Helix Repeat Research Articles

CTHRC1 and PD‑1/PD‑L1 expression predicts tumor recurrence in prostate cancer.

Collagen triple helix repeat containing 1 (CTHRC1) is a gene that has been associated with tumor progression in human prostate cancer (PC). The tumor immune microenvironment has been linked with disease outcome in PC. In the present study, the correlation between CTHRC1 with PC recurrence and the tumor immunological microenvironment was investigated. Using the data supplied by the Tumor Immune Estimation Resource (TIMER), the expression of CTHRC1, programmed cell death protein 1 (PD-1), and programmed cell death 1 ligand 1 (PD-L1) were analyzed. Immunohistochemical staining of CTHRC1, PD-1 and PD-L1 was performed using a tissue microarray construction of prostate adenocarcinoma (PRAD) specimens. In PRAD, an association was reported between the CTHRC1 expression and the disease free survival (DFS) rate (P=0.022). Overexpression of CTHRC1 was correlated with increased levels of PD-1 (R=0.272, P=0.021) and PD-L1 (R=0.298, P=0.016), elevated levels of infiltrating B cells (P=9.51e−11), CD4+ cells (P=1.51e−11), macrophages (P=8.25e−5), neutrophils (P=2.17e−9) and dendritic cells (P=3.13e−13). Bioinformatics analysis revealed that CTHRC1 was correlated with the expression levels of matrix metalloproteinase-9, mucin 1 and solute carrier organic anion transporter family member 2B1 genes, which exert an influence in PRAD. The occurrence of this condition is most likely to be associated with regulation of the tumor microenvironment. Taken together, we demonstrated that the prognosis and immunity of PC are closely linked to CTHRC1 upregulation. Furthermore, these results suggest that the immune function of PC may be suppressed by CTHRC1-targeting therapy.

TNF deficiency causes alterations in the spatial organization of neurogenic zones and alters the number of microglia and neurons in the cerebral cortex

BackgroundAlthough tumor necrosis factor (TNF) inhibitors are used to treat chronic inflammatory diseases, there is little information about how long-term inhibition of TNF affects the homeostatic functions that TNF maintains in the intact CNS. Materials and methodsTo assess whether developmental TNF deficiency causes alterations in the naïve CNS, we estimated the number of proliferating cells, microglia, and neurons in the developing neocortex of E13.5, P7 and adult TNF knock out (TNF−/−) mice and wildtype (WT) littermates. We also measured changes in gene and protein expression and monoamine levels in adult WT and TNF−/− mice. To evaluate long-term effects of TNF inhibitors, we treated healthy adult C57BL/6 mice with either saline, the selective soluble TNF inhibitor XPro1595, or the nonselective TNF inhibitor etanercept. We estimated changes in cell number and protein expression after two months of treatment. We assessed the effects of TNF deficiency on cognition by testing adult WT and TNF−/− mice and mice treated with saline, XPro1595, or etanercept with specific behavioral tasks. ResultsTNF deficiency decreased the number of proliferating cells and microglia and increased the number of neurons. At the same time, TNF deficiency decreased the expression of WNT signaling-related proteins, specifically Collagen Triple Helix Repeat Containing 1 (CTHRC1) and Frizzled receptor 6 (FZD6). In contrast to XPro1595, long-term inhibition of TNF with etanercept in adult C57BL/6 mice decreased the number of BrdU+ cells in the granule cell layer of the dentate gyrus. Etanercept, but not XPro1595, also impaired spatial learning and memory in the Barnes maze memory test. ConclusionTNF deficiency impacts the organization of neurogenic zones and alters the cell composition in brain. Long-term inhibition of TNF with the nonselective TNF inhibitor etanercept, but not the soluble TNF inhibitor XPro1595, decreases neurogenesis in the adult mouse hippocampus and impairs learning and memory after two months of treatment.

CTHRC1 May Serve As A Prognostic Biomarker For Hepatocellular Carcinoma.

