Collagen triple helix repeat containing-1 inhibits transforming growth factor-β1-induced collagen type I expression in keloid

Li, J.; Cao, Juan; Li, M.; Yu, Yan; Yang, Yan; Xiao, Xue; Wu, Ziyan; Wang, L.; Tu, Yiji; Chen, H.

doi:10.1111/j.1365-2133.2011.10215.x

Cited by 45 publications

(43 citation statements)

References 37 publications

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“…Hepatic stellate cells are the most crucial non-parenchymal cells during liver fibrosis. A study reported that Cthrc1 was derived from keloid fibroblasts and colud be induced by TGF-β[22]. Hence, we speculated that HSCs might be a source of Cthrc1.…”

Section: 1 Resultsmentioning

confidence: 92%

Treatment of cholestatic fibrosis by altering gene expression of Cthrc1: Implications for autoimmune and non-autoimmune liver disease

Bian

Miao

Zhong

et al. 2015

Journal of Autoimmunity

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Collagen triple helix repeat containing-1 (Cthrc1) is a documented specific inhibitor of TGF-β signaling. Based on this observation, we developed the hypothesis that knocking in/knocking out the Cthrc1 gene in murine models of cholestasis would alter the natural history of cholestatic fibrosis. To study this thesis, we studied two murine models of fibrosis, first, common bile duct ligation (CBDL) and second, feeding of 3, 5-diethoxy-carbonyl-1, 4-dihydrocollidine (DDC). In both models, we administered well-defined adenoviral vectors that expressed either Cthrc1 or, alternatively, a short hairpin RNA (shRNA)-targeting Cthrc1 either before or after establishment of fibrosis. Importantly, when Cthrc1 gene expression was enhanced, we noted a significant improvement of hepatic fibrosis, both microscopically and by analysis of fibrotic gene expression. In contrast, when Cthrc1 gene expression was deleted, there was a significant exacerbation of fibrosis. To identify the mechanism of action of these significant effects produced by knocking in/knocking out Cthrc gene expression, we thence studied the interaction of Cthrc1 gene expression using hepatic stellate cells (HSCs) and human LX-2 cells. Importantly, we demonstrate that Cthrc1 is induced by TGF-β1 via phospho-Smad3 binding to the promoter with subsequent transcription activation. In addition, we demonstrate that Cthrc1 inhibits TGF-β signaling by accelerating degradation of phospho-Smad3 through a proteosomal pathway. Importantly, the anti-fibrotic effects can be recapitulated with a truncated fragment of Cthrc1. In conclusion, our findings uncover a critical negative feedback regulatory loop in which TGF-β1 induces Cthrc1, which can attenuate fibrosis by accelerating degradation of phospho-Smad3.

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Section: 1 Resultsmentioning

confidence: 92%

Treatment of cholestatic fibrosis by altering gene expression of Cthrc1: Implications for autoimmune and non-autoimmune liver disease

Bian

Miao

Zhong

et al. 2015

Journal of Autoimmunity

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“…Finally, CTHRC1 has been shown to inhibit TGF- signaling in fibroblasts (LeClair et al, 2007;Li et al, 2011). In appears, therefore, that KC-MVs induce expression of both positive and negative modulators of the TGF- signaling pathway, resulting in selective regulation of matrix protein genes.…”

Section: Discussionmentioning

confidence: 97%

Keratinocyte Microvesicles Regulate the Expression of Multiple Genes in Dermal Fibroblasts

