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REVIEW ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 4  |  Page : 621-624

Role of collagen triple helix repeat containing-1 in tumor and inflammatory diseases


Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China

Date of Web Publication13-Sep-2017

Correspondence Address:
Hongsheng Sun
Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jing Wu Road, Jinan, Shandong 250021
P.R. China
Qingrui Yang
Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jing Wu Road, Jinan, Shandong 250021
P.R. China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_410_17

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 > Abstract 

Initially, collagen triple helix repeat containing-1 (CTHRC1) is expressed mainly in adventitial fibroblasts and neointimal smooth muscle cells of balloon-injured vessels, and increases cell migration, promotes tissue repair in response to injury. A variety of studies demonstrated that over-expression of CTHRC1 in solid tumors results in enhancement of migration and invasion of tumor cells, and is associated with decreased overall survival and disease-free survival. CTHRC1 expression is elevated in hepatitis B virus-infected patients and highly correlated with hepatocellular carcinoma progression as well. Furthermore, CTHRC1 plays a pivotal role in a great many fields, including increases bone mass, prevents myelination, reverses collagen synthesis in keloid fibroblasts, and increases fibroblast-like synoviocytes migration speed and abundant production of arthritic pannus in rheumatoid arthritis. Therefore, it will provide new insight into the pathogenesis of tumor and autoimmune diseases, and will shed new light on the therapy of related clinical diseases.

Keywords: Bone mass, collagen triple helix repeat containing-1, dermatofibrosarcoma protuberans, keloid fibroblasts, myelination, rheumatoid arthritis, tumors


How to cite this article:
Wu Q, Yang Q, Sun H. Role of collagen triple helix repeat containing-1 in tumor and inflammatory diseases. J Can Res Ther 2017;13:621-4

How to cite this URL:
Wu Q, Yang Q, Sun H. Role of collagen triple helix repeat containing-1 in tumor and inflammatory diseases. J Can Res Ther [serial online] 2017 [cited 2017 Sep 21];13:621-4. Available from: http://www.cancerjournal.net/text.asp?2017/13/4/621/214471


 > Introduction Top


Collagen triple helix repeat containing-1 (CTHRC1) is a 28-kD extracellular matrix glycoprotein. It contains an NH2-terminal peptide for extracellular secretion, a short collagen triple helix repeat of 36 amino acids, and a COOH-terminal globular domain.[1] CTHRC1 shares 92% of homolog sequences in human compared to that of rat,[1],[2] and is highly conserved in lower chordates and higher mammals.[1]

CTHRC1 is expressed mostly in adventitial fibroblasts and neointimal smooth muscle cells of balloon-injured vessels.[1],[3] It encodes a secreted glycoprotein with 12 repeats of the Gly-X-Y motif and increases cell motility by limiting the deposition of the collagen matrix and promoting cell migration, by which it plays an important role in tissue repair in vascular remodeling in response to injury.[1]

CTHRC1 is induced by transforming growth factor (TGF-β) 1 through phospho-Smad3 binding to the promoter with subsequent transcription activation,[4] and its elevated expression is associated with increased cell migration and invasion.[5],[6] To the contrary, CTHRC1 inhibits TGF-β signaling by accelerating degradation of phospho-Smad3 through a proteosomal pathway.[7],[8] Furthermore, CTHRC1 can mediate the activities of the Rho GTPase family members, including Rac1 RhoA and Cdc42, which plays pivotal effects in cytoskeletal reorganization and cell adhesion.[9],[10]

Recently, a variety of studies explored the expression and potential mechanisms of CTHRC1 in several human tumors. Moreover, several studies also uncovered the effects of CTHRC1 on bone mass, myelination, synoviocytes and collagen synthesis in keloid fibroblasts. Here, we reviewed the emerging roles of CTHRC1 in multiple clinical diseases.