BackgroundHepatocellular carcinoma is a common malignant cancer and the second most common cause of cancer-related deaths worldwide. Collagen triple helix repeat containing 1 (CTHRC1) has been increasingly reported to be involved in tumorigenesis and/or tumor progression. However, limited data are available regarding the role of CTHRC1 in hepatocellular carcinoma.MethodsParaffin-embedded specimens from a total of 29 patients with HCC were collected in our study. The expression of CTHRC1 in hepatocellular carcinoma was evaluated using immunohistochemistry and bioinformatics analysis. Furthermore, Spearman analysis was performed to identify factors of correlation between CTHRC1 and clinicopathological features. Survival curves for hepatocellular carcinoma were produced using the Kaplan-Meier method and the log rank test.ResultsIn this study, we confirmed that CTHRC1 is highly expressed in tissues and hepatoma cell lines. The statistical analysis revealed that the levels of CTHRC1 were significantly correlated with cirrhosis (P=0.024), tumor size (P=0.006), vascular invasion (P<0.001), TNM stage (P<0.001), and BCLC stage (P<0.001). High expression of CTHRC1 in hepatocellular carcinoma tissues is significantly associated with poor survival.ConclusionCTHRC1 may serve as a prognostic biomarker for hepatocellular carcinoma.

CTHRC1 expression in primary biliary cholangitis.

Collagen triple helix repeat containing-1 (CTHRC1) is a highly conserved extracellular matrix glycoprotein that is overexpressed in two murine models of cholestatic liver fibrosis. Elevated CTHRC1 has been found to attenuate liver fibrosis in these murine models, thus we aimed to study the expression of CTHRC1 in patients with cholestatic liver diseases and its correlation with hepatic conditions. Ninety patients with chronic liver disease, including 48 had primary biliary cholangitis (PBC), 18 had primary sclerosing cholangitis (PSC) and 24 had chronic hepatitis B (CHB), together with five healthy controls (HC), were recruited to this study. Participants' liver sections were analyzed using immunohistochemistry. Serum CTHRC1 levels in another cohort of 59 patients with PBC and 10 age-matched HC were detected by enzyme-linked immunosorbent assay. CTHRC1 protein was primarily expressed in activated hepatic stellate cells (HSC). CTHRC1 expression was significantly increased in the PBC and PSC groups, compared with the HC and CHB groups. Importantly, the hepatic fibrosis stage of the PBC group was positively correlated with hepatic CTHRC1 expression (r = 0.425, P = 0.003). Meanwhile, there were significant correlations between serum CTHRC1 levels and both the degrees of hepatic inflammation and fibrosis stage in the PBC group (r = 0.300, P = 0.022; r = 0.321, P = 0.012). CTHRC1 may play a role in hepatic fibrogenesis in PBC and that serum CTHRC1 may be a potential novel noninvasive biomarker in the assessment of liver fibrosis and inflammation.

CTHRC1: A New Candidate Biomarker for Improved Rheumatoid Arthritis Diagnosis.

Background: The purpose of this study was to determine whether plasma levels of the collagen triple helix repeat containing 1 (CTHRC1) protein can serve as a blood-based biomarker for improved diagnosis of rheumatoid arthritis (RA) patients and monitoring of RA disease activity.Methods: We measured levels of CTHRC1 in the plasma of patients diagnosed with RA, osteoarthritis (OA), reactive arthritis (ReA), as well as in healthy individuals. We then assessed the correlation between CTHRC1 protein and a range of indices including the 28-joint disease activity score (DAS28), rheumatoid factor (RF), C-reactive protein (CRP), anti-citrullinated protein antibodies (ACPA), erythrocyte sedimentation rate (ESR), as well as a panel of cytokines, including interleukin 1 beta (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), and interferon gamma (IFNγ). Receiver operating characteristic (ROC) analysis was further performed to assess the diagnostic value of CTHRC1.Results: CTHRC1 plasma levels were significantly elevated in RA patients compared to healthy individuals, OA and ReA patients. ROC curve and risk score analysis suggested that plasma CTHRC1 can accurately discriminate patients with RA from healthy controls and may have practical value for RA diagnosis. CTHRC1 levels were positively associated with RF, ACPA, CRP, and disease activity based on the combined index of DAS28 with CRP (DAS28-CRP), and also strongly correlated with IL-1β, IL-6, IL-8, and IFNγ.Conclusion: Our studies show that CTHRC1 is a sensitive and easy-to-measure plasma marker that differentiates between RA and healthy status and also distinguishes between RA and other forms of arthritis, such as OA and ReA. At the current level of understanding, plasma CTHRC1 levels may improve the diagnosis of RA and these findings warrant confirmation in a larger, more comprehensive patient population.

