and bioinformatics as pillars of precision medicine in oncology. Medicina , 2019, 796, 587-592.
[14]
Fu, Y.; Ling, Z.; Arabnia, H.; Deng, Y. Current trend and development in bioinformatics research. BMC Bioinformatics, 2020, 21(S9)(Suppl. 9), 538.
[http://dx.doi.org/10.1186/s12859-020-03874-y] [PMID: 33272214]
[15]
Huang, X.; Liu, S.; Wu, L.; Jiang, M.; Hou, Y. High throughput single cell RNA sequencing, bioinformatics analysis and applications. Adv. Exp. Med. Biol., 2018, 1068, 33-43.
[http://dx.doi.org/10.1007/978-981-13-0502-3_4] [PMID: 29943294]
[16]
Scharf, G.M.; Kilian, K.; Cordero, J.; Wang, Y.; Grund, A.; Hofmann, M.; Froese, N.; Wang, X.; Kispert, A.; Kist, R.; Conway, S.J.; Geffers, R.; Wollert, K.C.; Dobreva, G.; Bauersachs, J.; Heineke, J. Inactivation of Sox9 in fibroblasts reduces cardiac fibrosis and inflammation. JCI Insight, 2019, 5(15), 126721.
[http://dx.doi.org/10.1172/jci.insight.126721] [PMID: 31310588]
[17]
Zhang, H.; Deng, X.; Zhou, C.; Wu, W.; Zhang, H. Deoxynivalenol induces inflammation in IPEC-J2 cells by activating P38 Mapk and Erk1/2. Toxins (Basel), 2020, 12(3), E180.
[http://dx.doi.org/10.3390/toxins12030180] [PMID: 32183221]
[18]
Newton, H.; Bolissian, A.; Shanahan, D. The dangers of delaying treatment in oral cancer: A seventeenth-century perspective. Oral Oncol., 2020, 111, 104911.
[http://dx.doi.org/10.1016/j.oraloncology.2020.104911] [PMID: 32713808]
[19]
Reyimu, A.; Chen, Y.; Song, X.; Zhou, W.; Dai, J.; Jiang, F. Identification of latent biomarkers in connection with progression and prognosis in oral cancer by comprehensive bioinformatics analysis. World J. Surg. Oncol., 2021, 19(1), 240.
[http://dx.doi.org/10.1186/s12957-021-02360-w] [PMID: 34384424]
[20]
Sethi, S.; Grewal, H.; Aggarwal, P.; Narad, C. Pattern of tumor invasion, stromal inflammation, angiogenesis and vascular invasion in oral squamous cell carcinoma - A prognostic study. Curr. Probl. Cancer, 2021, 45(2), 100647.
[http://dx.doi.org/10.1016/j.currproblcancer.2020.100647] [PMID: 32893000]
[21]
Hartner, L. Chemotherapy for oral cancer. Dent. Clin. North Am., 2018, 62(1), 87-97.
[http://dx.doi.org/10.1016/j.cden.2017.08.006] [PMID: 29126496]
[22]
Zanoni, D.K.; Montero, P.H.; Migliacci, J.C.; Shah, J.P.; Wong, R.J.; Ganly, I.; Patel, S.G. Survival outcomes after treatment of cancer of the oral cavity (1985-2015). Oral Oncol., 2019, 90, 115-121.
[http://dx.doi.org/10.1016/j.oraloncology.2019.02.001] [PMID: 30846169]
[23]
Kane, G.; Petrosyan, V.; Ameerally, P. Oral cancer treatment through the ages: Part 1. J. Oral Maxillofacial Surg., 2019, 77(7), 1480-1483.
[http://dx.doi.org/10.1016/j.joms.2019.01.023]
[24]
Gonen, N.; Lovell-Badge, R. The regulation of Sox9 expression in the gonad. Curr. Top. Dev. Biol., 2019, 134, 223-252.
[http://dx.doi.org/10.1016/bs.ctdb.2019.01.004] [PMID: 30999977]
[25]
Stöckl, S.; Lindner, G.; Li, S.; Schuster, P.; Haferkamp, S.; Wagner, F.; Prodinger, P.M.; Multhoff, G.; Boxberg, M.; Hillmann, A.; Bauer, R.J.; Grässel, S. SOX9 knockout induces polyploidy and changes sensitivity to tumor treatment strategies in a chondrosarcoma cell line. Int. J. Mol. Sci., 2020, 21(20), E7627.
[http://dx.doi.org/10.3390/ijms21207627] [PMID: 33076370]
[26]
Lefebvre, V.; Angelozzi, M.; Haseeb, A. SOX9 in cartilage development and disease. Curr. Opin. Cell Biol., 2019, 61, 39-47.
[http://dx.doi.org/10.1016/j.ceb.2019.07.008] [PMID: 31382142]
[27]
Symon, A.; Harley, V. SOX9: A genomic view of tissue specific expression and action. Int. J. Biochem. Cell Biol., 2017, 87, 18-22.
