MicroRNA‑185 regulates transforming growth factor‑β1 and collagen‑1 in hypertrophic scar fibroblasts

Xiao,Kaiyan; Luo,Xusong; Wang,Xiuxia; Gao,Zhen

doi:10.3892/mmr.2017.6179

MicroRNA‑185 regulates transforming growth factor‑β1 and collagen‑1 in hypertrophic scar fibroblasts

Authors:
- Kaiyan Xiao
- Xusong Luo
- Xiuxia Wang
- Zhen Gao
View Affiliations

Affiliations: Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China
Published online on: February 8, 2017 https://doi.org/10.3892/mmr.2017.6179
Pages: 1489-1496
Copyright: © Xiao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Transforming growth factor-β1 (TGF-β1) and collagen type I (Col-1) serve a critical role in the development and progression of hypertrophic scarring (HS). The present study hypothesized that a post‑translational mechanism of microRNAs (miR) regulated the expression of TGF‑β1 and Col‑1 in HS fibroblasts (HSFBs). A collection of 20 HS tissues was compared with corresponding normal tissues from clinical patients, and the expression of miR‑185 was measured. Using PicTar, TargetScan and miRBase databases, it was identified that miR‑185 may be a regulator of TGF‑β1 and Col‑1 in humans. Based on these hypotheses, the expression of miR‑185, TGF‑β1 and Col‑1 in HS tissues was investigated. The results demonstrated that the expression of miR‑185 was markedly suppressed, and TGF‑β1 and Col‑1 levels were increased, in HS tissues. The expression levels of endogenous miR‑185 negatively correlated with the TGF‑β1 and Col‑1 mRNA levels (Pearson's correlation coefficient r=‑0.674, P<0.01 and r=‑0.590, P<0.01, respectively). In vitro, miR‑185 can regulate TGF‑β1 and Col‑1 through the predicted binding sites in its 3'‑untranslated region. miR‑185 had an effect on cell proliferation and apoptosis, thereby regulating HSFBs growth. In addition, miR‑185 gain‑of‑function decreased TGF‑β1 and Col‑1 protein expression, and miR‑185 loss‑of‑function increased TGF‑β1 and Col‑1 protein expression in HSFBs. In conclusion, overexpressed miR‑185 could inhibit HSFBs growth, and the underlying mechanism was mediated, at least partly, through the suppression of TGF‑β1 and Col‑1 expression. However, above all, miR‑185 might serve as a potential therapeutic approach for the treatment of HS.