Huang

Owen

et al. 2015

Journal of Investigative Dermatology

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Extracellular vesicles released from cells regulate many normal and pathological conditions. Little is known about the role of epidermal keratinocyte microvesicles (KC-MVs) in epithelial-stromal interaction that is essential for wound healing. We investigated, therefore, whether MV-like structures are present in human wounds and whether they affect wound healing-associated gene expression in dermal fibroblasts. In human wounds, MV-like vesicles were observed during active epithelial migration and early granulation tissue formation. When KC-MVs derived from keratinocyte-like cells (HaCaT) were added to fibroblast cultures, expression of 21 genes was significantly regulated (P<0.05) out of 80 genes investigated, including matrix metalloproteinase-1 and -3, interleukin-6 and -8, and genes associated with transforming growth factor-β signaling. Similar changes were observed at the protein level. MVs from normal epidermal keratinocytes showed similar response to HaCaT cells. KC-MVs activated ERK1/2, JNK, Smad, and p38 signaling pathways in fibroblasts with ERK1/2 signaling having the most prominent role in the MV-induced gene expression changes. KC-MVs stimulated fibroblast migration and induced fibroblast-mediated endothelial tube formation but did not affect collagen gel contraction by fibroblasts. The results demonstrate that keratinocyte microvesicles have a strong and a specific regulatory effect on fibroblasts that may modulate several aspects of wound healing.

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“…CTHRC1 is considered active and potent in extracellular matrix (ECM) protein degradation (Li et al, 2011). In the tumor micro-environment, the ECM, which consists of the basement membrane and interstitial connective tissue, has been shown to play a vital role in the processes of proliferation, migration, and metastasis of tumor cells (Kim et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…CTHRC1 has been shown to be expressed mainly in neointimal smooth muscle cells and adventitial fibroblasts of balloon-injured vessels (Chen et al, 2013). Clinical findings have demonstrated that CTHRC1 has the ability to promote the proliferation of certain cells, and inhibit the synthesis of type I collagen (Li et al, 2011). Moreover, it has been suggested that CTHRC1 may be largely involved in repairing damaged blood vessel tissues by limiting collagen matrix deposition and improving cell migration (Ip et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Clinical significance of CTHRC1 protein expression in human cancers: a meta-analysis

Wang

Yin

et al. 2016

Genet. Mol. Res.

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ABSTRACT. The aim of this meta-analysis was to investigate the overall diagnostic and prognostic values of CTHRC1 expression in human cancer development. Based on the inclusion and exclusion criteria, 8 cohort studies were included in the meta-analysis. The data were extracted, and analyses were performed using a random-effects model. Summary odds ratios (ORs) and effect sizes (ESs) with 95% confidence intervals (CIs) were calculated to assess the strength of the associations. A total of 1065 cancer patients from the 8 studies were included in the meta-analysis. The results revealed a positive correlation of CTHRC1 protein expression in tumors with tumor-node-metastasis (TNM) stage and with lymph node (LN) metastasis (TNM: OR = 2.98, 95%CI = 1.48-6.00, P = 0.002; LN: OR = 4.26, 95%CI = 1.88-9.67, P = 0.001). CTHRC1 expression was higher in tumors with sizes ≥5 cm than in tumors with sizes <5 cm (OR = 2.39, 95%CI = 1.12-5.09, P = 0.024). Patients with higher CTHRC1 expression had decreased overall survival (OS) (ES = 1.78, 95%CI = 1.23-2.33, P < 0.001) and poorer disease-free survival (DFS) (ES = 1.71, 95%CI = 1.11-2.31, P < 0.001). Disease-stratified analyses yielded significantly different estimates of CTHRC1 levels in the majority of the subgroups (all P < 0.05). In conclusion, increased CTHRC1 expression is associated with advanced TNM stage, increased LN metastasis and tumor size, and decreased OS and DFS, indicating that CTHRC1 may be a biomarker for prognosis of cancer patients.

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Collagen triple helix repeat containing-1 inhibits transforming growth factor-β1-induced collagen type I expression in keloid

Abstract: TGF-b1 was upregulated in keloid fibroblasts and recombinant Cthrc1 inhibited TGF-b1-stimulated collagen type I synthesis, which suggests that Cthrc1 may be a potential therapeutic option for keloids.

Cited by 45 publications

References 37 publications

Treatment of cholestatic fibrosis by altering gene expression of Cthrc1: Implications for autoimmune and non-autoimmune liver disease

Treatment of cholestatic fibrosis by altering gene expression of Cthrc1: Implications for autoimmune and non-autoimmune liver disease

Keratinocyte Microvesicles Regulate the Expression of Multiple Genes in Dermal Fibroblasts

Clinical significance of CTHRC1 protein expression in human cancers: a meta-analysis

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