Pirfenidone attenuates lung fibrotic fibroblast responses to transforming growth factor-\u03b21

BackgroundPirfenidone, an antifibrotic agent used for the treatment of idiopathic pulmonary fibrosis (IPF), functions by inhibiting myofibroblast differentiation, which is involved in transforming growth factor (TGF)-β1-induced IPF pathogenesis. However, unlike normal lung fibroblasts, the relationship between pirfenidone responses of TGF-β1-induced human fibrotic lung fibroblasts and lung fibrosis has not been elucidated.MethodsThe effects of pirfenidone were evaluated in lung fibroblasts isolated from fibrotic human lung tissues after TGF-β1 exposure. The ability of two new pharmacological targets of pirfenidone, collagen triple helix repeat containing protein 1(CTHRC1) and four-and-a-half LIM domain protein 2 (FHL2), to mediate contraction of collagen gels and migration toward fibronectin were assessed in vitro.ResultsCompared to control lung fibroblasts, pirfenidone significantly restored TGF-β1-stimulated fibroblast-mediated collagen gel contraction, migration, and CTHRC1 release in lung fibrotic fibroblasts. Furthermore, pirfenidone attenuated TGF-β1- and CTHRC1-induced fibroblast activity, upregulation of bone morphogenic protein-4(BMP-4)/Gremlin1, and downregulation of α-smooth muscle actin, fibronectin, and FHL2, similar to that observed post-CTHRC1 inhibition. In contrast, FHL2 inhibition suppressed migration and fibronectin expression, but did not downregulate CTHRC1.ConclusionsOverall, pirfenidone suppressed fibrotic fibroblast-mediated fibrotic processes via inverse regulation of CTHRC1-induced lung fibroblast activity. Thus, CTHRC1 can be used for predicting pirfenidone response and developing new therapeutic targets for lung fibrosis.

CTHRC1 facilitates bladder cancer cell proliferation and invasion through regulating the PI3K/Akt signaling pathway.

IntroductionEmerging evidence has illustrated that Collagen triple helix repeat containing 1 (CTHRC1) is crucial for tumorigenesis and development. However, the effects of CTHRC1 on bladder cancer progression remain largely unclear. Here, we aim to investigate the function and mechanism of CTHRC1 in behaviors of bladder cancer cells in vitro and in vivo.Material and methodsInterference assays were applied to determine the biological functions of CTHRC1. The expression of CTHRC1 was examined by quantitative real time-PCR (qRT-PCR), Western blot and immunohistochemical (IHC) analysis. Effects of CTHRC1 on proliferation, migration and invasion were evaluated by CCK-8, colony formation, flow cytometry, EdU staining, wound healing, transwell and western blot assays. Bladder cancer cells transfected with sh-CTHRC1 were injected into nude mice to explore the effect of CTHRC1 on tumorigenesis in vivo.ResultsCTHRC1 expression was increased in bladder cancer tissues and cell lines compared with normal controls, and associated with advanced clinical stage and lymph node metastasis. Also, patients with high levels of CTHRC1 expression were found to have a poor prognosis. Knockdown of CTHRC1 alleviated bladder cancer cell proliferation, migration and invasion in vitro and impeded tumorigenesis in vivo. Moreover, mechanistic investigation indicated that CTHRC1 could regulate the PI3K/Akt signaling pathway.ConclusionsOur data demonstrated that CTHRC1 played an oncogenic role in bladder cancer by modulating the PI3K/Akt signaling pathway, which sheds novel light on diagnosis and treatment of bladder cancer.

CTHRC1 promotes M2-like macrophage recruitment and myometrial invasion in endometrial carcinoma by integrin-Akt signaling pathway.

