Helix Repeat Research Articles

CTHRC1 is a Potential Prognostic Biomarker and Correlated with Macrophage Infiltration in Breast Cancer.

BackgroundTumor immune cell infiltration is closely associated with the occurrence and development of tumors. Collagen triple helix repeats containing 1 (CTHRC1), a regulator of collagen expression and cell migration, is involved in the metastasis and invasion of tumors. However, the role of CTHRC1 in breast cancer remains unclear. This study aimed to investigate the prognostic value of CTHRC1, and further explore its association with immune infiltration in breast cancer.MethodsCTHRC1 expression pattern and prognostic value were analyzed using ONCOMINE, PrognoScan, GEPIA, and Kaplan–Meier Plotter databases. We then detected CTHRC1 mRNA levels in breast cancer tissues and paired normal breast tissues by Q-PCR. Subsequently, the University of California Santa Cruz (UCSC) database was used to determine the methylation status of CTHRC1. Furthermore, CTHRC1 mutations were investigated using the Catalogue of Somatic mutations in Cancer (COSMIC) and cBioPortal databases. We also assessed the correlation between CTHRC1 expression and immune cell infiltration using TIMER. In addition, The relationship of CTHRC1 expression with the immune marker sets of various immune cells was evaluated using GEPIA and TIMER.ResultsCTHRC1 was highly expressed in a variety of tumors, including breast cancer. Elevated CTHRC1 expression was related to a poor prognosis. Notably, CTHRC1 expression was significantly associated with macrophage infiltration, especially the immune infiltration gene marker set of M2. Copy number variations, DNA mutations and methylation states might be potential mechanisms for regulating CTHRC1 expression. Protein digestion and absorption, human papillomavirus infection, ECM-receptor interaction, focal adhesion, and PI3K-Akt signaling pathways were identified as the potential CTHRC1-driven signaling pathways.ConclusionThese findings suggest that CTHRC1 could be a promising immune-related biomarker for the treatment of breast cancer patients.

Application of collagen triple helix repeat containing-1 and mitotic spindle apparatus antibody in small cell lung cancer diagnosis.

BackgroundThe clinical significance of serum collagen triple helix repeat protein‐1 (CTHRC1) and mitotic spindle apparatus antibody (MSA) in the diagnosis of small cell lung cancer (SCLC).MethodsOf the 229 lung tumor patients selected, 62 patients were divided into SCLC, 94 patients with non‐small cell lung cancer (NSCLC), and 73 patients with benign lung disease (BLD). The health controls (HC) had a span of 66 cases with normal physical condition. The serum extracted from each participator and enzyme‐linked immunosorbent assay was adopted for measuring the serum CTHRC1 and MSA; in the meantime, automatic electrochemiluminescence immunoassay was used for the quantitative determination of serum NSA and CEA. And then, the differences in serum CTHRC1, MSA, NSE, and CEA were compared among involved groups.Results① Compared with other groups, the concentrations of CTHRC1, MSA, and NSE showed a marked increase in the group of SCLC (all p < 0.01). Especially for SCLC patients with lymph node metastasis, CTHRC1 provided a notably higher level than those without metastasis. ② CTHRC1 and MSA established a diagnostic criterion with the specificity of 90.99% and 86.27% for SCLC, respectively. ③ In series, the specificity of CTHRC1 and NSE was the highest (99.30%), while MSA and NSE had the highest sensitivity (96.72%) in parallel. ④ Both CTHRC1 and MSA were hazardous factors interconnected with SCLC.ConclusionSerum CTHRC1 and MSA had a more exciting prospect of application. When used in conjunction with NSE and CEA, they could optimize the clinical diagnosis value of SCLC.

