Current Medical Science

, Volume 38, Issue 5, pp 894–902 | Cite as

Increased Cthrc1 Activates Normal Fibroblasts and Suppresses Keloid Fibroblasts by Inhibiting TGF-β/Smad Signal Pathway and Modulating YAP Subcellular Location

  • Meng-jie Zhao
  • Si-yuan Chen
  • Xiao-ying Qu
  • Bilal Abdul-fattah
  • Ting Lai
  • Meng Xie
  • Shi-di Wu
  • You-wen ZhouEmail author
  • Chang-zheng HuangEmail author


Keloid may induce severe impairment of life quality for the patients, although keloid is a cutaneous benign tumor. Collagen triple helix repeat containing protein 1 (Cthrc1) was identified as a novel gene that was originally found in adventitial fibroblasts after arterial injury. To address the role of Cthrc1 in keloid, the expression level of Cthrc1 was assessed in normal skin and keloid tissue, as well as in normal fibroblasts (NFs) and keloid fibroblasts (KFs) by using quantitative PCR, Western blotting and immunohistochemical analysis. The results showed that Cthrc1 was increased in keloid tissue and KFs as compared with normal skin and NFs. Meanwhile, CCK8 and Transwell assays found the cellular proliferation and migration of KFs were increased as compared with NFs. Further, to verify the function of Cthrc1 in NFs and KFs, we increased Cthrc1 expression by transfecting lentivirus (LV) vectors LV-Cthrc1. The cellular proliferation and migration, collagen synthesis and the influence on TGF-β and YAP signaling were tested. The cellular proliferation and migration were increased in NFs-Cthrc1 as compared with NFs-control. Meanwhile, YAP expression and nuclear-location was increased in NFs-Cthrc1. On the contrary, when Cthrc1 was overexpressed in KFs, the cellular migration was suppressed and YAP expression was reduced and transferred to cytoplasm in KFs-Cthrc1 as compared with KFs-control. But the expression level of collagen I was decreased and pSmad2/3 nucleus transfer was suppressed in both NFs-Cthrc1 and KFs-Cthrc1 by using Western blotting and immunofluorescence. Increased Cthrc1 activated NFs by promoting YAP nucleus translocation, whereas suppressed KFs by inhibiting YAP nucleus translocation. Enhanced Cthrc1 decreased collagen I in both NFs and KFs by inhibiting TGF-β/Smad pathway. In conclusion, Cthrc1 may play a role in the pathogenesis of keloid by inhibiting collagen synthesis and fibroblasts migration via suppressing TGF-β/Smad pathway and YAP nucleus translocation.

