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• Neurons express CD109 in the central nervous system. • CD109 is upregulated in the lumbar spinal cord of SOD1-G93A mice. • CD109 upregulation is mainly contributed by proliferated microglia. • CD109 inhibits TGFβ/SMAD pathway and attenuates inflammatory reactions in microglia. CD109 is a multifunctional coreceptor, whose function has been widely studied in tumor progression and metastasis. One of the reported primary roles of CD109 involves down-regulating TGFβ signaling. However, the role of CD109 in central nervous system, especially neurodegenerative disease, is barely known. Here, we examined the expression changes and cellular location of CD109 and TGFβ/SMAD pathway molecules in lumbar spinal cord of SOD1-G93A mice, and explored the role and mechanism of CD109 on LPS-treated BV2 microglia and primary microglia derived from SOD1-G93A mice. Our results showed an increased expression of CD109 and TGFβ/SMAD pathway molecules in lumbar spinal cord of SOD1-G93A mice. Further cellular localization analysis demonstrated that proliferating microglia contributed mainly to the upregulation of CD109 and TGFβ1. Moreover, CD109 intervention in vitro partially reduced inflammatory response and TGFβ/SMAD pathway activation in both LPS-treated BV2 microglia and primary SOD1-G93A microglia. Thus, CD109 was involved in pathogenesis of ALS mice, and interventions targeting on CD109 modulation could be a potential therapeutic strategy for ALS. [ABSTRACT FROM AUTHOR]

Leukocyte differentiation antigen CD109 (CD109) is a glycosylphosphatidylinositol (GPI)-associated cell surface antigen, belonging to the α-2 macroglobulin/C3, C4 and C5 super family complex, and is a transforming growth factor (TGF)-β/Smads co-receptor. CD109 regulates the occurrence and development of glioma and is closely related to drug resistance and recurrence of glioma. As a cell membrane protein, CD109 can be directly labeled by specific antibodies or enzymes, and may also be recognized by targeted vectors for drug delivery, which is expected to become an effective diagnostic molecular marker and pharmacological therapeutic target.

The glycosylphosphatidylinositol (GPI)‐anchored protein cluster of differentiation 109 (CD109) is expressed on many human cell types and modulates the transforming growth factor β (TGF‐β) signaling network. CD109 belongs to the alpha‐macroglobulin family of proteins, known for their protease‐triggered conformational changes. However, the effect of proteolysis on CD109 and its conformation are unknown. Here, we investigated the interactions of CD109 with proteases. We found that a diverse selection of proteases cleaved peptide bonds within the predicted bait region of CD109, inducing a conformational change that activated the thiol ester of CD109. We show CD109 was able to conjugate proteases with this thiol ester and decrease their activity toward protein substrates, demonstrating that CD109 is a protease inhibitor. We additionally found that CD109 has a unique mechanism whereby its GPI‐anchored macroglobulin 8 (MG8) domain dissociates during its conformational change, allowing proteases to release CD109 from the cell surface by a precise mechanism and not unspecific shedding. We conclude that proteolysis of the CD109 bait region affects both its structure and location, and that interactions between CD109 and proteases may be important to understanding its functions, for example, as a TGF‐β co‐receptor. [ABSTRACT FROM AUTHOR]

Multiple cellular pathways are affected by HPV E6 and E7 oncoproteins, including endocytic and cellular trafficking. HPV-16 E7 can target the adaptor protein (AP) complex, which contains proteins important during endocytosis transport. To further investigate the role of HPV E7 during this process, we analysed the expression of cell surface proteins in NIKS cells expressing HPV-16 E7. We show that different cell surface proteins are regulated by HPV-16 E7 via interaction with AP2. We observed that the expression of MET and CD109 membrane protein seems to be upregulated in cells expressing E7. Moreover, the interaction of MET and CD109 with AP2 proteins is disrupted by HPV-16 E7. In addition, in the absence of HPV-16 E7, there is a downregulation of the cell membrane expression of MET and CD109 in HPV-positive cell lines. These results expand our knowledge of the functions of E7 and open new potential cellular pathways affected by this oncoprotein.