CTHRC1 is a prognosis-related biomarker correlated with immune infiltrates in colon adenocarcinoma

BackgroundColon adenocarcinoma (COAD) is one of the common cancers worldwide. Collagen triple helix repeat containing 1 (CTHRC1) has been reported to be involved in cell invasion, angiogenesis, and the promotion of epithelial-mesenchymal transformation by mediating multiple signaling pathways. However, the role of CTHRC1 in COAD has not yet been determined.MethodsDifferentially expressed genes were evaluated using gene expression data from the Oncomine and TIMER databases. Correlations between CTHRC1 gene expression and clinicopathological factors were analyzed using gene expression data from UALCAN databases. Then, we searched the GEPIA database to evaluate the association of CTHRC1 gene expression with clinical outcomes. The cBioPortal database was used to analyze CTHRC1 genetic alterations. Subsequently, the TIMER website was chosen to assess the correlation of CTHRC1 with the tumor immune cell infiltration level. The TCGA dataset was used for a gene set enrichment analysis (GSEA).ResultCTHRC1 was highly expressed in COAD patients, and significantly related to poor prognosis. In addition, elevated expression of CTHRC1 was related to the clinical stage and pathological type of COAD. The GSEA analysis showed that CTHRC1 was enriched in Gα signaling, GCPR ligand binding, neutrophil degranulation, interleukin signaling, and tumor-associated pathways. In addition, CTHRC1 was significantly associated with the expression of multiple immune markers related to specific immune cells.ConclusionThis study suggest that CTHRC1 expression is related to the prognosis and immune infiltration of COAD patients. Therefore, CTHRC1 may be a new candidate prognostic biomarker for determining immune infiltration levels and providing COAD prognoses.

Application Potential of CTHRC1 as a Diagnostic and Prognostic Indicator for Colon Adenocarcinoma.

Colon adenocarcinoma (COAD), ranking third in incidence and second in mortality, is one of the most common cancer types in the world. The initial stages of COAD usually show no obvious clinical symptoms; moreover, effective screening or diagnostic indicators with high sensitivity and specificity are lacking, which often leads to missed treatment opportunities. Collagen triple helix repeat containing 1 (CTHRC1) is a glycosylated protein secreted during tissue repair, which reduces collagen matrix deposition and promotes cell migration. Under physiological conditions, the expression of CTHRC1 is conducive to wound healing; however, the pathological overexpression of CTHRC1 promotes tumour growth and proliferation. In this study, we evaluated the application potential of CTHRC1 as an early diagnosis and prognostic survival monitoring biomarker for COAD in addition to unravelling its molecular mechanism in the development of COAD and exploring new therapeutic targets. Therefore, various tumour databases were used to investigate the expression of CTHRC1 in COAD at the mRNA and protein levels. CTHRC1 expression was found to be significantly increased in COAD, regardless of clinical cancer stage, age, sex or race. Moreover, CTHRC1 expression was significantly correlated with poor prognosis and positively correlated with CD8+ T cell, CD4+ T cell, neutrophil, macrophage and dendritic cell infiltration. The relevant function pathways and neighbouring proteins to CTHRC1 in COAD were identified as ROR2, VAPA, LY6E and several collagen family proteins. Therefore, this study suggests that CTHRC1 is a potential diagnostic and prognostic biomarker for patients with COAD.

CTHRC1 expressed in periodontitis and human periodontal fibroblasts exposed to inflammatory stimuli.

Collagen triple helix repeat containing-1 (CTHRC1) is a glycoprotein that can be secreted extracellularly and is involved in the regulation of collagen matrix in a variety of diseases. The expression level of CTHRC1 in periodontitis was detected in this study. The gingival tissues from clinically healthy subjects (15 cases) and those with periodontitis (30 cases) were taken for immunohistochemical staining. Lipopolysaccharide of the Porphyromonas gingivalis was added in the periodontal ligament fibroblast culture in vitro. Cells were collected, and the mRNA levels of the intracellular CTHRC1 and protein expression of the extracellular CTHRC1 were detected. The protein expression of CTHRC1 in the periodontitis group was higher than that of the clinically healthy group. The in vitro cell experiments showed that 10μg/ml of P.g LPS could induce a significant increase in protein secretion of CTHRC1, and 5μg/ml P.g LPS had a significant effect on promoting the mRNA expression of CTHRC1. Collagen triple helix repeat containing-1might be involved in the development of periodontitis, and the expression level might be significantly correlated with the stimulation of P.g LPS on fibroblasts. Different stimulation intensities of P.g LPS might result in different expression patterns of CTHRC1.