The infiltration of tumor-associated macrophages (TAMs) is associated with tumor progression and poor prognosis in endometrial cancer (EC). Collagen triple helix repeat containing 1 (CTHRC1), a secreted ECM protein, has been reported to have important roles in promoting cancer invasion and metastasis, but the functional role of CTHRC1 and its association with TAMs in EC remain unclear. Here we report that, in EC patients, CTHRC1 expression was up-regulated in endometrial cancer tissues compared with normal endometrium (P < 0.0001), and is positively correlated with tumor grade and depth of myometrial invasion (P = 0.024 and P = 0.0002, respectively). Meanwhile, CTHRC1 expression was positively correlated with an increased number of infiltrating TAMs, especially M2-like TAMs (P = 0.003, P = 0.001). In the tumor microenvironment of EC, CTHRC1 not only promoted myometrial invasion by interacting with Integrin β3-Akt signaling pathway, but also promoted infiltration of M2-like TAMs by upregulating Fractalkine chemokine receptor (CX3CR1) expression in macrophages. Changing levels of recombinant CTHRC1 protein (rCTHRC1) promoted tumor migration and invasion via enhancing macrophage recruitment in vitro. In summary, our findings eventually provided a novel role for CTHRC1 in remodeling the tumor immune microenvironment to promote tumor metastasis in EC patients.

Collagen triple helix repeat containing 1a (Cthrc1a) regulates cell adhesion and migration during gastrulation in zebrafish

Cell adhesion and migration are key cell behaviours during gastrulation in early embryos and metastasis in cancers. Cthrc1 is a secreted protein highly conserved among vertebrates; it is upregulated in injured and diseased arteries, as well as in malignant cancers. There is increasing evidence showing that its expression and activity are associated with cancer progression and inflammatory diseases. However, the mechanism by which it regulates cell migration, and its implication during early development remains unclear. Here we show that zebrafish Cthrc1a is expressed in hypoblast cells, and is required for cell adhesion and migration during gastrulation. Knockdown of cthrc1a in whole embryo inhibits epiboly and convergent extension movements, and reduces the elongation of anteroposterior axis. Cell adhesion assay indicates that Cthrc1a is necessary for mesendoderm cells to interact with fibronectin-coated substratum, and to extend polarised cellular protrusions. Moreover, secreted Cthrc1a proteins diffuse efficiently between blastoderm cells and are recruited by neighbouring cells in an integrin-dependent manner. Consistently, there exists a functional interaction between Cthrc1a and integrin β1 in anteroposterior axis elongation. These results provide insight into the function of Cthrc1a in the regulation of cell adhesion and migration during embryonic axis elongation.

CTHRC1 promotes wound repair by increasing M2 macrophages via regulating the TGF-β and notch pathways

The healing of acute wounds is vital to humans and is a well-orchestrated process that involves systemic and local factors. However, there is a lack of effective and safe clinical therapies. The collagen triple helix repeat containing 1 (CTHRC1) protein is a type of exocrine protein that has been recently reported to contribute to tissue repair. Our aim is to validate the promoting effects of CTHRC1 on the healing of acute wounds and to elucidate the underlying molecular mechanism. Therefore, we first established acute wound healing mouse models and confirmed that CTHRC1 accelerates the healing process of acute wounds. Then, we characterized wound macrophages using a polyvinylalcohol (PVA) sponge model and used Western blotting to investigate the molecular mechanism. We found that CTHRC1 increased the M2 macrophage population and the TGF-β expression level as a result of the activation of the TGF-β and Notch pathways, which eventually contributed to the promotion of wound healing. Inhibition of the Notch pathway showed attenuated M2 macrophage recruitment, and it decreased the TGF-β expression level. These results substantiate our hypothesis that CTHRC1 promotes wound healing by recruiting M2 macrophages and regulating the TGF-β and Notch pathways.

Effect of calcium phosphate phases affecting the crosstalk between osteoblasts and osteoclasts in vitro.

