Gene expression profiling analysis of keloids with and without hydrocortisone treatment

Wang,Hongyi; Quan,Liangliang; Liang,Jiulong; Shi,Jie; Qiu,Tao; Zhang,Ye; Wang,Yang; Hui,Qiang; Zhang,Yu; Tao,Kai

doi:10.3892/etm.2017.5263

Gene expression profiling analysis of keloids with and without hydrocortisone treatment

Authors:
- Hongyi Wang
- Liangliang Quan
- Jiulong Liang
- Jie Shi
- Tao Qiu
- Ye Zhang
- Yang Wang
- Qiang Hui
- Yu Zhang
- Kai Tao
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Affiliations: Department of Plastic Surgery, General Hospital of Shenyang Military Area Command, PLA, Shenyang, Liaoning 110016, P.R. China
Published online on: October 3, 2017 https://doi.org/10.3892/etm.2017.5263
Pages: 5283-5288
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study aimed to investigate the genetic effects of hydrocortisone (HC) treatment on keloids and screen medicines to be used in a combination therapy of keloids with HC. The dataset GSE7890 was downloaded from Gene Expression Omnibus. It contained data regarding 4 fibroblast samples from normal scar tissue and 5 samples from keloid tissue with HC treatment, as well as 5 samples from normal scar and 5 samples from keloids without HC treatment. Following the identification of differentially expressed genes (DEGs), the functions of these DEGs were analyzed by Gene Ontology (GO) and pathway enrichment analyses. Furthermore, adverse effects of HC were identified using WebGestalt. Additionally, candidate small molecule drugs associated with keloids were selected from a connectivity map database. A total of 166 and 41 DEGs, with and without HC treatment respectively, were only present in dermal fibroblasts from keloids (termed genesets A and B, respectively). A set of 26 DEGs was present following both treatments (geneset C). A number of DEGs in geneset B (COL18A1 and JAG1) were associated with endothelial cell differentiation. However, in genesets A and C, certain genes (CCNB1 and CCNB2) were involved in the cell cycle and p53 signaling pathways, and a number of genes (IL1R1 and COL1A1) were associated with bone loss. Additionally, numerous small molecule drugs (including acemetacin) were associated with keloids. Thus, it has been determined that HC may treat keloids by targeting genes associated to endothelial cell differentiation (COL18A1 and JAG1). However, HC has a number of adverse effects, including bone loss. Acemetacin may be applied in a combination therapy, along with HC, to treat keloids.