Epicardial-derived cells (EPDCs) are involved in the regulation of myocardial growth and coronary vascularization and are critically important for proper development of the atrioventricular (AV) valves. SOX9 is a transcription factor expressed in a variety of epithelial and mesenchymal cells in the developing heart, including EPDCs. To determine the role of SOX9 in epicardial development, an epicardial-specific Sox9 knockout mouse model was generated. Deleting Sox9 from the epicardial cell lineage impairs the ability of EPDCs to invade both the ventricular myocardium and the developing AV valves. After birth, the mitral valves of these mice become myxomatous with associated abnormalities in extracellular matrix organization. This phenotype is reminiscent of that seen in humans with myxomatous mitral valve disease (MVD). An RNA-seq analysis was conducted in an effort to identify genes associated with this myxomatous degeneration. From this experiment, Cd109 was identified as a gene associated with myxomatous valve pathogenesis in this model. Cd109 has never been described in the context of heart development or valve disease. This study highlights the importance of SOX9 in the regulation of epicardial cell invasion—emphasizing the importance of EPDCs in regulating AV valve development and homeostasis—and reports a novel expression profile of Cd109 , a gene with previously unknown relevance in heart development. [Display omitted] • SOX9 controls epicardial-derived cell invasion into the developing heart. • Epicardial-derived cells are needed to maintain atrioventricular valve homeostasis. • Cd109 is identified as novel gene associated with valve development and disease. [ABSTRACT FROM AUTHOR]

Objective: Our research group in the early stage identified CD109 as the target of aptamer S3 in nasopharyngeal carcinoma (NPC). This study was to use S3 to connect DNA tetrahedron (DT) and load doxorubicin (Dox) onto DT to develop a targeted delivery system, and explore whether S3-DT-Dox can achieve targeted therapy for NPC. Methods: Aptamer S3-conjugated DT was synthesized and loaded with Dox. The effects of S3-DT-Dox on NPC cells were investigated with laser confocal microscopy, flow cytometry, and MTS assays. A nude mouse tumor model was established from NPC 5-8F cells, and the in vivo anti-tumor activity of S3-DT-Dox was examined by using fluorescent probe labeling and hematoxylin–eosin staining. Results: The synthesized S3-DT had high purity and stability. S3-DT specifically recognized 5-8F cells and NPC tissues in vitro. When the ratio of S3-DT to Dox was 1:20, S3-DT had the best Dox loading efficiency. The drug release rate reached the maximum (0.402 ± 0.029) at 48 h after S3-DT-Dox was prepared and mixed with PBS. S3-DT did not affect Dox toxicity to 5-8F cells, but reduced Dox toxicity to non-target cells. Meanwhile, S3-DT-Dox was able to specifically target the transplanted tumors and inhibit their growth in nude mice, with minor damage to normal tissues. Conclusion: Our study highlights the ability and safety of S3-DT-Dox to target NPC cells and inhibit the development NPC. [ABSTRACT FROM AUTHOR]

Drug resistance is a considerable obstacle to gastric cancer (GC) treatment. The current work aimed to elucidate the functional mechanism of CD109 in 5‐fluorouracil (5‐FU) resistance in GC. In this study, we demonstrated that CD109 was extremely heightened in 5‐FU‐resistant GC cells. CD109 deficiency lessened the IC50 value, impaired cell viability and metastatic capability, and induced cell apoptosis after 5‐FU treatment in cells. In addition, we found that PAX5 bound p300 increased the enrichment of H3K27ac at the promoter region of the CD109 gene, which resulted in the upregulation of CD109 in GC. Moreover, we also revealed that CD109 triggered 5‐FU resistance via activating the JNK/MAPK signaling. Blockage of JNK/MAPK signaling using JNK inhibitor, SP600125, abolished CD109 upregulation‐induced changes of IC50 values, cell viability, metastasis and apoptosis in NCI‐N87/5‐FU and SNU‐1/5‐FU cells. Importantly, CD109 silencing enhanced the therapeutic efficacy of 5‐FU, leading to reduced tumor growth in vivo. In conclusion, our results unveiled that H3K27 acetylation activated‐CD109 enhanced 5‐FU resistance of GC cells via modulating the JNK/MAPK signaling pathway, which might provide an attractive therapeutic target for GC. [ABSTRACT FROM AUTHOR]