Secondary Structures of the Transmembrane Domain of SARS-CoV-2 Spike Protein in Detergent Micelles.

Spike protein of SARS-CoV-2 contains a single-span transmembrane (TM) domain and plays roles in receptor binding, viral attachment and viral entry to the host cells. The TM domain of spike protein is critical for viral infectivity. Herein, the TM domain of spike protein of SARS-CoV-2 was reconstituted in detergent micelles and subjected to structural analysis using solution NMR spectroscopy. The results demonstrate that the TM domain of the protein forms a helical structure in detergent micelles. An unstructured linker is identified between the TM helix and heptapeptide repeat 2 region. The linker is due to the proline residue at position 1213. Side chains of the three tryptophan residues preceding to and within the TM helix important for the function of S-protein might adopt multiple conformations which may be critical for their function. The side chain of W1212 was shown to be exposed to solvent and the side chains of residues W1214 and W1217 are buried in micelles. Relaxation study shows that the TM helix is rigid in solution while several residues have exchanges. The secondary structure and dynamics of the TM domain in this study provide insights into the function of the TM domain of spike protein.

Collagen triple helix repeat containing-1 promotes functional recovery of sweat glands by inducing adjacent microvascular network reconstruction in vivo.

BackgroundSweat glands (SGs) have low regenerative potential after severe burns or trauma and their regeneration or functional recovery still faces many obstacles. In practice, restoring SG function requires not only the structural integrity of the gland itself, but also its neighboring tissues, especially blood vessels. Collagen triple helix repeat containing-1 (CTHRC1) was first identified in vascular repair, and increasing reports showed a close correlation between cutaneous appendage specification, patterning and regeneration. The purpose of the present study was to clarify the role of CTHRC1 in SGs and their adjacent microvessels and find therapeutic strategies to restore SG function.MethodsThe SGs and their adjacent microvascular network of Cthrc1−/− mice were first investigated using sweat test, laser Doppler imaging, tissue clearing technique and transcriptome analysis. The effects of CTHRC1 on dermal microvascular endothelial cells (DMECs) were further explored with cell proliferation, DiI-labeled acetylated low-density lipoprotein uptake, tube formation and intercellular junction establishment assays. The effects of CTHRC1 on SG function restoration were finally confirmed by replenishing the protein into the paws of Cthrc1−/− mice.ResultsCTHRC1 is a key regulator of SG function in mice. At the tissue level, Cthrc1 deletion resulted in the disorder and reduction of the microvascular network around SGs. At the molecular level, the knockout of Cthrc1 reduced the expression of vascular development genes and functional proteins in the dermal tissues. Furthermore, CTHRC1 administration considerably enhanced SG function by inducing adjacent vascular network reconstruction.ConclusionsCTHRC1 promotes the development, morphogenesis and function execution of SGs and their neighboring vasculature. Our study provides a novel target for the restoration or regeneration of SG function in vivo.