 > Collagen Triple Helix Repeat Containing-1 Promotes the Migration and Invasion of Tumor Cells Top


At present, many studies have revealed that CTHRC1 is highly up-regulated in solid tumors, including melanoma, non-small-cell lung cancer,[11] gastric cancer,[12] hepatocellular cancer,[3] breast cancer,[13] pancreatic cancer,[9] colorectal cancer,[2],[14] as well as cancers of esophagus, ovary, thyroid.[2],[15],[16],[17],[18] CTHRC1 expression was also showed to be associated with the tumor-node-metastasis stage (TNM), disease progression and prognosis, indicating its significant role in cancer pathogenic mechanism.[17],[19],[20]

Wang et al.[21] found a positive correlation of CTHRC1 protein expression in tumors with TNM stage and lymph node metastasis (LNM). CTHRC1 expression was higher in tumors with sizes ≥5 cm than <5 cm. Similarly, Lee et al.[22] demonstrated that the CTHRC1 mRNA level was significantly increased in oral squamous cell carcinoma, and over-expression of CTHRC1 was associated with LNM and poor prognosis. CTHRC1 expression was also showed to be up-regulated in paraffin-embedded epithelial ovarian cancer compared to borderline or benign tumor tissues, and closely correlated with tumor size, clinical stage and LNM.[23] Gu et al.[16] reported that CTHRC1 was highly expressed in gastric carcinoma compared with normal tissues, and increased expression of CTHRC1 was correlated with the American Joint Committee on Cancer stage classification, gastric wall invasion depth, LNM, lymphovascular space involvement and recurrence. Moreover, CTHRC1 gene is overexpressed in hepatocellular carcinoma (HCC) and associated with larger tumor size and advanced tumor stage.[3]

What is more, CTHRC1 was found to promote colorectal cancer cell migration, invasion and proliferation in vitro.[24] It was also reported that CTHRC1 expression was significantly higher in breast cancer than in normal tissue or precursor lesions, and CTHRC1 stromal expression was enhanced in patients with bone metastasis.[19] Park et al.[9] showed that CTHRC1 is highly expressed in pancreatic cancer, and promotes primary tumor growth and distant metastasis. Kim et al.[25] found that CTHRC1 expression is elevated in colon cancer cell lines and clinical specimens, and promotes cancer cell invasion through extracellular signal-regulated kinase-dependent induction of MMP9 expression.

Moreover, recent studies revealed that CTHRC1 may induce and regulate cell migration and adhesion by activating multiple signaling pathways including RhoA, Src, focal adhesion kinase, paxillin, mitogen-activated protein kinase, Wnt/β-catenin, Wnt/PCP-Rho, Wnt/PCP, GSK-3β/β-catenin focal adhesion kinase, extracellular signal-regulated kinase and Rac1.[3],[11],[23],[24],[26]

In conclusion, over-expression of CTHRC1 is associated with the advanced TNM stage, increased LN metastasis and tumor size, decreased overall survival and disease-free survival. Furthermore, the increased expression of CTHRC1 results in the enhancement of migration and invasion of tumor cells,[3],[26] indicating that CTHRC1 may be an independent prognostic factor for cancer patients.


 > Over-Expression of Collagen Triple Helix Repeat Containing-1 is Correlated with Hepatocellular Carcinoma Progression Top


Several studies [27],[28] revealed that hepatitis B virus (HBV) stimulates CTHRC1 expression by activating nuclear factor-kappa B and cyclic adenosine monophosphate response element binding protein, through ERK/c-Jun N-terminal kinase pathway. Subsequently, CTHRC1 down-regulates the signal transducer and activator of transcription ½ phosphorylation, IFN-stimulated genes production, and Type I Interferon activity. Hence, HBV facilitates HCC development through activating CTHRC1, which in turn accelerates invasion of hepatoma cells through regulating multiple cellular factors and signal cascades. Therefore, CTHRC1 expression is elevated in HBV-infected patients and highly correlated with HCC progression by the above-mentioned mechanisms.


 > Collagen Triple Helix Repeat Containing-1 Increases Bone Mass Top


Osteoporosis is a significant public health issue mainly affecting women, men and elderly. Increasement of bone mass and prevention of fragility fractures significantly avoids mortality and morbidity and saves direct and indirect costs to the economy.[29] Current therapy of osteoporosis includes lifestyle changing, drug intakes, and surgery.[30]

Bone remodeling is pivotal to the maintenance of bone integrity.[31] Related research also showed that CTHRC1 expression in bone is increased in a high-turnover state, but decreased in conditions associated with suppressed bone turnover.