Aims αv integrins are implicated in fibrosis in a number of organs through their ability to activate TGF-β. However their role in vascular fibrosis and collagen accumulation is only partially understood. Here we have used αv conditional knockout mice and cell lines to determine how αv contributes to vascular smooth muscle cell (VSMC) function in vascular fibrosis and the role of TGF-β in that process. Methods and results Angiotensin II (Ang II) treatment causes upregulation of αv and β3 expression in the vessel wall, associated with increased collagen deposition. We found that deletion of αv integrin subunit from VSMCs (αvSMKO) protected mice against angiotensin II-induced collagen production and assembly. Transcriptomic analysis of the vessel wall in αvSMKO mice and controls identified a significant reduction in expression of fibrosis and related genes in αvSMKO mice. In contrast, αvSMKO mice showed prolonged expression of CD109, which is known to affect TGF-β signalling. Using cultured mouse and human VSMCs, we showed that overexpression of CD109 phenocopied knockdown of αv integrin, attenuating collagen expression, TGF-β activation, and Smad2/3 signalling in response to angiotensin II or TGF-β stimulation. CD109 and TGF-β receptor were internalized in early endosomes. Conclusion We identify a role for VSMC αv integrin in vascular fibrosis and show that αv acts in concert with CD109 to regulate TGF-β signalling. [ABSTRACT FROM AUTHOR]

Asthma is a chronic airway inflammatory disease characterized by airway hyperreactivity (AHR) and eosinophilic airway inflammation. Dendritic cells (DCs) are essential for the development of asthma via presenting allergens, causing T-helper cell type 2 (Th2) skewing and eosinophil inflammation. Recent studies have revealed that CD109, a glycosylphosphatidylinositolanchored glycoprotein, is involved in the pathogenesis of inflammatory diseases such as rheumatoid arthritis and psoriasis. However, no study has addressed the role of CD109 in asthma. This study sought to address the role of CD109 on DCs in the development of AHR and allergic inflammation. CD109-deficient mice (CD109-/-) were sensitized with house dust mite or ovalbumin and compared with wild-type mice for induction of AHR and allergic inflammation. CD109-deficient mice had reduced AHR and eosinophilic inflammation together with lower Th2 cytokine expression compared with wild-type mice. Interestingly, CD109 expression was induced in lung conventional DC2s (cDC2s), but not lung cDC1s, upon allergic challenge. Lung cDC2s from CD109-/- mice had a poor ability to induce cytokine production in ex vivo DC--T cell cocultures with high expression of RUNX3 (runt-related transcription factor 3), resulting in suppression of Th2 differentiation. Adoptive transfer of bone marrow--derived CD109-/- DCs loaded with house dust mite failed to develop AHR and eosinophilic inflammation. Finally, administration of monoclonal anti-CD109 antibody reduced airway eosinophils and significantly decreased AHR. Our results suggest the involvement of CD109 in asthma pathogenesis. CD109 is a novel therapeutic target for asthma. [ABSTRACT FROM AUTHOR]

