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BMC Oral Health
Published in: BMC Oral Health 1/2021

Open Access 01-12-2021 | Stomatitis Aphthosa | Research

STAT1: a novel candidate biomarker and potential therapeutic target of the recurrent aphthous stomatitis

Authors: Mingchen Cao, Lei Li, Long Xu, Mengxiang Fang, Xiaomin Xing, Changkai Zhou, Wei Ren, Longyuan Wang, Fanbo Jing

Published in: BMC Oral Health | Issue 1/2021

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Abstract

Background

The recurrent aphthous stomatitis (RAS) frequently affects patient quality of life as a result of long lasting and recurrent episodes of burning pain. However, there were temporarily few available effective medical therapies currently. Drug target identification was the first step in drug discovery, was usually finding the best interaction mode between the potential target candidates and probe small molecules. Therefore, elucidating the molecular mechanism of RAS pathogenesis and exploring the potential molecular targets of medical therapies for RAS was of vital importance.

Methods

Bioinformatics data mining techniques were applied to explore potential novel targets, weighted gene co-expression network analysis (WGCNA) was used to construct a co-expression module of the gene chip data from GSE37265, and the hub genes were identified by the Molecular Complex Detection (MCODE) plugin.

Results

A total of 16 co-expression modules were identified, and 30 hub genes in the turquoise module were identified. In addition, functional analysis of Hub genes in modules of interest was performed, which indicated that such hub genes were mainly involved in pathways related to immune response, virus infection, epithelial cell, signal transduction. Two clusters (highly interconnected regions) were determined in the network, with score = 17.647 and 10, respectively, cluster 1 and cluster 2 are linked by STAT1 and ICAM1, it is speculated that STAT1 may be a primary gene of RAS. Finally, genistein, daidzein, kaempferol, resveratrol, rosmarinic acid, triptolide, quercetin and (-)-epigallocatechin-3-gallate were selected from the TCMSP database, and both of them is the STAT-1 inhibitor. The results of reverse molecular docking suggest that in addition to triptolide, (-)-Epigallocatechin-3-gallate and resveratrol, the other 5 compounds (flavonoids) with similar structures may bind to the same position of STAT1 protein with different docking score.