CTHRC1 was secreted by osteoclast.[31],[32] It targets stromal cells to stimulate osteogenesis, enhances the differentiation and function of osteoblast,[33],[34] and upregulates osteoblastic bone formation,[35] which suggests its important role in bone formation and bone mass maintenance.

Similarly, Kimura [35] identified that CTHRC1 transgenic mice expressed elevated levels of several osteoblast-specific genes and bone mass, whereas CTHRC1-null mice displayed reverse manner, indicating that CTHRC1 increases bone mass as a positive regulator of osteoblastic bone formation, and may offer a novel treatment prospect for osteoporosis.


 > Collagen Triple Helix Repeat Containing-1 Increases Fibroblast-Like Synoviocytes Migration and Arthritic Pannus Production in Rheumatoid Arthritis Top


Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovial inflammation and subsequent joint destruction and is facilitated and sustained by various proinflammatory cytokines including tumor necrosis factor-alpha, interleukin-1 (IL-1) and IL-6.[36] The formation of destructive hypercellular pannus is important and critical to joint damage in RA.

Recent research [37] reported that CTHRC1 was produced by activated fibroblast-like synoviocytes (FLS) located at the synovial intimal lining and the bone-pannus interface in murine experimental arthritis. CTHRC1 was also highly expressed in plasma of RA patients. CTHRC1 primarily promotes FLS polarization along the front-tail axis and increases the migration and directness of cell movement, resulting in the abundant production of arthritic pannus and consequent damage of arthritis. Furthermore, Kudryavtseva et al.[38] also found that CTHRC1 was correlated with the genes of the proinflammatory cytokines IL-1β and IL-6, and strongly associated with arthritis severity in arthritic joints of mice. Therefore, CTHRC1 may increase the progression of RA and act as a critical prognostic factor for RA patients.


 > Collagen Triple Helix Repeat Containing-1 Prevents Myelination Top


The exploration of molecular mechanisms involved in the interaction between neurons and Schwann cells is crucial for understanding the myelination process. Recently, CTHRC1 was identified to be upregulated in Schwann cells. It enhances Schwann cell proliferation but leads to a delay in myelin formation, demonstrating that CTHRC1 plays a negative role in myelination.[39]


 > The Expression of Collagen Triple Helix Repeat Containing-1 in Dermatofibrosarcoma Protuberans Top


Wang et al.[40] detected the expression of CTHRC1 in patients with dermatofibrosarcoma protuberans (DFSP) and dermatofibroma (DF) using immunohistochemical staining, and found that CTHRC1 was positive in 96% of DFSP samples but negative in 91% of DF samples. They confirmed that CTHRC1 is a positive marker for DFSP and might be more reliable than traditional markers.


 > Collagen Triple Helix Repeat Containing-1 Reverses Collagen Synthesis in Keloid Fibroblasts Top


Li reported that [41] the expression of CTHRC1 and TGF-β1 was significantly increased in keloid compared with normal skin, and TGF-β1 induced the CTHRC1 expression in a concentration-dependent way. Meanwhile, CTHRC1 reversed the TGF-β1 stimulated Type I collagen expression and collagen synthesis, indicating that CTHRC1 may play potential therapeutic effects on keloids.


 > Conclusion Top


CTHRC1 promotes tissue repair in response to injury by increasing cell motility and migration. Over-expression of CTHRC1 is correlated with TNM stage, LNM, tumor size, disease progression and prognosis. As well, it increases the FLS migration, arthritic pannus production and joint damage in RA. Moreover, it functions as an important factor and biomarker in a variety of clinical aspects. Thus, it will provide a novel research target for the pathogenesis and therapy of clinical diseases, especially for autoimmune diseases.

Acknowledgments

The study was supported by the National Natural Science Foundation of China (CN) (No. 81501399/H1008).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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