Simple Summary: Squamous cell carcinoma is a type of cancer resulting from cancer of the squamous cells that line some organs of the body such as the skin, lungs, and vulva. It is one of the leading causes of cancer-related deaths worldwide. In the current study, we show that a protein called CD109 plays an important role in the progression of this type of cancer. We also show that CD109 acts by associating with another protein called the epidermal growth factor receptor (EGFR), stabilizing its levels and promoting its action, leading to increased progression of squamous cell carcinoma. Together, these findings highlight a potential clinical utility for targeting CD109 in squamous cell carcinoma. (1) Background: Squamous cell carcinoma (SCC) is one of the leading causes of cancer-related deaths worldwide. CD109 is overexpressed in many cancers including SCC. Although a pro-tumorigenic role for CD109 has been shown in non-SCC cancers, and in one type of SCC, the mechanisms and signaling pathways reported are discrepant. (2) Methods: The CD109-EGFR interaction and CD109-mediated regulation of EGFR expression, signaling, and stemness were studied using microarray, immunoblot, immunoprecipitation, qPCR, immunofluorescence, and/or spheroid formation assays. The role of CD109 in tumor progression and metastasis was studied using xenograft tumor growth and metastatic models. (3) Results: We establish the in vivo tumorigenicity of CD109 in vulvar SCC cells and demonstrate that CD109 is an essential regulator of EGFR expression at the mRNA and protein levels and of EGFR/AKT signaling in vulvar and hypopharyngeal SCC cells. Furthermore, we show that the mechanism involves EGFR-CD109 heteromerization and colocalization, leading to the stabilization of EGFR levels. Additionally, we demonstrate that the maintenance of epithelial morphology and in vitro tumorigenicity of SCC cells require CD109 localization to the cell surface. (4) Conclusions: Our study identifies an essential role for CD109 in vulvar SCC progression. We demonstrate that CD109 regulates SCC cellular stemness and epithelial morphology via a cell-surface CD109-EGFR interaction, stabilization of EGFR levels and EGFR/AKT signaling. [ABSTRACT FROM AUTHOR]

Classic galactosemia (CG) is a rare disorder of autosomal recessive inheritance. It is caused predominantly by point mutations as well as deletions in the gene encoding the enzyme galactose‐1‐phosphate uridyltransferase (GALT). The majority of the more than 350 mutations identified in the GALT gene cause a significant reduction in GALT enzyme activity resulting in the toxic buildup of galactose metabolites that in turn is associated with cellular stress and injury. Consequently, developing a therapeutic strategy that reverses both the oxidative and ER stress in CG cells may be helpful in combating this disease. Recombinant adeno‐associated virus (AAV)‐mediated gene therapy to restore GALT activity offers the potential to address the unmet medical needs of galactosemia patients. Here, utilizing fibroblasts derived from CG patients we demonstrated that AAV‐mediated augmentation of GALT protein and activity resulted in the prevention of ER and oxidative stress. We also demonstrate that these CG patient fibroblasts exhibit reduced CD109 and TGFβRII protein levels and that these effectors of cellular homeostasis could be restored following AAV‐mediated expression of GALT. Finally, we show initial in vivo proof‐of‐concept restoration of galactose metabolism in a GALT knockout mouse model following treatment with AAV‐GALT. [ABSTRACT FROM AUTHOR]

CD109 is a glycosylphosphatidylinositol-anchored glycoprotein, whose expression is upregulated in some types of malignant tumors. High levels of CD109 in tumor cells have been reported to correlate with poor prognosis; however, significance of CD109 stromal expression in human malignancy has not been elucidated. In this study, we investigated the tumorigenic properties of CD109 in pancreatic ductal adenocarcinoma (PDAC). Immunohistochemical analysis of 92 PDAC surgical specimens revealed that positive CD109 expression in tumor cells was significantly associated with poor prognosis (disease-free survival, p = 0.003; overall survival, p = 0.002), and was an independent prognostic factor (disease-free survival, p = 0.0173; overall survival, p = 0.0104) in PDAC. Furthermore, CD109 expression was detected in the stroma surrounding tumor cells, similar to that of α-smooth muscle actin, a histological marker of cancer-associated fibroblasts. The stromal CD109 expression significantly correlated with tumor progression in PDAC (TNM stage, p = 0.033; N factor, p = 0.024; lymphatic invasion, p = 0.028). In addition, combined assessment of CD109 in tumor cells and stroma could identify the better prognosis group of patients from the entire patient population. In MIA PaCa-2 PDAC cell line, we demonstrated the involvement of CD109 in tumor cell motility, but not in PANC-1. Taken together, CD109 not only in the tumor cells but also in the stroma is involved in the progression and prognosis of PDAC, and may serve as a useful prognostic marker in PDAC. [ABSTRACT FROM AUTHOR]