Assessment of Plasma Level of CTHRC-I in Patients with Rheumatoid Arthritis

Background: Rheumatoid arthritis (RA) is a chronic progressive, autoimmune disease that affects about 1.5% of the community. New markers are needed for early diagnosis of RA as seronegativity in early RA remains a major limitation of both anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF). Objective: To measure the plasma levels of the collagen triple helix, repeat containing-1 (CTHRC-1) protein in RA patients. Methods: 103 RA patients (56 new diagnostic without treatment group and 47 patients on treatment were included in this study according to American College of Rheumatology (ACR) criteria, in addition to 25 subjects as healthy control group. CTHRC-1 level was measured by using Immunoassay System in plasma samples. Results: The mean and SD of CTHRC1 was (49.10±6.51 ng/ml) in RA patients was significantly higher than its mean in healthy controls (6.20±2.81 ng/ml), (p value =0.002). The distribution of CTHRC1 was insignificantly associated with patient treated or not (P value 1.000, 0.273) respectively, or were the patients had positive or negative RF (P value 0.118, 1.000) respectively. Conclusion:sing the Immunoassay System for CTHRC-1 quantification, CTHRC1 could be used as a plasma marker that can aid in the diagnosis of RA although it has no association with seropositivity with RF or treatment. Keywords: Collagen triple helix repeat containing-1, rheumatoid arthritis, serum rheumatoid factor, anti-CCP Citation: Alwan SA, Abdul-Ridha RA, Ali AI. Assessment of plasma level of CTHRC-I in patients with rheumatoid arthritis. Iraqi JMS. 2021; 19(2): 189-193. doi: 10.22578/IJMS.19.2.8

GPR180 is a component of TGF\u03b2 signalling that promotes thermogenic adipocyte function and mediates the metabolic effects of the adipocyte-secreted factor CTHRC1

Activation of thermogenic brown and beige adipocytes is considered as a strategy to improve metabolic control. Here, we identify GPR180 as a receptor regulating brown and beige adipocyte function and whole-body glucose homeostasis, whose expression in humans is associated with improved metabolic control. We demonstrate that GPR180 is not a GPCR but a component of the TGFβ signalling pathway and regulates the activity of the TGFβ receptor complex through SMAD3 phosphorylation. In addition, using genetic and pharmacological tools, we provide evidence that GPR180 is required to manifest Collagen triple helix repeat containing 1 (CTHRC1) action to regulate brown and beige adipocyte activity and glucose homeostasis. In this work, we show that CTHRC1/GPR180 signalling integrates into the TGFβ signalling as an alternative axis to fine-tune and achieve low-grade activation of the pathway to prevent pathophysiological response while contributing to control of glucose and energy metabolism.

Pan-cancer analysis combined with experiments predicts CTHRC1 as a therapeutic target for human cancers

BackgroundThe function of collagen triple helix repeat containing 1 (CTHRC1) as an oncogene has been reported in a growing number of publications. Bioinformatics methods represent a beneficial approach to examine the mechanism and function of the CTHRC1 gene in the disease process of cancers from a pan-cancer perspective.MethodsIn this study, using the online databases UCSC, NCBI, HPA, TIMER2, Oncomine, GEPIA, UALCAN, cBioPortal, COSMIC, MEXPRESS, STRING, CCLE, LinkedOmics, GTEx, TCGA, CGGA, and SangerBox, we focused on the relationship between CTHRC1 and tumorigenesis, progression, methylation, immunity, and prognosis. qPCR was used to detect CTHRC1 expression in glioma tissues and cell lines.ResultsThe pan-cancer analysis showed that CTHRC1 was overexpressed in most tumors, and a significant correlation was observed between CTHRC1 expression and the prognosis of patients with cancer. CTHRC1 genetic alterations occur in diverse tumors and are associated with tumor progression. Levels of CTHRC1 promoter methylation were decreased in most cancer tissues compared with normal tissues. In addition, CTHRC1 coordinated the activity of ICP genes through diverse signal transduction pathways, was also associated with immune cell infiltration and the tumor microenvironment, and potentially represented a promising immunotherapy target. We identified CTHRC1-related genes across cancers using the GEPIA2 tool. The single-gene GO analysis of CTHRC1 across cancers showed that it was involved in some signaling pathways and biological processes, such as the Wnt signaling pathway, cell migration, and positive regulation of protein binding. The expression and function of CTHRC1 were also further verified in glioma tissues and cell lines.ConclusionsCTHRC1 is overexpressed in various cancer types and functions as an important oncogene that may promote tumorigenesis and development through different mechanisms. CTHRC1 may represent an important therapeutic target for human cancers.

Tgfβ1-Cthrc1 Signaling Plays an Important Role in the Short-Term Reparative Response to Heart Valve Endothelial Injury.