Previous studies have reported that octacalcium phosphate (OCP) enhances osteoblast differentiation and osteoclast formation during the hydrolysis process to hydroxyapatite (HA). However, the crystal phases that affect the crosstalk between osteoclasts and osteoblasts are unknown, which should determine the bone substitute material's property of OCP. The present study was designed to investigate whether the chemical composition and crystal structure of calcium phosphates affect osteoclast formation and the osteoclast-osteoblast crosstalk. Biodegradable β-tricalcium phosphate (β-TCP) was used as the control material. Osteoclasts were cultured on HA/OCP or HA/TCP disks and their cellular responses were assessed. Both OCP and β-TCP had a similar ability to create multinucleated osteoclasts. However, OCP promoted the expression of complement component 3a (C3a), a positive coupling factor, in osteoclasts, whereas β-TCP enhanced that of EphrinB2 (EfnB2) and collagen triple helix repeat containing 1 (Cthrc1). During osteoclast culture, phosphate ions were released from the crystals, and OCP-HA conversion was advanced in HA/OCP mixtures and OCP. X-ray diffraction analysis revealed no remarkable changes in the crystal structures of HA/TCP mixtures and β-TCP before and after osteoclast culture. These results indicate that the distinct chemical environment induced by the calcium phosphate phases affects the crosstalk between osteoclasts and osteoblasts. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1001-1013, 2019.

Expressions of Yes-associated protein 1 and collagen triple helix repeat containing 1 in triple-negative breast cancer and their correlations with expression of E-cadherin

Objective To investigate the clinical significances of the expressions of Yes-associated protein 1 (YAP1) and collagen triple helix repeat containing 1 (CTHRC1) in triple-negative breast cancer (TNBC) and their correlations with expression of E-cadherin. Methods Immunohistochemical analysis (SABC) was performed to detect expressions of YAP1 and CTHRC1 in 73 specimens of TNBC and adjacent cancer tissues collected from patients in Dandong First Hospital from January 2006 to December 2017. The correlations between the expressions of YAP1 and CTHRC1 and clinicopathologic features and E-cadherin expression were analyzed. Results The expression rates of YAP1 and CTHRC1 in TNBC were 71.23% (52/73) and 79.45% (58/73), and 13.70% (10/73) and 27.40% (20/73) in adjacent cancer tissues, respectively, and the differences were statistically significant (χ2 values were 49.452 and 39.748, both P 0.05). The expressions of YAP1 and CTHRC1 were negatively correlated with expression of E-cadherin in TNBC (r=-0.371, P = 0.001; r = -0.323, P = 0.005). Conclusion YAP1 and CTHRC1 is closely related to the occurrence and development of TNBC and may participate in the invasion of TNBC through epithelial mesenchymal transition. Key words: Breast neoplasms; Immunohistochemistry; Yes-associated protein 1; Collagen triple helix repeat containing 1; Cadherins; Epithelial-mesenchymal transition

Autocrine CTHRC1 activates hepatic stellate cells and promotes liver fibrosis by activating TGF-β signaling.

BackgroundHepatic fibrosis is caused by chronic liver injury and may progress toward liver cirrhosis, and even hepatocellular carcinoma. However, current treatment is not satisfactory. Therefore, there is a mandate to find novel therapeutic targets to improve therapy, and biomarkers to monitor therapeutic response.MethodsLiver fibrosis was induced by carbon tetrachloride (CCl4) or thioacetamide (TAA) in wild type (WT) or CTHRC1−/− mice, followed by immunofluorescence and immunohistochemical analyses. CTHRC1 monoclonal antibody (mAb) was used to abrogate the effect of CTHRC1 in vitro and in vivo.ResultsHere, we reported that collagen triple helix repeat containing 1 (CTHRC1), a secreted protein derived from hepatic stellate cells (HSCs), was significantly up-regulated in fibrotic liver tissues. CTHRC1 promoted HSCs transformation from a quiescent to an activated state, and enhanced migratory or contractile capacities of HSCs by activating TGF-β signaling. Meanwhile, CTHRC1 competitively bound to Wnt noncononical receptor and promoted the contractility but not activation of HSCs. CCl4 or TAA-induced liver fibrosis was attenuated in CTHRC−/− mice compared with littermate control, while a monoclonal antibody of CTHRC1 suppressed liver fibrosis in WT mice treated with CCl4 or TAA.InterpretationWe demonstrated that CTHRC1 is a new regulator of liver fibrosis by modulating TGF-β signaling. Targeting CTHRC1 could be a promising therapeutic approach, which can suppress TGF-β signaling and avoid the side effects caused by directly targeting TGF-β. CTHRC1 could also be a potential biomarker for monitoring response to anti-fibrotic therapy.FundThis study was supported by the National Natural Science Foundation of China (ID 81672358, 81871923, 81872242, 81802890), the Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (ID 20181708), the Natural Science Foundation of Shanghai (ID 17ZR1428300, 18ZR1436900), and Shanghai Municipal Health Bureau (ID 2018BR32). The funders did not play a role in manuscript design, data collection, data analysis, interpretation nor writing of the manuscript.