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1	Marneros AG, Norris JE, Watanabe S, Reichenberger E and Olsen BR: Genome scans provide evidence for keloid susceptibility loci on chromosomes 2q23 and 7p11. J Invest Dermatol. 122:1126–1132. 2004. View Article : Google Scholar : PubMed/NCBI
2	Fong CY, Biswas A, Subramanian A, Srinivasan A, Choolani M and Bongso A: Human keloid cell characterization and inhibition of growth with human Wharton's jelly stem cell extracts. J Cell Biochem. 115:826–838. 2014. View Article : Google Scholar : PubMed/NCBI
3	Asboe-Hansen G, Brodthagen H and Zachariae L: Treatment of keloids with topical injections of hydrocortisone acetate. AMA Arch Derm. 73:162–165. 1956. View Article : Google Scholar : PubMed/NCBI
4	Russell JD, Russell SB and Trupin KM: Differential effects of hydrocortisone on both growth and collagen metabolism of human fibroblasts from normal and keloid tissue. J Cell Physiol. 97:221–229. 1978. View Article : Google Scholar : PubMed/NCBI
5	Russell SB, Russell JD and Trupin JS: Alteration of amino acid transport by hydrocortisone. Different effects in human fibroblasts derived from normal skin and keloid. J Biol Chem. 257:9525–9531. 1982.PubMed/NCBI
6	Trupin JS, Russell SB and Russell JD: Variation in prolyl hydroxylase activity of keloid-derived and normal human fibroblasts in response to hydrocortisone and ascorbic acid. Coll Relat Res. 3:13–23. 1983. View Article : Google Scholar : PubMed/NCBI
7	Ladin DA, Hou Z, Patel D, McPhail M, Olson JC, Saed GM and Fivenson DP: p53 and apoptosis alterations in keloids and keloid fibroblasts. Wound Repair Regen. 6:28–37. 1998. View Article : Google Scholar : PubMed/NCBI
8	Meyer LJ, Russell SB, Russell JD, Trupin JS, Egbert BM, Shuster S and Stern R: Reduced hyaluronan in keloid tissue and cultured keloid fibroblasts. J Investig Dermatol. 114:953–959. 2000. View Article : Google Scholar : PubMed/NCBI
9	Mantripragada KK, Buckley PG, de Ståhl Diaz T and Dumanski JP: Genomic microarrays in the spotlight. Trends Genet. 20:87–94. 2004. View Article : Google Scholar : PubMed/NCBI
10	Smith JC, Boone BE, Opalenik SR, Williams SM and Russell SB: Gene profiling of keloid fibroblasts shows altered expression in multiple fibrosis-associated pathways. J Invest Dermatol. 128:1298–1310. 2008. View Article : Google Scholar : PubMed/NCBI
11	Seo J and Hoffman EP: Probe set algorithms: Is there a rational best bet? BMC Bioinformatics. 7:3952006. View Article : Google Scholar : PubMed/NCBI
12	Smyth GK: Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 3:Article32004. View Article : Google Scholar : PubMed/NCBI
13	Bland JM and Altman DG: Multiple significance tests: The Bonferroni method. BMJ. 310:1701995. View Article : Google Scholar : PubMed/NCBI
14	Huang da W, Sherman BT and Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 4:44–57. 2009. View Article : Google Scholar : PubMed/NCBI
15	Xie C, Mao X, Huang J, Ding Y, Wu J, Dong S, Kong L, Gao G, Li CY and Wei L: KOBAS 2.0: A web server for annotation and identification of enriched pathways and diseases. Nucleic Acids Res. 39:W316–W322. 2011. View Article : Google Scholar : PubMed/NCBI
16	Wang J, Duncan D, Shi Z and Zhang B: WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): Update 2013. Nucleic Acids Res. 41:W77–W83. 2013. View Article : Google Scholar : PubMed/NCBI
17	Lamb J: The Connectivity Map: A new tool for biomedical research. Nat Rev Cancer. 7:54–60. 2007. View Article : Google Scholar : PubMed/NCBI
18	Pufe T, Petersen WJ, Miosge N, Goldring MB, Mentlein R, Varoga DJ and Tillmann BN: Endostatin/collagen XVIII-an inhibitor of angiogenesis-is expressed in cartilage and fibrocartilage. Matrix Biol. 23:267–276. 2004. View Article : Google Scholar : PubMed/NCBI
19	Mogili NS, Krishnaswamy VR, Jayaraman M, Rajaram R, Venkatraman A and Korrapati PS: Altered angiogenic balance in keloids: A key to therapeutic intervention. Transl Res. 159:182–189. 2012. View Article : Google Scholar : PubMed/NCBI
20	Deshpande M, Papp S, Schaffer L and Pouyani T: Hydrocortisone and triiodothyronine regulate hyaluronate synthesis in a tissue-engineered human dermal equivalent through independent pathways. J Biosci Bioeng. 119:226–236. 2015. View Article : Google Scholar : PubMed/NCBI