Key words

keloid Collagen triple helix repeat containing protein 1 TGF-β YAP 


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  1. 1.
    Arno AI, Gauglitz GG, Barret JP, et al. Up-to-date approach to manage keloids and hypertrophic scars: A useful guide. Burns, 2014,40(7):1255–1266CrossRefGoogle Scholar
  2. 2.
    Liu F, Lagares D, Choi KM, et al. Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am J Physiol Lung Cell Mol Physiol, 2014,308(4):L344–L357CrossRefGoogle Scholar
  3. 3.
    Pyagay P, Heroult M, Wang Q, et al. Collagen triple helix repeat containing 1, a novel secreted protein in injured and diseased arteries, inhibits collagen expression and promotes cell migration. Circ Res, 2005,96(2):261–268CrossRefGoogle Scholar
  4. 4.
    Durmus T, LeClair RJ, Park KS, et al. Expression analysis of the novel gene collagen triple helix repeat containing-1 (Cthrc1). Gene Expr Patterns, 2006,6(8):935–940CrossRefGoogle Scholar
  5. 5.
    LeClair R, Lindner V. The role of collagen triple helix repeat containing 1 in injured arteries, collagen expression, and transforming growth factor beta signaling. Trends Cardiovasc Med, 2007,17(6):202–205CrossRefGoogle Scholar
  6. 6.
    Bian Z, Miao Q, Zhong W, et al. Treatment of cholestatic fibrosis by altering gene expression of Cthrc1: Implications for autoimmune and nonautoimmune liver disease. J Autoimmun, 2015,63:76–87CrossRefGoogle Scholar
  7. 7.
    Unahabhokha T, Sucontphunt A, Nimmannit U, et al. Molecular signalings in keloid disease and current therapeutic approaches from natural based compounds. Pharm Biol, 2015,53(3):457–463CrossRefGoogle Scholar
  8. 8.
    LeClair RJ, Durmus T, Wang Q, et al. Cthrc1 is a novel inhibitor of transforming growth factor-beta signaling and neointimal lesion formation. Circ Res, 2007,100(6):826–833CrossRefGoogle Scholar
  9. 9.
    Li J, Cao J, Li M, et al. Collagen triple helix repeat containing-1 inhibits transforming growth factor-β1-induced collagen type I expression in keloid. Br J Dermatol. 2011,164(5):1030–1036CrossRefGoogle Scholar
  10. 10.
    Lee MJ, Byun MR, Furutani-Seiki M, et al. YAP and TAZ Regulate Skin Wound Healing. J Invest Dermatol, 2014,134(2):518–525CrossRefGoogle Scholar
  11. 11.
    Zhao B, Li L, Lu Q, et al. Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. Genes Dev, 2011,25(1):51–63CrossRefGoogle Scholar
  12. 12.
    Barry ER, Morikawa T, Butler BL, et al. Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature, 2013,493(7430):106–110CrossRefGoogle Scholar
  13. 13.
    Liu M, Zou W, Huang M, et al. Isolation and cultivation of bovine corneal stromal fibroblasts by two-step collagenase digestion method. Zhongguo Zuzhi Gongcheng Yanjiu (Chinese). 2012,16(7):1201–1205Google Scholar
  14. 14.
    Ke Z, He W, Lai Y, et al. Overexpression of collagen triple helix repeat containing 1 (CTHRC1) is associated with tumour aggressiveness and poor prognosis in human non-small cell lung cancer. Oncotarget, 2014,5(19):9410–9424CrossRefGoogle Scholar
  15. 15.
    Tan F, Liu F, Liu H, et al. CTHRC1 is associated with peritoneal carcinomatosis in colorectal cancer: a new predictor for prognosis. Med Oncol, 2013,30(1):473CrossRefGoogle Scholar
  16. 16.
    Hou M, Cheng Z, Shen H, et al. High expression of CTHRC1 promotes EMT of epithelial ovarian cancer (EOC) and is associated with poor prognosis. Oncotarget, 2015,6(34):35813–35829CrossRefGoogle Scholar
  17. 17.
    Wang L, Xiang YN, Zhang YH, et al. Collagen triple helix repeat containing-1 in the differential diagnosis of dermatofibrosarcoma protuberans and dermatofibrom. Br J Dermatol, 2011,164(1):135–140CrossRefGoogle Scholar
  18. 18.
    Ip W, Wellman-Labadie O, Tang L, et al. Collagen triple helix repeat containing 1 promotes melanoma cell adhesion and survival. J Cutan Med Surg, 2011,15(2):103–110CrossRefGoogle Scholar
  19. 19.
    Kharaishvili G, Magdalena C, Katerina B, et al. Collagen triple helix repeat containing 1 protein, periostin and versican in primary and metastatic breast cancer: an immunohistochemical study. J Clin Pathol, 2011,64(11):977–982CrossRefGoogle Scholar
  20. 20.
    Gurtner GC, Werner S, Barrandon Y, et al. Wound repair and regeneration. Nature, 2008,453(7193):314–321CrossRefGoogle Scholar
  21. 21.
    Liu X, He H, Yin JQ. Therapeutic strategies against TGF-beta signaling pathway in hepatic fibrosis. Liver Int, 2006,26(1):8–22CrossRefGoogle Scholar
  22. 22.
    Mehal WZ, Iredale J, Friedman SL. Scraping fibrosis: expressway to the core of fibrosis. Nat Med, 2011,17(5):552–553CrossRefGoogle Scholar
  23. 23.
    Denton CP, Merkel PA, Furst DE, et al. Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum, 2007,56(1):323–333CrossRefGoogle Scholar
  24. 24.
    Wang L, Xiang YN, Zhang YH, et al. CTHRC1 is upregulated by promoter demethylation and transforming growth factor-beta1 and may be associated with metastasis in human gastric cancer. Cancer Sci, 2012,103(7):1327–1333CrossRefGoogle Scholar
  25. 25.
    Piersma B, Bank RA, Boersema M. Signaling in fibrosis: TGF-beta, WNT, and YAP/TAZ converge. Front Med (Lausanne), 2015,2:59Google Scholar
  26. 26.
    Varelas X, Wrana JL. Coordinating developmental signaling: novel roles for the Hippo pathway. Trends Cell Biol, 2012,22(2):88–96CrossRefGoogle Scholar
  27. 27.
    Preisser F, Giehl K, Rehm M, et al. Inhibitors of oxygen sensing prolyl hydroxylases regulate nuclear localization of the transcription factors Smad2 and YAP/TAZ involved in CTGF synthesis. Biochim Biophys Acta, 2016,1863(8):2027–2036CrossRefGoogle Scholar
  28. 28.
    Grannas K, Arngarden L, Lonn P, et al. Crosstalk between Hippo and TGFβ: subcellular localization of YAP/TAZ/Smad complexes. J Mol Biol, 2015,427(21):3407–3415CrossRefGoogle Scholar

Copyright information

© Huazhong University of Science and Technology 2018

Authors and Affiliations

  • Meng-jie Zhao
    • 1
  • Si-yuan Chen
    • 1
  • Xiao-ying Qu
    • 2
  • Bilal Abdul-fattah
    • 1
  • Ting Lai
    • 1
  • Meng Xie
    • 1
  • Shi-di Wu
    • 1
  • You-wen Zhou
    • 3
    Email author
  • Chang-zheng Huang
    • 1
    Email author
  1. 1.Department of Dermatology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  2. 2.Department of Dermatologythe 457th Airforce HospitalWuhanChina
  3. 3.Department of Dermatology and Skin Science, Vancouver Coastal Health Research InstituteUniversity of British ColumbiaVancouverCanada

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