CTHRC1 overexpression promotes cervical carcinoma progression by activating the Wnt/PCP signaling pathway.

The tumorigenesis and metastasis of tumors are associated with human collagen triple helix repeats containing 1 (CTHRC1). To study the effects and possible impacting mechanisms of CTHRC1 on human cervical carcinoma development, samples of paraffin-embedded cervical carcinoma and HeLa cells were examined. Immunofluorescence, cell wound scratch assay, western blot analysis and Transwell invasion assay were used to evaluate HeLa cells in response to silencing of the CTHRC1 gene in cervical carcinoma. The expression levels of gap-associated proteins of the Wnt/PCP pathway in paraffin-embedded cervical carcinoma samples were also evaluated by immunohistochemical staining. CTHRC1 promoted the migration and invasion of HeLa cells in vitro, downregulated Ror2 and p-c-Jun and activated the Wnt/PCP pathway. Furthermore, the expression of p-c-Jun, Ror2 and Wnt5a was increased after overexpression of CTHRC1 as revealed in HeLa cells compared to control group. The present experiments revealed that CTHRC1 promoted HeLa cell progression by activating the Wnt/PCP signaling pathway and may play a key role in the invasion and metastasis of cervical carcinoma.

Coupling factors involved in preserving bone balance.

Coupling during bone remodeling refers to the spatial and temporal coordination of bone resorption with bone formation. Studies have assessed the subtle interactions between osteoclasts and osteoblasts to preserve bone balance. Traditionally, coupling research related to osteoclast function has focused on bone resorption activity causing the release of growth factors embedded in the bone matrix. However, considerable evidence from in vitro, animal, and human studies indicates the importance of the osteoclasts themselves in coupling phenomena, and many osteoclast-derived coupling factors have been identified. These include sphingosine-1-phosphate, vesicular-receptor activator of nuclear factor-κB, collagen triple helix repeat containing 1, and cardiotrophin-1. Interestingly, neuronal guidance molecules, such as slit guidance ligand 3, semaphorin (SEMA) 3A, SEMA4D, and netrin-1, originally identified as instructive cues allowing the navigation of growing axons to their targets, have been shown to be involved in the intercellular cross-talk among bone cells. This review discusses osteoclast-osteoblast coupling signals, including recent advances and the potential roles of these signals as therapeutic targets for osteoporosis and as biomarkers predicting human bone health.

Comparative genomic and methylome analysis of non-virulent D74 and virulent Nagasaki Haemophilus parasuis isolates.

Haemophilus parasuis is a respiratory pathogen of swine and the etiological agent of Glässer's disease. H. parasuis isolates can exhibit different virulence capabilities ranging from lethal systemic disease to subclinical carriage. To identify genomic differences between phenotypically distinct strains, we obtained the closed whole-genome sequence annotation and genome-wide methylation patterns for the highly virulent Nagasaki strain and for the non-virulent D74 strain. Evaluation of the virulence-associated genes contained within the genomes of D74 and Nagasaki led to the discovery of a large number of toxin-antitoxin (TA) systems within both genomes. Five predicted hemolysins were identified as unique to Nagasaki and seven putative contact-dependent growth inhibition toxin proteins were identified only in strain D74. Assessment of all potential vtaA genes revealed thirteen present in the Nagasaki genome and three in the D74 genome. Subsequent evaluation of the predicted protein structure revealed that none of the D74 VtaA proteins contain a collagen triple helix repeat domain. Additionally, the predicted protein sequence for two D74 VtaA proteins is substantially longer than any predicted Nagasaki VtaA proteins. Fifteen methylation sequence motifs were identified in D74 and fourteen methylation sequence motifs were identified in Nagasaki using SMRT sequencing analysis. Only one of the methylation sequence motifs was observed in both strains indicative of the diversity between D74 and Nagasaki. Subsequent analysis also revealed diversity in the restriction-modification systems harbored by D74 and Nagasaki. The collective information reported in this study will aid in the development of vaccines and intervention strategies to decrease the prevalence and disease burden caused by H. parasuis.