Aortic valve disease is a common worldwide health burden with limited treatment options. Studies have shown that the valve endothelium is critical for structure-function relationships, and disease is associated with its dysfunction, damage, or injury. Therefore, therapeutic targets to maintain a healthy endothelium or repair damaged endothelial cells could hold promise. In this current study, we utilize a surgical mouse model of heart valve endothelial cell injury to study the short-term response at molecular and cellular levels. The goal is to determine if the native heart valve exhibits a reparative response to injury and identify the mechanisms underlying this process. Approach and Results: Mild aortic valve endothelial injury and abrogated function was evoked by inserting a guidewire down the carotid artery of young (3 months) and aging (16-18 months) wild-type mice. Short-term cellular responses were examined at 6 hours, 48 hours, and 4 weeks following injury, whereas molecular profiles were determined after 48 hours by RNA-sequencing. Within 48 hours following endothelial injury, young wild-type mice restore endothelial barrier function in association with increased cell proliferation, and upregulation of transforming growth factor beta 1 (Tgfβ1) and the glycoprotein, collagen triple helix repeat containing 1 (Cthrc1). Interestingly, this beneficial response to injury was not observed in aging mice with known underlying endothelial dysfunction. Data from this study suggests that the healthy valve has the capacity to respond to mild endothelial injury, which in short term has beneficial effects on restoring endothelial barrier function through acute activation of the Tgfβ1-Cthrc1 signaling axis and cell proliferation.

CTHRC1 expression is a novel shared diagnostic and prognostic biomarker of survival in six different human cancer subtypes

According to the previous reports, the collagen triple helix repeat containing 1 (CTHRC1) causes tumorigenesis by modulating the tumor microenvironment, however, the evidence is limited to a few human cancer subtypes. In the current study, we analyzed and validated the CTHRC1 expression variations in 24 different human cancer tissues paired with normal tissues using publically available databases. We observed that CTHRC1 was overexpressed in all the 24 major subtypes of human cancers and its overexpression was significantly associated with the reduced overall survival (OS) duration of head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), Lung adenocarcinoma (LUAD), stomach adenocarcinoma (STAD), and Uterine corpus endometrial carcinoma (UCEC). This implies that CTHRC1 plays a significant role in the development and progression of these cancers. We further noticed that CTHRC1 was also overexpressed in HNSC, KIRC, LIHC, LUAD, STAD, and UCEC patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of CTHRC1 associated genes in seven diverse pathways. We also explored few interesting correlations between CTHRC1 expression and promoter methylation, genetic alterations, CNVs, CD8+ T immune cells infiltration, and tumor purity. In conclusion, CTHRC1 can serve as a shared diagnostic and prognostic biomarker in HNSC, KIRC, LIHC, LUAD, STAD, and UCEC patients of different clinicopathological features.

Cancer-associated fibroblast-secreted collagen triple helix repeat containing-1 promotes breast cancer cell migration, invasiveness and epithelial-mesenchymal transition by activating the Wnt/β-catenin pathway.

Cancer-associated fibroblasts (CAFs) are continuously activated and are one of the most important cellular components of the tumor matrix. The role of CAFs in the tumor microenvironment has been widely recognized. However, the underlying molecular mechanism by which CAFs promote tumor characteristics in breast cancer (BC) remains poorly understood. The aim of the present study was to investigate the potential mechanisms and the possible pathways of collagen triple helix repeat containing-1 (CTHRC1) in the epithelial-mesenchymal transition (EMT) of BC cells. The level of CTHRC1 in BC tissues was found to be higher than that in adjacent-normal tissues. CAFs isolated from BC tissues secreted significantly greater amounts of CTHRC1 than normal fibroblasts. Furthermore, CAFs promoted the migration, invasiveness and EMT of BC cells by secreting CTHRC1, which activates the Wnt/β-catenin signaling pathway. However, the use of neutralizing antibodies towards CTHRC1, or the specific inhibitor Dickkopf-1, to inhibit the Wnt/β catenin pathway significantly alleviated the CAF-induced malignant phenotypes of BC cells. Collectively, the data indicate that CAFs in the tumor microenvironment promote BC cell malignant behaviors via the CTHRC1/Wnt/β-catenin signaling pathway. Furthermore, weakening CAF-BC cell communication by suppressing CTHRC1 expression may be a novel strategy for treating BC.