Background and Objectives: Alloantibodies to human platelet antigen‐15b (anti‐HPA‐15b) have been detected in mothers with foetal–neonatal alloimmune thrombocytopenia and in multiply transfused patients. Assays used to detect this antibody, which aids in disease diagnosis, can be unreliable and vary in sensitivity. The objective was to generate a stable, lyophilized anti‐HPA‐15b preparation and evaluate its suitability as a World Health Organization (WHO) reference reagent for use in the quality control of platelet alloantibody detection assays. Results from an international collaborative study to evaluate the preparation were used to assign a minimum potency at which laboratories can be expected to detect the antibody. Materials and Methods: Recalcified plasma containing anti‐HPA‐15b was aliquotted, lyophilized and coded 18/220. Twenty‐five laboratories in 16 countries tested doubling dilutions of the reconstituted material in glycoprotein‐specific assays such as the monoclonal antibody–specific immobilization of platelet antigen assay and reported the last positive (or endpoint) dilution. Results: Twenty‐four laboratories (96%) detected antibodies with HPA‐15b specificity in preparation 18/220. Reported endpoint dilutions were normally distributed with a modal dilution of 1 in 16 and ranged from 1 in 2 to 1 in 128. Only two laboratories (8%) failed to detect anti‐HPA‐15b at 1 in 8 dilution. Conclusions: When diluted 1 in 8, most laboratories detected anti‐HPA‐15b in preparation 18/220 using HPA‐15bb platelets but not with HPA‐15aa platelets. The participants agreed this to be an appropriate dilution for assignment as the minimum potency. In October 2020, the WHO Expert Committee on Biological Standardization approved 18/220 as an International Reference Reagent. [ABSTRACT FROM AUTHOR]

Transforming growth factor‐β (TGF‐β) superfamily signaling via their cognate receptors is frequently modified by TGF‐β superfamily co‐receptors. Signaling through SMAD‐mediated pathways may be enhanced or depressed depending on the specific co‐receptor and cell context. This dynamic effect on signaling is further modified by the release of many of the co‐receptors from the membrane to generate soluble forms that are often antagonistic to the membrane‐bound receptors. The co‐receptors discussed here include TβRIII (betaglycan), endoglin, BAMBI, CD109, SCUBE proteins, neuropilins, Cripto‐1, MuSK, and RGMs. Dysregulation of these co‐receptors can lead to altered TGF‐β superfamily signaling that contributes to the pathophysiology of many cancers through regulation of growth, metastatic potential, and the tumor microenvironment. Here we describe the role of several TGF‐β superfamily co‐receptors on TGF‐β superfamily signaling and the impact on cellular and physiological functions with a particular focus on cancer, including a discussion on recent pharmacological advances and potential clinical applications targeting these co‐receptors. Key Findings: TGF‐β superfamily co‐receptors primarily modify ligand interactions with their cognate receptor complexes to enhance or suppress downstream SMAD signaling.Many TGF‐β superfamily co‐receptors are secreted or shed from the cell surface to further modify surface receptor signaling via ligand sequestration.Dysregulation of TGF‐β superfamily co‐receptors contribute to the pathophysiology of many cancers and a rational for the pharmacological targeting of these co‐receptors is on the rise. [ABSTRACT FROM AUTHOR]

Background Ovarian epithelial cancer (OEC) is the second-most common gynecologic malignancy. CD109 expression is elevated in human tumor cell lines and carcinomas. A previous study showed that CD109 expression is elevated in human tumor cell lines and CD109 plays a role in cancer progression. Therefore, this study aimed to determine whether CD109 is expressed in OEC and can be useful in predicting the prognosis. Methods Immunohistochemical staining for CD109 and reverse transcription-quantitative polymerase chain reaction was performed. Then we compared CD109 expression and chemoresistance, overall survival, and recurrence-free survival of OEC patients. Chemoresistance was evaluated by dividing into good-response group and poor-response group by the time to recurrence after chemotherapy. Results CD109 expression was associated with overall survival (p = .020), but not recurrence-free survival (p = .290). CD109 expression was not an independent risk factor for overall survival due to its reliability (hazard ratio, 1.58; p = .160; 95% confidence interval, 0.82 to 3.05), although we found that CD109 positivity was related to chemoresistance. The poor-response group showed higher rates of CD109 expression than the good-response group (93.8% vs 66.7%, p = .047). Also, the CD109 mRNA expression level was 2.88 times higher in the poor-response group as compared to the good-response group (p = .001). Conclusions Examining the CD109 expression in patients with OEC may be helpful in predicting survival and chemotherapeutic effect.