View Figures

View References

1	Zhang H, Liu X, Liu Y, Wu Y, Li H, Zhao C, Li H, Meng Q and Li W: Effect of hematoporphyrin monomethyl ether-sonodynamic therapy (HMME-SDT) on hypertrophic scarring. PLoS One. 9:e860032014. View Article : Google Scholar : PubMed/NCBI
2	Crawford J, Nygard K, Gan BS and O'Gorman DB: Periostin induces fibroblast proliferation and myofibroblast persistence in hypertrophic scarring. Exp Dermatol. 24:120–126. 2015. View Article : Google Scholar : PubMed/NCBI
3	Gras C, Ratuszny D, Hadamitzky C, Zhang H, Blasczyk R and Figueiredo C: miR-145 contributes to hypertrophic scarring of the skin by inducing myofibroblast activity. Mol Med. 21:296–304. 2015. View Article : Google Scholar : PubMed/NCBI
4	Kathju S, Gallo PH and Satish L: Scarless integumentary wound healing in the mammalian fetus: Molecular basis and therapeutic implications. Birth Defects Res C Embryo Today. 96:223–236. 2012. View Article : Google Scholar : PubMed/NCBI
5	Gauglitz GG, Korting HC, Pavicic T, Ruzicka T and Jeschke MG: Hypertrophic scarring and keloids: Pathomechanisms and current and emerging treatment strategies. Mol Med. 17:113–125. 2011. View Article : Google Scholar : PubMed/NCBI
6	Niessen FB, Spauwen PH, Schalkwijk J and Kon M: On the nature of hypertrophic scars and keloids: a review. Plast Reconstr Surg. 104:1435–1458. 1999. View Article : Google Scholar : PubMed/NCBI
7	Nirodi CS, Devalaraja R, Nanney LB, Arrindell S, Russell S, Trupin J and Richmond A: Chemokine and chemokine receptor expression in keloid and normal fibroblasts. Wound Repair Regen. 8:371–382. 2000. View Article : Google Scholar : PubMed/NCBI
8	Rahmani-Neishaboor E, Yau FM, Jalili R, Kilani RT and Ghahary A: Improvement of hypertrophic scarring by using topical anti-fibrogenic/anti-inflammatory factors in a rabbit ear model. Wound Repair Regen. 18:401–408. 2010. View Article : Google Scholar : PubMed/NCBI
9	Fan C, Dong Y, Xie Y, Su Y, Zhang X, Leavesley D and Upton Z: Shikonin reduces TGF-β1-induced collagen production and contraction in hypertrophic scar-derived human skin fibroblasts. Int J Mol Med. 36:985–991. 2015.PubMed/NCBI
10	Liu S, Jiang L, Li H, Shi H, Luo H, Zhang Y, Yu C and Jin Y: Mesenchymal stem cells prevent hypertrophic scar formation via inflammatory regulation when undergoing apoptosis. J Invest Dermatol. 134:2648–2657. 2014. View Article : Google Scholar : PubMed/NCBI
11	Wang X, Chu J, Wen CJ, Fu SB, Qian YL, Wo Y, Wang C and Wang DR: Functional characterization of TRAP1-like protein involved in modulating fibrotic processes mediated by TGF-β/Smad signaling in hypertrophic scar fibroblasts. Exp Cell Res. 332:202–211. 2015. View Article : Google Scholar : PubMed/NCBI
12	Chen Z, Li W, Ning Y, Liu T, Shao J and Wang Y: Ski diminishes TGF-β1-induced myofibroblast phenotype via up-regulating Meox2 expression. Exp Mol Pathol. 97:542–549. 2014. View Article : Google Scholar : PubMed/NCBI
13	Wu CS, Wu PH, Fang AH and Lan CC: FK506 inhibits the enhancing effects of transforming growth factor (TGF)-β1 on collagen expression and TGF-β/Smad signalling in keloid fibroblasts: Implication for new therapeutic approach. Br J Dermatol. 167:532–541. 2012. View Article : Google Scholar : PubMed/NCBI
14	Tang H, Liu Q, Liu X, Ye F, Xie X, Xie X and Wu M: Plasma miR-185 as a predictive biomarker for prognosis of malignant glioma. J Cancer Res Ther. 11:630–634. 2015. View Article : Google Scholar : PubMed/NCBI
15	Jing R, Chen W, Wang H, Ju S, Cong H, Sun B, Jin Q, Chu S, Xu L and Cui M: Plasma miR-185 is decreased in patients with esophageal squamous cell carcinoma and might suppress tumor migration and invasion by targeting RAGE. Am J Physiol Gastrointest Liver Physiol. 309:G719–G729. 2015. View Article : Google Scholar : PubMed/NCBI
16	Kashiyama K, Mitsutake N, Matsuse M, Ogi T, Saenko VA, Ujifuku K, Utani A, Hirano A and Yamashita S: miR-196a downregulation increases the expression of type I and III collagens in keloid fibroblasts. J Invest Dermatol. 132:1597–1604. 2012. View Article : Google Scholar : PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
18	Takahashi Y, Forrest AR, Maeno E, Hashimoto T, Daub CO and Yasuda J: MiR-107 and MiR-185 can induce cell cycle arrest in human non small cell lung cancer cell lines. PLoS One. 4:e66772009. View Article : Google Scholar : PubMed/NCBI
19	Li S, Ma Y, Hou X, Liu Y, Li K, Xu S and Wang J: miR-185 acts as a tumor suppressor by targeting AKT1 in non-small cell lung cancer cells. Int J Clin Exp Pathol. 8:11854–11862. 2015.PubMed/NCBI
20	Tang H, Liu P, Yang L and Xie X, Ye F, Wu M, Liu X, Chen B, Zhang L and Xie X: miR-185 suppresses tumor proliferation by directly targeting E2F6 and DNMT1 and indirectly upregulating BRCA1 in triple-negative breast cancer. Mol Cancer Ther. 13:3185–3197. 2014. View Article : Google Scholar : PubMed/NCBI
21	Qadir XV, Han C, Lu D, Zhang J and Wu T: miR-185 inhibits hepatocellular carcinoma growth by targeting the DNMT1/PTEN/Akt pathway. Am J Pathol. 184:2355–2364. 2014. View Article : Google Scholar : PubMed/NCBI
22	Tan Z, Jiang H, Wu Y, Xie L, Dai W, Tang H and Tang S: miR-185 is an independent prognosis factor and suppresses tumor metastasis in gastric cancer. Mol Cell Biochem. 386:223–231. 2014. View Article : Google Scholar : PubMed/NCBI
23	Wang XC, Zhan XR, Li XY, Yu JJ and Liu XM: MicroRNA-185 regulates expression of lipid metabolism genes and improves insulin sensitivity in mice with non-alcoholic fatty liver disease. World J Gastroenterol. 20:17914–17923. 2014.PubMed/NCBI
24	Yang W and Yee AJ: Versican 3′-untranslated region (3′UTR) promotes dermal wound repair and fibroblast migration by regulating miRNA activity. Biochim Biophys Acta. 1843:1373–1385. 2014. View Article : Google Scholar : PubMed/NCBI
25	Varga J and Abraham D: Systemic sclerosis: A prototypic multisystem fibrotic disorder. J Clin Invest. 117:557–567. 2007. View Article : Google Scholar : PubMed/NCBI
26	Madala SK, Edukulla R, Phatak M, Schmidt S, Davidson C, Acciani TH, Korfhagen TR, Medvedovic M, Lecras TD, Wagner K and Hardie WD: Dual targeting of MEK and PI3K pathways attenuates established and progressive pulmonary fibrosis. PLoS One. 9:e865362014. View Article : Google Scholar : PubMed/NCBI
27	Zheng L, Hui Q, Tang L, Zheng L, Jin Z, Yu B, Wang Z, Lin P, Yu W, Li H, et al: TAT-mediated acidic fibroblast growth factor delivery to the dermis improves wound healing of deep skin tissue in rat. PLoS One. 10:e01352912015. View Article : Google Scholar : PubMed/NCBI
28	Goldberg MT, Han YP, Yan C, Shaw MC and Garner WL: TNF-alpha suppresses alpha-smooth muscle actin expression in human dermal fibroblasts: An implication for abnormal wound healing. J Invest Dermatol. 127:2645–2655. 2007. View Article : Google Scholar : PubMed/NCBI
29	He T, Bai X, Yang L, Fan L, Li Y, Su L, Gao J, Han S and Hu D: Loureirin B inhibits hypertrophic scar formation via inhibition of the TGF-β1-ERK/JNK pathway. Cell Physiol Biochem. 37:666–676. 2015. View Article : Google Scholar : PubMed/NCBI