Collagen triple helix repeat containing 1 (CTHRC1) protein: A promising biomarker for evaluation of rheumatoid arthritis patients

Aim of the workTo assess serum collagen triple helix repeat containing 1 (CTHRC1) protein level in rheumatoid arthritis (RA) patients and compare it with healthy controls. In addition, to evaluate the relation of its level with RA activity and severity Patients and methodsThe study included 60 adult RA patients and 60 matched controls. Disease activity score (DAS28), modified health assessment questionnaire (MHAQ) and RA medical records-based index of severity (RARBIS) were assessed in RA patients. Serum CTHRC1 levels were measured in patients and controls by enzyme linked immunosorbent assay (ELISA) ResultsThey were 49 females and 11 males patients with a mean age of 43.6 ± 10.8 years and disease duration of 8.8 ± 0.9 years. The mean of DAS28 was 4.9 ± 2 (1.95–8.6). Serum CTHRC1 levels were significantly higher in patients than controls (1009.5 ± 79.4 vs. 470.7 ± 8.2 ng/ml, p < 0.001).The optimum cut-off value of CTHRC1 to discriminate patients from control was > 583.5 ng/ml with sensitivity of 98.3% and specificity of 100%. CTHRC1 significantly correlated with DAS28 (r = 0.81, p < 0.001), MHAQ (r = 0.14, p = 0.002), RARBIS (r = 0.41, p = 0.006), erythrocyte sedimentation rate (ESR) (r = 0.57, p < 0.001), C-reactive protein (CRP) (r = 0.41, p = 0.002), rheumatoid factor (RF) (r = 0.31, p = 0.037) and anti-cyclic citrullinated peptide (anti-CCP) (r = 0.27, p = 0.036). The significant predictors of increase CTHRC1 among patients were elevation in DAS28 (ß=287.6; p = 0.007, CI = 83.4–491.9) and MHAQ (ß=369.7; p = 0.042, CI = 14.5–724.9) ConclusionSerum CTHRC1 is a promising biomarker for evaluation of RA patients. It can be used as a marker for RA diagnosis and in monitoring the disease activity and severity.

MiR-509-3p Suppresses Migration, Invasion, and Epithelial- Mesenchymal Transition in Melanoma Cells by Targeting Collagen Triple Helix Repeat Containing 1.

Background: microRNAs (miRNAs) are ubiquitously dysregulated in numerous tumor cell types, including melanoma cells. The anti-tumor effect of miR-509-3p was widely evaluated in various cancers.Aims: To determine the functional role of miR-509-3p in melanoma.Study Design: Cell culture study.Methods: Expression of miR-509-3p in melanoma cell models were assessed by qRT-PCR. Cell migration and invasion were analyzed by wound healing and transwell assays, respectively. Expression levels of biomarkers of epithelial–mesenchymal transition were determined by Western blot. Luciferase vectors containing wildtype or mutant miR-509-3p binding site were constructed, and then dual-luciferase reporter assay.Results: Dysregulated miR-509-3p level was found in melanoma cells. Elevated miR-509-3p expression suppressed melanoma cell migration (P < .001) and invasion (P < .001) capacities. Epithelial–mesenchymal transition of melanoma cells was repressed by miR-509-3p, along with increased α-catenin/E-cadherin (P < .001) and decreased vimentin/fibronectin (P < .001). CTHRC1 (collagen triple helix repeat containing 1) contained a potential binding site for miR-509-3p, and miR-509-3p decreased protein expression of CTHRC1 in melanoma cells (P < .001). CTHRC1 promoted melanoma cell migration and invasion (P < .001), as well as contributed to epithelial–mesenchymal transition. Increased CTHRC1 expression attenuated miR-509-3p-induced inhibition of melanoma cell migration (P < .001), invasion, and epithelial–mesenchymal transition.Conclusion: miR-509-3p suppressed the biological function of melanoma cells through negatively regulating CTHRC1, shedding light on miR-509-3p as a potential candidate for melanoma therapeutics and treatments.