Cluster of differentiation 109 (CD109) is a glycosylphosphatidylinositol (GPI)-anchored protein expressed on primitive hematopoietic stem cells, activated platelets, CD4+ and CD8+ T cells, and keratinocytes. In recent years, CD109 was also associated with different tumor entities and identified as a possible future diagnostic marker linked to reduced patient survival. Also, different cell signaling pathways were proposed as targets for CD109 interference including the TGFβ, JAK-STAT3, YAP/TAZ, and EGFR/AKT/mTOR pathways. Here, we identify the metalloproteinase meprin β to cleave CD109 at the cell surface and thereby induce the release of cleavage fragments of different size. Major cleavage was identified within the bait region of CD109 residing in the middle of the protein. To identify the structural localization of the bait region, homology modeling and single-particle analysis were applied, resulting in a molecular model of membrane-associated CD109, which allows for the localization of the newly identified cleavage sites for meprin β and the previously published cleavage sites for the metalloproteinase bone morphogenetic protein-1 (BMP-1). Full-length CD109 localized on extracellular vesicles (EVs) was also identified as a release mechanism, and we can show that proteolytic cleavage of CD109 at the cell surface reduces the amount of CD109 sorted to EVs. In summary, we identified meprin β as the first membrane-bound protease to cleave CD109 within the bait region, provide a first structural model for CD109, and show that cell surface proteolysis correlates negatively with CD109 released on EVs.

Multiple cellular pathways are affected by HPV E6 and E7 oncoproteins, including endocytic and cellular trafficking. HPV-16 E7 can target the adaptor protein (AP) complex, which contains proteins important during endocytosis transport. To further investigate the role of HPV E7 during this process, we analysed the expression of cell surface proteins in NIKS cells expressing HPV-16 E7. We show that different cell surface proteins are regulated by HPV-16 E7 via interaction with AP2. We observed that the expression of MET and CD109 membrane protein seems to be upregulated in cells expressing E7. Moreover, the interaction of MET and CD109 with AP2 proteins is disrupted by HPV-16 E7. In addition, in the absence of HPV-16 E7, there is a downregulation of the cell membrane expression of MET and CD109 in HPV-positive cell lines. These results expand our knowledge of the functions of E7 and open new potential cellular pathways affected by this oncoprotein., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The author is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for [Tumour Virus Research] and was not involved in the editorial review or the decision to publish this article., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Abstract Squamous cell carcinoma (SCC) is well-known for its high rate of metastasis with poor prognosis. CD109 is a glycosylphosphatidylinositol-anchored cell-surface glycoprotein. Recently, CD109 emerges as a potential biomarker and a therapeutic target for SCCs. Accumulating studies have reported that CD109 is highly expressed in human SCCs of multiple organs, and may contribute to the progression of SCCs. In this review, we summarized the findings on expression pattern of CD109 in SCCs, and discussed the molecular mechanisms underlying the roles of CD109 in pathogenesis of SCCs.

Stromal invasion is considered an important prognostic factor in patients with lung adenocarcinoma. The mechanisms underlying the formation of tumor stroma and stromal invasion have been studied in the lung; however, they are still unclear. CD109 is a glycosylphosphatidylinositol‐anchored glycoprotein highly expressed in several types of human malignant tumors including lung cancers. In this study, we investigated the in vivo functions of CD109 protein in malignant lung tumors. Initially, we identified an association between higher expression of CD109 protein in human lung adenocarcinoma and a significantly worse prognosis, according to immunohistochemical analysis. We also showed that CD109 deficiency significantly reduced the area of stromal invasive lesions in a genetically engineered CD109‐deficient lung adenocarcinoma mouse model, which correlated with the results observed in human lung adenocarcinoma. Furthermore, we identified latent TGF‐β binding protein‐1 (LTBP1) as a CD109‐interacting protein using mass spectrometry and confirmed their interaction by co‐immunoprecipitation. Importantly, increased CD109 expression enhanced stromal TGF‐β activation in the presence of LTBP1. Therefore, these data suggest the significance of the regulation of TGF‐β signaling through CD109 and LTBP1 interaction in tumor stroma and also reveal the importance of CD109 expression levels in promoting lung cancer cell proliferation, migration, and invasion, and thus predicting the outcome of patients suffering from lung adenocarcinoma. Therefore, CD109 protein could be a potential therapeutic target for this disease. [ABSTRACT FROM AUTHOR]