Elevated CTHRC1 expression is an indicator for poor prognosis and lymph node metastasis in cervical squamous cell carcinoma

Collagen triple helix repeat containing 1 (CTHRC1) is overexpressed in different kinds of cancer tissues and may thus promote tumor formation. Thus, we aimed to explore whether CTHRC1 could be a predictor of clinical significance including survival in cervical squamous cell carcinoma (CSCC). Western blot analysis was conducted in 20 frozen tissue specimens of CSCC and 10 frozen tissue sections of normal cervix. Immunohistochemistry was performed in 130 tissues with CSCC. The relationships of CTHRC1 expression with clinicopathological variables, and prognosis of CSCCs were explored. Statistical analyses were carried out using χ2 test, multivariate Cox proportional-hazard model, Kaplan-Meier method, and univariate and multivariate logistic regression. The expression of the CTHRC1 protein was significantly higher in tumors than in normal tissues (P < .001). CTHRC1 overexpression was strongly associated with the International Federation of Gynecology and Obstetrics stage (P = .038), histologic grade (P < .001), stromal infiltration depth (P < .001), lymphovascular space invasion (P = .023), lymph node metastasis (P = .001), and recurrence (P = .021). The multivariate proportional-hazard model revealed that CTHRC1 overexpression was an independent predictor of overall survival and disease-free survival (P = .034 and P = .025, respectively). Multivariate logistic regression analysis revealed that high CTHRC1 expression was positively correlated with lymph node metastasis (odds ratio: 2.658; 95% confidence interval: 1.120-6.305; P = .020). Therefore, CTHRC1 may be a valuable biomarker for predicting the prognosis and metastasis of CSCC and a potential therapeutic target for treatment of the disease.

Collagen triple helix repeat containing-1: a novel biomarker associated with disease activity in Systemic lupus erythematosus.

The objective of this article is to investigate whether the aberrant expression of collagen triple helix repeat containing-1 (CTHRC1) from patients with systemic lupus erythematosus (SLE) could contribute to the pathogenesis of lupus. We divided SLE patients into active groups (Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score ≥ 6) and inactive groups (SLEDAI score < 6). Serum concentrations of CTHRC1, interferon alpha, interleukin (IL)-28A and IL-28B were determined using an enzyme-linked immunosorbent assay in a group of 40 patients with SLE. Results were compared with those from 23 healthy controls. Serum CTHRC1 protein levels were higher in patients with SLE compared with healthy controls. Patients with active disease displayed higher CTHRC1 levels compared with those with inactive disease as well. There was a positive association between serum CTHRC1 levels and SLEDAI and erythrocyte sedimentation rate, and a negative correlation with complement 3 and 4. Moreover, serum CTHRC1 levels were higher in SLE patients with arthritis and anemia compared with patients without the above-mentioned manifestations. These findings indicate CTHRC1 probably plays an important part in the pathogenesis of SLE, and is positively associated with disease activity, while it also likely refers to the development of arthritis and anemia in SLE. Therefore, CTHRC1 may provide a novel research target and shed new light on the pathogenesis and therapy of SLE.

CTHRC1 overexpression predicts poor survival and enhances epithelial-mesenchymal transition in colorectal cancer.

Collagen triple helix repeat containing (CTHRC1), which was identified as a cancer‐related factor, is a promigratory protein involved in multiple processes, including vascular remodeling, antifibrosis, metabolism, bone formation, and cancer. In this study, we aimed to investigate the clinical significance and possible role of CTHRC1 in the process of epithelial‐mesenchymal transition (EMT) in colorectal cancer (CRC). Here, we revealed that CTHRC1 mRNA and protein levels are both upregulated in CRC tissues compared with those of paired noncancerous tissues. Moreover, the overexpression of CTHRC1 correlated with poor prognosis in patients with CRC (especially colon cancer). Furthermore, we showed that CTHRC1 induced EMT and promoted cell motility in CRC cells. Importantly, we demonstrated that CTHRC1 promoted EMT by activating transforming growth factor‐β (TGF‐β) signaling, revealing a possible effective therapeutic treatment for patients with CRC.

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

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.