Conclusions

Our study identified STAT1 as the potential biomarkers that might contribute to the diagnosis and potential therapeutic target of RAS, and we can also screen RAS therapeutic drugs from STAT-1 inhibitors.
Literature
1.
Saikaly SK, Saikaly TS, Saikaly LE. Recurrent aphthous ulceration: a review of potential causes and novel treatments. J Dermatol Treat. 2018;29(6):542–52.CrossRef
2.
3.
Ślebioda Z, Szponar E, Kowalska A. Etiopathogenesis of recurrent aphthous stomatitis and the role of immunologic aspects: literature review. Arch Immunol Ther Exp. 2014;62(3):205–15.CrossRef
4.
Ślebioda Z, Szponar E, Kowalska A. Recurrent aphthous stomatitis: genetic aspects of etiology. Adv Dermat Allergol/Postȩpy Dermatologii I Alergologii. 2013;30(2):96.CrossRef
5.
Tarakji B, Gazal G, Al-Maweri SA, Azzeghaiby SN, Alaizari N. Guideline for the diagnosis and treatment of recurrent aphthous stomatitis for dental practitioners. J Int Oral Health: JIOH. 2015;7(5):74.PubMedPubMedCentral
6.
Albrektson M, Hedström L, Bergh H. Recurrent aphthous stomatitis and pain management with low-level laser therapy: a randomized controlled trial. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;117(5):590–4.CrossRefPubMed
7.
Belenguer-Guallar I, Jiménez-Soriano Y, Claramunt-Lozano A. Treatment of recurrent aphthous stomatitis. A literature review. J Clin Exp Dent. 2014;6(2):e168.CrossRefPubMedPubMedCentral
8.
Mangul S, Martin LS, Langmead B, Sanchez-Galan JE, Toma I, Hormozdiari F, Pevzner P, Eskin E. How bioinformatics and open data can boost basic science in countries and universities with limited resources. Nat Biotechnol. 2019;37(3):324–6.CrossRefPubMed
9.
Attwood TK, Blackford S, Brazas MD, Davies A, Schneider MV. A global perspective on evolving bioinformatics and data science training needs. Brief Bioinform. 2019;20(2):398–404. CrossRefPubMed
10.
Pei G, Chen L, Zhang W. WGCNA application to proteomic and metabolomic data analysis. Method Enzymol. 2017;585: 135–158.
11.
Tian Z, He W, Tang J, Liao X, Yang Q, Wu Y, Wu G. Identification of important modules and biomarkers in breast cancer based on WGCNA. Onco Targets Ther. 2020;13:6805.CrossRefPubMedPubMedCentral
12.
Yadav BS, Tripathi V. Recent advances in the system biology-based target identification and drug discovery. Curr Top Med Chem. 2018;18(20):1737–1744. 
13.
Katsila T, Spyroulias GA, Patrinos GP, Matsoukas MT. Computational approaches in target identification and drug discovery. Comput Struct Biotechnol J. 2016;14:177–84.CrossRefPubMedPubMedCentral
14.
Katara P. Computational approaches for drug target identification. In: Computer-aided drug design. Singapore: Springer. 2020. p. 163–185.
15.
Karagkouni D, et al. DIANA-TarBase v8: a decade-long collection of experimentally supported miRNA–gene interactions. Nucleic Acids Res. 2018;46(D1):D239–45.CrossRefPubMed
16.
Licata L, Lo Surdo P, Iannuccelli M, et al. SIGNOR 2.0, the SIGnaling network open resource 2.0: 2019 update. Nucleic Acids Res. 2020;48(D1):D504–D510.
17.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci. 2005;102(43):15545–50.CrossRefPubMedPubMedCentral
18.
Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P, Jensen LJ. STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47(D1):D607–13.CrossRefPubMed
19.
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):2498–504.CrossRefPubMedPubMedCentral
20.
Ru J, Li P, Wang J, Zhou W, Li B, Huang C, Li P, Guo Z, Tao W, Yang Y, Xu X. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform. 2014;6(1):13.CrossRefPubMedPubMedCentral
21.
Wang X, Shen Y, Wang S, Li S, Zhang W, Liu X, Lai L, Pei J, Li H. PharmMapper 2017 update: a web server for potential drug target identification with a comprehensive target pharmacophore database. Nucleic Acids Res. 2017;45(W1):W356–60.CrossRefPubMedPubMedCentral
22.
Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31(2):455–61.PubMedPubMedCentral
23.
DeLano WL. The PyMOL molecular graphics system, Version 2.0. Schrödinger LLC. 2002.
24.
Laver T, Nozell SE, Benveniste EN. Ifn-beta-mediated inhibition of il-8 expression requires the isgf3 components stat1, stat2, and irf-9. J Interf Cytokine Res. 2008.
25.
Ryan N, Anderson K, Volpedo G, Hamza O, Oghumu S. Abstract A11: STAT1 mediates resistance to experimental oral cancer that is associated with enhanced antitumor T-cell responses. In: Abstracts: AACR-AHNS head and neck cancer conference: optimizing survival and quality of life through basic, clinical, and translational research; April 29–30, 2019; Austin, TX. 2020.
26.