[http://dx.doi.org/10.1016/j.biocel.2017.03.005] [PMID: 28323209]
[28]
Jana, S.; Madhu Krishna, B.; Singhal, J.; Horne, D.; Awasthi, S.; Salgia, R.; Singhal, S.S. SOX9: The master regulator of cell fate in breast cancer. Biochem. Pharmacol., 2020, 174, 113789.
[http://dx.doi.org/10.1016/j.bcp.2019.113789] [PMID: 31911091]
[29]
Luo, H.; Wang, C.; Liu, M.; Yin, B. A, P.; Huang, D.; Ye, L. Inhibition of SOX9 promotes inflammatory and immune responses of dental pulp. J. Endod., 2018, 44(5), 792-799.
[http://dx.doi.org/10.1016/j.joen.2018.02.004] [PMID: 29571909]
[30]
Higo, N.; Okumura, H.; Uchikado, Y.; Omoto, I.; Sasaki, K.; Kita, Y.; Ryosuke, D.; Noda, M.; Owaki, T.; Ishigami, S.; Natsugoe, S. Expression of SOX9 is related to prognosis in patients with oesophageal squamous cell carcinoma. In Vivo, 2018, 32(4), 835-838.
[http://dx.doi.org/10.21873/invivo.11316] [PMID: 29936467]
[31]
Haga, K.; Yamazaki, M.; Maruyama, S.; Kawaharada, M.; Suzuki, A.; Hoshikawa, E.; Chan, N.N.; Funayama, A.; Mikami, T.; Kobayashi, T.; Izumi, K.; Tanuma, J.I. Crosstalk between oral squamous cell carcinoma cells and cancer-associated fibroblasts via the TGF-β/SOX9 axis in cancer progression. Transl. Oncol., 2021, 14(12), 101236.
[http://dx.doi.org/10.1016/j.tranon.2021.101236] [PMID: 34624685]
[32]
Boraschi, D.; Italiani, P.; Weil, S.; Martin, M.U. The family of the interleukin-1 receptors. Immunol. Rev., 2018, 281(1), 197-232.
[http://dx.doi.org/10.1111/imr.12606] [PMID: 29248002]
[33]
Mantovani, A.; Dinarello, C.A.; Molgora, M.; Garlanda, C. Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity, 2019, 50(4), 778-795.
[http://dx.doi.org/10.1016/j.immuni.2019.03.012] [PMID: 30995499]
[34]
Murakami, T.; Takahata, Y.; Hata, K.; Nishimura, R. Role of interleukin-1 and inflammasomes in oral disease. J. Oral Biosci., 2020, 62(3), 242-248.
[http://dx.doi.org/10.1016/j.job.2020.07.003]
[35]
Li, H.; Duan, N.; Zhang, Q.; Shao, Y. IL1A & IL1B genetic polymorphisms are risk factors for thyroid cancer in a Chinese Han population. Int. Immunopharmacol., 2019, 76, 105869.
[http://dx.doi.org/10.1016/j.intimp.2019.105869] [PMID: 31499272]
[36]
Su, H.; Rei, N.; Zhang, L.; Cheng, J. Meta-analyses of IL1A polymorphisms and the risk of several autoimmune diseases published in databases. PLoS One, 2018, 13(6), e0198693.
[http://dx.doi.org/10.1371/journal.pone.0198693] [PMID: 29879187]
[37]
Ji, H.; Lu, L.; Huang, J.; Liu, Y.; Zhang, B.; Tang, H.; Sun, D.; Zhang, Y.; Shang, H.; Li, Y.; Lu, H. IL1A polymorphisms is a risk factor for colorectal cancer in Chinese Han population: A case control study. BMC Cancer, 2019, 19(1), 181.
[http://dx.doi.org/10.1186/s12885-019-5395-9] [PMID: 30819119]
[38]
Ebersole, J.L.; Nagarajan, R.; Kirakodu, S.; Gonzalez, O.A. Oral microbiome and gingival gene expression of inflammatory biomolecules with aging and periodontitis. Frontiers Oral Health, 2021, 2, 725115.
[http://dx.doi.org/10.3389/froh.2021.725115]
[39]
Xia, H.; Chen, Y.; Meng, J.; Liang, C. Effect of polymorphism on IL1A to cancer susceptibility: Evidence based on 34,016 subjects. Artif. Cells Nanomed. Biotechnol., 2019, 47(1), 3138-3152.
[http://dx.doi.org/10.1080/21691401.2019.1646750] [PMID: 31359795]
[40]
Karjalainen, J.; Joki-Erkkilä, V.P.; Hulkkonen, J.; Pessi, T.; Nieminen, M.M.; Aromaa, A.; Klaukka, T.; Hurme, M. The IL1A genotype is associated with nasal polyposis in asthmatic adults. Allergy, 2003, 58(5), 393-396.
[http://dx.doi.org/10.1034/j.1398-9995.2003.00118.x] [PMID: 12752325]
[41]
Malik, A.; Kanneganti, T.D. Function and regulation of IL-1α in inflammatory diseases and cancer. Immunol. Rev., 2018, 281(1), 124-137.
[http://dx.doi.org/10.1111/imr.12615] [PMID: 29247991]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy