In vitro analysis of the role of tumor necrosis factor‑stimulated gene‑6 in keloid

Li,Xinyi; Chen,Zhao; Li,Xiaojing; Wang,Hui

doi:10.3892/mmr.2018.9767

In vitro analysis of the role of tumor necrosis factor‑stimulated gene‑6 in keloid

Authors:
- Xinyi Li
- Zhao Chen
- Xiaojing Li
- Hui Wang
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Affiliations: Department of Plastic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
Published online on: December 14, 2018 https://doi.org/10.3892/mmr.2018.9767
Pages: 919-926
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

An increasing number of studies have demonstrated that tumor necrosis factor‑stimulated gene‑6 (TSG‑6) has a key role in the progression of fibrosis; however, the exact effects of TSG‑6 in keloid fibroblasts (KFs) remain unknown. The aim of the current study was to investigate the role of TSG‑6 in the pathogenesis of keloids. Primary fibroblasts from 10 patients with keloid were cultured and transfected with pLVX‑Puro or pLVX‑Puro‑TSG‑6. Alterations of TSG‑6 expression were then determined by reverse transcription‑polymerase chain reaction (RT‑PCR) and regulation was observed in KFs transfected with pLVX‑Puro‑TSG‑6. Compared with the control group, transfection with pLVX‑Puro‑TSG‑6 induced growth suppression, cell apoptosis and G2/M arrest in KFs. In addition, the mitochondrial apoptosis pathway was activated in KFs transfected with pLVX‑Puro‑TSG‑6. These findings indicate that TSG‑6 is a novel regulator of keloid fibrogenesis, and thus could be used/targeted TSG‑6 as a promising treatment for keloid.

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1	Gupta J, Gantyala SP, Kashyap S and Tandon R: Diagnosis, management, and histopathological characteristics of corneal keloid: A case series and literature review. Asia Pac J Ophthalmol (Phila). 5:354–359. 2016. View Article : Google Scholar : PubMed/NCBI
2	Jeon YR, Ahn HM, Choi IK, Yun CO, Rah DK, Lew DH and Lee WJ: Hepatocyte growth factor-expressing adenovirus upregulates matrix metalloproteinase-1 expression in keloid fibroblasts. Int J Dermatol. 55:356–361. 2016. View Article : Google Scholar : PubMed/NCBI
3	Syed F, Singh S and Bayat A: Superior effect of combination vs. single steroid therapy in keloid disease: A comparative in vitro analysis of glucocorticoids. Wound Repair Regen. 21:88–102. 2013. View Article : Google Scholar : PubMed/NCBI
4	Har-Shai Y and Zouboulis CC: Intralesional cryotherapy for the treatment of keloid scars: A prospective study. Plast Reconstr Surg. 136:397e–398e. 2015. View Article : Google Scholar : PubMed/NCBI
5	Lee MJ, Kim DH, Ryu JS, Ko AY, Ko JH, Kim MK, Wee WR, Khwarg SI and Oh JY: Topical TSG-6 administration protects the ocular surface in two mouse models of inflammation-related dry eye. Invest Ophthalmol Vis Sci. 56:5175–5181. 2015. View Article : Google Scholar : PubMed/NCBI
6	Kim JA, Ko JH, Ko AY, Lee HJ, Kim MK, Wee WR, Lee RH, Fulcher SF and Oh JY: TSG-6 protects corneal endothelium from transcorneal cryoinjury in rabbits. Invest Ophthalmol Vis Sci. 55:4905–4912. 2014. View Article : Google Scholar : PubMed/NCBI
7	Baranova NS, Nilebäck E, Haller FM, Briggs DC, Svedhem S, Day AJ and Richter RP: The inflammation-associated protein TSG-6 cross-links hyaluronan via hyaluronan-induced TSG-6 oligomers. J Biol Chem. 286:25675–25686. 2011. View Article : Google Scholar : PubMed/NCBI
8	Tan KT, McGrouther DA, Day AJ, Milner CM and Bayat A: Characterization of hyaluronan and TSG-6 in skin scarring: Differential distribution in keloid scars, normal scars and unscarred skin. J Eur Acad Dermatol Venereol. 25:317–327. 2011. View Article : Google Scholar : PubMed/NCBI
9	Mahoney DJ, Swales C, Athanasou NA, Bombardieri M, Pitzalis C, Kliskey K, Sharif M, Day AJ, Milner CM and Sabokbar A: TSG-6 inhibits osteoclast activity via an autocrine mechanism and is functionally synergistic with osteoprotegerin. Arthritis Rheum. 63:1034–1043. 2011. View Article : Google Scholar : PubMed/NCBI
10	Kehlen A, Pachnio A, Thiele K and Langner J: Gene expression induced by interleukin-17 in fibroblast-like synoviocytes of patients with rheumatoid arthritis: Upregulation of hyaluronan-binding protein TSG-6. Arthritis Res Ther. 5:R186–R192. 2003. View Article : Google Scholar : PubMed/NCBI
11	Wang H, Chen Z, Li XJ, Ma L and Tang YL: Anti-inflammatory cytokine TSG-6 inhibits hypertrophic scar formation in a rabbit ear model. Eur J Pharmacol. 751:42–49. 2015. View Article : Google Scholar : PubMed/NCBI
12	Zhang GY, Yi CG, Li X, Zheng Y, Niu ZG, Xia W, Meng Z, Meng CY and Guo SZ: Inhibition of vascular endothelial growth factor expression in keloid fibroblasts by vector-mediated vascular endothelial growth factor shRNA: A therapeutic potential strategy for keloid. Arch Dermatol Res. 300:177–184. 2008. View Article : Google Scholar : PubMed/NCBI
13	Hochman B, Isoldi FC, Furtado F and Ferreira LM: New approach to the understanding of keloid: Psychoneuroimmune-endocrine aspects. Clin Cosmet Investig Dermatol. 8:67–73. 2015.PubMed/NCBI
14	Parikh DA, Ridgway JM and Ge NN: Keloid banding using suture ligature: A novel technique and review of literature. Laryngoscope. 118:1960–1965. 2008. View Article : Google Scholar : PubMed/NCBI
15	Hong X, Li X and Ning J: Expression of TSG-6 and its significance in pathological scar. Acta Univ Med Anhui. 48:685–687. 2013.(In Chinese).
16	Milner CM, Higman VA and Day AJ: TSG-6: A pluripotent inflammatory mediator? Biochem Soc Trans. 34:446–450. 2006. View Article : Google Scholar : PubMed/NCBI
17	Park Y, Jowitt TA, Day AJ and Prestegard JH: Nuclear magnetic resonance insight into the multiple glycosaminoglycan binding modes of the link module from human TSG-6. Biochemistry. 55:262–276. 2016. View Article : Google Scholar : PubMed/NCBI
18	Nagyeri G, Radacs M, Ghassemi-Nejad S, Tryniszewska B, Olasz K, Hutas G, Gyorfy Z, Hascall VC, Glant TT and Mikecz K: TSG-6 protein, a negative regulator of inflammatory arthritis, forms a ternary complex with murine mast cell tryptases and heparin. J Biol Chem. 286:23559–23569. 2011. View Article : Google Scholar : PubMed/NCBI
19	Baranova NS, Foulcer SJ, Briggs DC, Tilakaratna V, Enghild JJ, Milner CM, Day AJ and Richter RP: Inter-a-inhibitor impairs TSG-6-induced hyaluronan cross-linking. J Biol Chem. 288:29642–29653. 2013. View Article : Google Scholar : PubMed/NCBI
20	Zhang S, He H, Day AJ and Tseng SC: Constitutive expression of inter-a-inhibitor (IaI) family proteins and tumor necrosis factor-stimulated gene-6 (TSG-6) by human amniotic membrane epithelial and stromal cells supporting formation of the heavy chain-hyaluronan (HC-HA) complex. J Biol Chem. 287:12433–12444. 2012. View Article : Google Scholar : PubMed/NCBI
21	Zhang GY, Wu LC, Liao T, Chen GC, Chen YH, Zhao YX, Chen SY, Wang AY, Lin K, Lin DM, et al: A novel regulatory function for miR-29a in keloid fibrogenesis. Clin Exp Dermatol. 41:341–345. 2016. View Article : Google Scholar : PubMed/NCBI
22	Lin L, Wang Y, Liu W and Huang Y: BAMBI inhibits skin fibrosis in keloid through suppressing TGF-b1-induced hypernomic fibroblast cell proliferation and excessive accumulation of collagen I. Int J Clin Exp Med. 8:13227–13234. 2015.PubMed/NCBI
23	Shin JU, Lee WJ, Tran TN, Jung I and Lee JH: Hsp70 knockdown by siRNA decreased collagen production in keloid fibroblasts. Yonsei Med J. 56:1619–1626. 2015. View Article : Google Scholar : PubMed/NCBI
24	Garcia GE, Wisniewski HG, Lucia MS, Arevalo N, Slaga TJ, Kraft SL, Strange R and Kumar AP: 2-Methoxyestradiol inhibits prostate tumor development in transgenic adenocarcinoma of mouse prostate: Role of tumor necrosis factor-alpha-stimulated gene 6. Clin Cancer Res. 12:980–988. 2006. View Article : Google Scholar : PubMed/NCBI
25	Park JI, Cao L, Platt VM, Huang Z, Stull RA, Dy EE, Sperinde JJ, Yokoyama JS and Szoka FC: Antitumor therapy mediated by 5-fluorocytosine and a recombinant fusion protein containing TSG-6 hyaluronan binding domain and yeast cytosine deaminase. Mol Pharm. 6:801–812. 2009. View Article : Google Scholar : PubMed/NCBI