21	Bolós V, Grego-Bessa J and de la Pompa JL: Notch signaling in development and cancer. Endocr Rev. 28:339–363. 2007. View Article : Google Scholar : PubMed/NCBI
22	Syed F and Bayat A: Notch signaling pathway in keloid disease: Enhanced fibroblast activity in a Jagged-1 peptide-dependent manner in lesional vs. Extralesional fibroblasts. Wound Repair Regen. 20:688–706. 2012. View Article : Google Scholar : PubMed/NCBI
23	Ehrlich HP, Desmoulière A, Diegelmann RF, Cohen IK, Compton CC, Garner WL, Kapanci Y and Gabbiani G: Morphological and immunochemical differences between keloid and hypertrophic scar. Am J Pathol. 145:105–113. 1994.PubMed/NCBI
24	Kischer CW, Thies AC and Chvapil M: Perivascular myofibroblasts and microvascular occlusion in hypertrophic scars and keloids. Hum Pathol. 13:819–824. 1982. View Article : Google Scholar : PubMed/NCBI
25	Nör JE, Christensen J, Mooney DJ and Polverini PJ: Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. Am J Pathol. 154:375–384. 1999. View Article : Google Scholar : PubMed/NCBI
26	Gira AK, Brown LF, Washington CV, Cohen C and Arbiser JL: Keloids demonstrate high-level epidermal expression of vascular endothelial growth factor. J Am Acad Dermatol. 50:850–853. 2004. View Article : Google Scholar : PubMed/NCBI
27	Fujiwara M, Muragaki Y and Ooshima A: Upregulation of transforming growth factor-beta1 and vascular endothelial growth factor in cultured keloid fibroblasts: Relevance to angiogenic activity. Arch Dermatol Res. 297:161–169. 2005. View Article : Google Scholar : PubMed/NCBI
28	Javad F, Marriage F, Bayat A and Day PJ: Perturbation of cell cycle expression in keloid fibroblast. Skinmed. 10:152–159. 2012.PubMed/NCBI
29	Huang L, Wong Y, Cai Y, Lung I, Leung C and Burd A: Low-dose 5-fluorouracil induces cell cycle G2 arrest and apoptosis in keloid fibroblasts. Br J Dermatol. 163:1181–1185. 2010. View Article : Google Scholar : PubMed/NCBI
30	Lane DP: The regulation of p53 function: Steiner Award Lecture. Int J Cancer. 57:623–627. 1994. View Article : Google Scholar : PubMed/NCBI
31	Tanaka A, Hatoko M, Tada H, Iioka H, Niitsuma K and Miyagawa S: Expression of p53 family in scars. J Dermatol Sci. 34:17–24. 2004. View Article : Google Scholar : PubMed/NCBI
32	Lukert BP and Raisz LG: Glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am. 20:629–650. 1994.PubMed/NCBI
33	Wichers M, Springer W, Bidlingmaier F and Klingmüller D: The influence of hydrocortisone substitution on the quality of life and parameters of bone metabolism in patients with secondary hypocortisolism. Clin Endocrinol (Oxf). 50:759–765. 1999. View Article : Google Scholar : PubMed/NCBI
34	Langdahl BL, Løkke E, Carstens M, Stenkjær LL and Eriksen EF: Osteoporotic Fractures Are Associated with an 86-Base Pair Repeat Polymorphism in the Interleukin-1-Receptor Antagonist Gene But Not with Polymorphisms in the Interleukin-1beta Gene. J Bone Miner Res. 15:402–414. 2000. View Article : Google Scholar : PubMed/NCBI
35	Kimble RB, Vannice JL, Bloedow DC, Thompson RC, Hopfer W, Kung VT, Brownfield C and Pacifici R: Interleukin-1 receptor antagonist decreases bone loss and bone resorption in ovariectomized rats. J Clin Invest. 93:1959–1967. 1994. View Article : Google Scholar : PubMed/NCBI
36	Chen HY, Chen WC, Wu MC, Tsai FJ and Lin CC: Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphism in postmenopausal women: Correlation to bone mineral density and susceptibility to osteoporosis. Maturitas. 44:49–54. 2003. View Article : Google Scholar : PubMed/NCBI
37	Mann V and Ralston SH: Meta-analysis of COL1A1 Sp1 polymorphism in relation to bone mineral density and osteoporotic fracture. Bone. 32:711–717. 2003. View Article : Google Scholar : PubMed/NCBI
38	Viguet-Carrin S, Garnero P and Delmas P: The role of collagen in bone strength. Osteoporos Int. 17:319–336. 2006. View Article : Google Scholar : PubMed/NCBI
39	Sun Y, Sun Q, Fan C, Shen J, Zhao W, Guo Y, Su T, Wang W, Ning G and Bian L: Diagnosis and therapy for Cushing's disease with negative dynamic MRI finding: A single-centre experience. Clin Endocrinol (Oxf). 76:868–876. 2012. View Article : Google Scholar : PubMed/NCBI
40	Bori Segura G, Rubio Torres y Gutierrez A, Herrera Gómez LE and Olguín Uribe J: Efficacy and tolerability of acemetacin, a non-steroidal anti-inflammatory drug, in Mexican patients: Result of the ETAPAM Study. Proc West Pharmacol Soc. 45:pp. 104–107. 2002, PubMed/NCBI