Yockell-Lelievre J, Spriet C, Cantin P, Malenfant P, Heliot L, De Launoit Y, Audette M. Functional cooperation between Stat-1 and ets-1 to optimize icam-1 gene transcription. Biochem Cell Biol. 2009;87(6):905–18.CrossRefPubMed
27.
Janowska-Wieczorek A, Marquez LA, Dobrowsky A, Ratajczak MZ, Cabuhat ML. Differential MMP and TIMP production by human marrow and peripheral blood CD34+ cells in response to chemokines. Exp Hematol. 2000;28(11):1274–85.CrossRefPubMed
28.
Robinson SC, Scott KA, Balkwill FR. Chemokine stimulation of monocyte matrix metalloproteinase-9 requires endogenous TNF-α. Eur J Immunol. 2002;32(2):404–12.CrossRefPubMed
29.
Hatfield KJ, Reikvam H, Bruserud O. The crosstalk between the matrix metalloprotease system and the chemokine network in acute myeloid leukemia. Curr Med Chem. 2010;17(36):4448–61.CrossRefPubMed
30.
Karasneh JA, Bani‐Hani ME, Alkhateeb AM, et al. Association of MMP but not TIMP-1 gene polymorphisms with recurrent aphthous stomatitis. Oral Dis. 2014;20(7):693–699.
31.
Kang Y, Zhany Y. Expression and significance of MMP-9 in recurrent aphthous ulcer. J Pract Stomatol. 2008;(05):710–713.
32.
Kang YY, Zhang Y, Sun Y. Study of expression and significance of MMP-28 in RAU, OLP. OLK Stomatol. 2011;9:5.
33.
Isola G, Polizzi A, Alibrandi A, et al. Analysis of galectin‐3 levels as a source of coronary heart disease risk during periodontitis. J Periodontal Res. 2021;56(3):597–605.
34.
Isola G, Giudice AL, Polizzi A, Alibrandi A, Murabito P, Indelicato F. Identification of the different salivary Interleukin-6 profiles in patients with periodontitis: a cross-sectional study. Arch Oral Biol. 2021;122:104997.CrossRefPubMed
35.
Astorgues-Xerri L, Riveiro ME, Tijeras-Raballand A, Serova M, Neuzillet C, Albert S, Raymond E, Faivre S. Unraveling galectin-1 as a novel therapeutic target for cancer. Cancer Treat Rev. 2014;40(2):307–19.CrossRefPubMed
36.
de Boer RA, Voors AA, Muntendam P, et al. Galectin-3: a novel mediator of heart failure development and progression. Eur J Heart Fail. 2009;11(9):811–817.
37.
Metwally H, Tanaka T, Li S, Parajuli G, Kang S, Hanieh H, Hashimoto S, Chalise JP, Gemechu Y, Standley DM, Kishimoto T. Noncanonical STAT1 phosphorylation expands its transcriptional activity into promoting LPS-induced IL-6 and IL-12p40 production. Sci Signal. 2020;13(624).
38.
Hämäläinen M, Nieminen R, Vuorela P, Heinonen M, Moilanen E. Anti-inflammatory effects of flavonoids: genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-κB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-κB activation along with their inhibitory effect on iNOS expression and NO production in activated macrophages. Mediat inflamm. 2007;2007:1–10.
39.
Hamed F, Mcdonagh A, Almaghrabi S, Bakri Y, Tazi-Ahnini R. Epigallocatechin-3 gallate inhibits stat-1/jak2/irf-1/hla-dr/hla-b and reduces cd8 mkg2d lymphocytes of alopecia areata patients. Int J Environ Res Public Health. 2018;15(12):2882.CrossRefPubMedCentral
40.
Hongqin T, Xinyu L, Heng G, Lanfang X, Yongfang W, Shasha S. Triptolide inhibits IFN-γ signaling via the Jak/STAT pathway in HaCaT keratinocytes. Phytother Res. 2011;25(11):1678–85.CrossRefPubMed
41.
Ma C, Wang Y, Dong L, Li M, Cai W. Anti-inflammatory effect of resveratrol through the suppression of NF-κB and JAK/STAT signaling pathways. Acta Biochim Biophys Sin. 2015;47(3):207–13.CrossRefPubMed
42.
Yang JH, Yoo JM, Lee E, Lee B, Cho WK, Park KI, Ma JY. Anti-inflammatory effects of Perillae Herba ethanolic extract against TNF-α/IFN-γ-stimulated human keratinocyte HaCaT cells. J Ethnopharmacol. 2018;211:217–23.CrossRefPubMed
43.
Guo L, Zhao ZY, Bai J, et al. Preparation and treatment for oral ulcer of quercetin and the drug-loaded chitosan composite material. Adv Mater Res. 2012;583:44–48.
44.
Chen PN, Chu SC, Kuo WH, Chou MY, Lin JK, Hsieh YS. Epigallocatechin-3 gallate inhibits invasion, epithelial−mesenchymal transition, and tumor growth in oral cancer cells. J Agric Food Chem. 2011;59(8):3836–44.CrossRefPubMed
45.
Huang B, Chen H. (−)-Epigallocatechin-3-gallate inhibits matrix metalloproteinases in oral ulcers. RSC Adv. 2015;5(30):23758–66.CrossRef
Metadata
Title
STAT1: a novel candidate biomarker and potential therapeutic target of the recurrent aphthous stomatitis
Authors
Mingchen Cao
Lei Li
Long Xu
Mengxiang Fang
Xiaomin Xing
Changkai Zhou
Wei Ren
Longyuan Wang
Fanbo Jing
Publication date
01-12-2021
Publisher
BioMed Central
Published in
BMC Oral Health / Issue 1/2021
Electronic ISSN: 1472-6831
DOI
https://doi.org/10.1186/s12903-021-01776-w

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