CTHRC1 promotes growth, migration and invasion of trophoblasts via reciprocal Wnt/β-catenin regulation.

Preeclampsia (PE) is a pregnancy complication that is characterized by high blood pressure and is associated with high maternal and fetal morbidities. At a mechanistic level, PE is characterized by reduced invasion ability of trophoblasts. Collagen triple helix repeat containing-1 (CTHRC1) is a well-known tumor-promoting factor in several malignant tumors, but its role in trophoblasts remains unknown. In this study, we characterized the expression of CTHRC1 in placenta tissue samples from PE pregnancies and from normal pregnancies. We used the trophoblasts cell lines HTR-8/SVneo and JEG-3 to investigate the role of CTHRC1 in cell migration, invasion and proliferation. Western blot, PCR and TOP/FOP luciferase activity assays were used to investigate the molecular mechanisms underlying these cell behaviors. Placenta tissue samples obtained from pregnant women with PE expressed lower levels of CTHRC1 than those of placenta tissues from women with normal pregnancies. Down-regulation of CTHRC1 impaired cell proliferation, migration and invasion of trophoblasts, while CTHRC1 overexpression promoted nuclear translocation of β-catenin, a result that was further confirmed by TOP/FOP luciferase activity assay. Our findings suggest that CTHRC1 promotes migration and invasion of trophoblasts via reciprocal Wnt/β-catenin signaling pathway. Down-regulation of CTHRC1 may be a potential mechanism underpinning the development of preeclampsia.

CTHRC1 promotes liver metastasis by reshaping infiltrated macrophages through physical interactions with TGF-β receptors in colorectal cancer.

Metastasis is a major cause of cancer-related deaths. Tumor-intrinsic properties can determine whether tumor metastasis occurs or not. Here, by comparing the gene expression patterns in primary colorectal cancer (CRC) patients with or without metastasis, we found that Collagen Triple Helix Repeat Containing 1 (CTHRC1) in primary CRC served as a metastasis-associated gene. Animal experiments verified that CTHRC1 secreted by CRC cells promoted hepatic metastasis, which was closely correlated with macrophage infiltration. Depletion of macrophages by liposomal clodronate largely abolished the promoting effect of CTHRC1 on CRC liver metastasis. Furthermore, we demonstrated that CTHRC1 modulated macrophage polarization to M2 phenotypes through TGF-β signaling. A mechanistic study revealed that CTHRC1 bound directly to TGF-β receptor II and TGF-β receptor III, stabilized the TGF-β receptor complex, and activated TGF-β signaling. The combination treatment of CTHRC1 monoclonal antibody and anti-PD-1 blocking antibody effectively suppressed CRC hepatic metastasis. Taken together, our data demonstrated that CTHRC1 is an intrinsic marker of CRC metastasis and further revealed that CTHRC1 promoted CRC liver metastasis by reshaping infiltrated macrophages through TGF-β signaling, suggesting that CTHRC1 could be a potential biomarker for the early prediction of and a therapeutic target of CRC hepatic metastasis.

Collagen triple helix repeat containing-1 exerts antifibrotic effects on human skin fibroblast and bleomycin-induced dermal fibrosis models

BackgroundSystemic scleroderma (SSc) is an acquired disorder characterized by excessive deposition of extracellular matrix in the skin and internal organs. So far, the molecular mechanisms underpinning the pathogenesis of SSc have remained unknown. Collagen triple helix repeat containing-1 (CTHRC1) has been indicated to be a cell type-specific inhibitor of transforming growth factor-β (TGF-β), which could have the potential for extensive clinical application owing to its ability to reduce collagen deposition. Our previous studies showed that CTHRC1 inhibited TGF-β1-induced collagen type I synthesis in keloid fibroblasts. In our present research, we attempted to probe the role of CTHRC1 in dermal fibrosis in bleomycin (BLM)-treated mice.MethodsCTHRC1 and TGF-β1 expression was detected in dermal tissues from patients with SSc and BLM-treated mice by immunohistochemistry. A 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay was used to assess TGF-β1-induced proliferation of human dermal fibroblasts. Collagen expression and fibroblast synthesis were evaluated by quantitative real-time polymerase chain reaction and the 3H-proline incorporation. Masson’s trichrome staining and western blotting were carried out to analyze the deposits and protein levels of type I collagen, respectively.ResultsCompared with those in normal tissues, the levels of CTHRC1 and TGF-β1 were elevated in dermal tissues from patients with SSc and in skin tissues from BLM-treated mice, respectively. Furthermore, recombinant CTHRC1 was found to inhibit TGF-β1-stimulated collagen deposition by fibroblasts. Finally, the in vivo experiments showed that CTHRC1 alleviated BLM-induced dermal fibrotic changes.ConclusionsCTHRC1 can inhibit human dermal fibroblast collagen deposition and can also exert protective effects against BLM-induced dermal fibrosis in mice. This research provides an indication that CTHRC1 may be a promising treatment choice for dermal fibrosis in SSc patients.

CTHRC1 Knockdown Promotes Inflammatory Responses Partially by p38 MAPK Activation in Human Periodontal Ligament Cells.

Collagen triple helix repeat containing 1 (CTHRC1), a secreted glycoprotein, is widely expressed in many tissues. It has been recently defined as a novel marker for rheumatoid arthritis (RA), a systemic inflammatory disorder. However, the precise role of CTHRC1 in other chronic inflammatory diseases, like periodontal disease, remains unclear. This research aimed to explore the presence of CTHRC1 in periodontal inflammation, determine the precise role in inflammatory response modulation in periodontal ligament cells (PDLCs), and explore its underlying mechanisms. In vivo gingival crevicular fluid (GCF) and gingivae were obtained from healthy people and chronic periodontitis patients. Maxillary tissues of mice with or without ligature-induced periodontitis were immunostained for CTHRC1. In vitro human PDLCs were treated with tumor necrosis factor alpha (TNF-α) to mimic the inflammatory environment. Small interfering RNA (siRNA) was used to silence CTHRC1. SB203580 was used to inhibit the p38 mitogen-activated protein kinase (MAPK) pathway. CTHRC1 was highly expressed in GCF and gingival tissues of periodontitis patients. Animal models also revealed the same tendency. CTHRC1 knockdown promoted inflammatory cytokine production and activated the p38 MAPK signaling pathway in PDLCs. Inhibiting the p38 MAPK signaling pathway partially attenuated the inflammatory responses. This study revealed that CTHRC1 was highly expressed in periodontitis and suggested that CTHRC1 might play an important role in modulating periodontal inflammation.

The Role of Collagen Triple Helix Repeat-Containing 1 Protein (CTHRC1) in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease causing inflammation of joints, cartilage destruction and bone erosion. Biomarkers and new drug targets are actively sought and progressed to improve available options for patient treatment. The Collagen Triple Helix Repeat Containing 1 protein (CTHRC1) may have an important role as a biomarker for rheumatoid arthritis, as CTHRC1 protein concentration is significantly elevated in the peripheral blood of rheumatoid arthritis patients compared to osteoarthritis (OA) patients and healthy individuals. CTHRC1 is a secreted glycoprotein that promotes cell migration and has been implicated in arterial tissue-repair processes. Furthermore, high CTHRC1 expression is observed in many types of cancer and is associated with cancer metastasis to the bone and poor patient prognosis. However, the function of CTHRC1 in RA is still largely undefined. The aim of this review is to summarize recent findings on the role of CTHRC1 as a potential biomarker and pathogenic driver of RA progression. We will discuss emerging evidence linking CTHRC1 to the pathogenic behavior of fibroblast-like synoviocytes and to cartilage and bone erosion through modulation of the balance between bone resorption and repair.