Lung cancer is the most commonly diagnosed cancer worldwide, and metastasis in lung cancer is the leading cause of cancer‐related deaths. Thus, understanding the mechanism of lung cancer metastasis will improve the diagnosis and treatment of lung cancer patients. Herein, we found that expression of cluster of differentiation 109 (CD109) was correlated with the invasive and metastatic capacities of lung adenocarcinoma cells. CD109 is upregulated in tumorous tissues, and CD109 overexpression was associated with tumor progression, distant metastasis, and a poor prognosis in patient with lung adenocarcinoma. Mechanistically, expression of CD109 regulates protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling via its association with the epidermal growth factor receptor (EGFR). Inhibition of CD109 decreases EGFR phosphorylation, diminishes EGF‐elicited activation of AKT/mTOR, and sensitizes tumor cells to an EGFR inhibitor. Taken together, our results show that CD109 is a potential diagnostic and therapeutic target in lung cancer patients. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates that CD109, a glycosylphosphatidylinositol-anchored glycoprotein, is highly expressed in human epithelial carcinomas of multiple organs including the pancreas, but its functional role in carcinoma development has not yet been fully clarified. The aim of this study was to investigate the role of CD109 in the malignancy of pancreatic ductal adenocarcinoma (PDAC). PDAC specimens of 145 cases were immunostained for CD109, and correlations between CD109 expression and clinicopathological conditions were analyzed. CD109 expression in PANC-1 cells, a PDAC-derived cell line, was decreased by siRNA or shRNA and its effect on the malignancy of PANC-1 cells was examined. Suppression of CD109 expression in PANC-1 cells resulted in reduction of in vitro cell motility and tumorigenicity in xenografts. Based on these results, we investigated the relationship between CD109 expression and metastasis of PDAC using tumor tissue specimens. Among 106 recurrent cases of 145 PDAC, there was a tendency for CD109-positive cases to be accompanied by distant metastasis. CD109 plays a critical role in the promotion of tumorigenic ability and cellular motility relating to metastasis of PDAC cells. [ABSTRACT FROM AUTHOR]

• Circulating proteomic profiles may affect postoperative recurrence in CRSwNP. • Serum TGF-β1 and CD109 were possible predictive biomarkers for CRSwNP recurrence. • CD109 suppressing TGF-β1-induced EMT contributes to CRSwNP recurrence. Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common inflammatory disorder with a high rate of recurrence. This study aimed to explore biomarkers for identifying patients with recurrent CRSwNP (rCRSwNP). We recruited two independent cohorts. In the discovery cohort, rCRSwNP patients and non-recurrent CRSwNP (non-rCRSwNP) patients were recruited, and the serum proteomic profile was characterized. The top 5 upregulated and downregulated proteins were confirmed in the validation cohort by ELISA, WB, and qRT-PCR, and their predictive values for postoperative recurrence were assessed. In vitro, human nasal epithelial cells (HNEpCs) were employed to assess the ability of candidate proteins to induce epithelial-mesenchymal transition (EMT). Serum proteomics identified 53 different proteins, including 30 increased and 23 decreased, between the rCRSwNP and non-rCRSwNP groups. ELISA results revealed that serum levels of CD163 and TGF-β1 were elevated, CD109 and PRDX2 were decreased in the rCRSwNP group compared to the non-rCRSwNP group, and serum CD163, TGF-β1, and CD109 levels were proved to be associated with the risk of postoperative recurrence. In addition, qRT-PCR and WB revealed that tissue CD163, TGF-β1, and CD109 expressions in rCRSwNP patients were enhanced compared to those non-rCRSwNP patients. Kaplan-Meier analysis showed that increased CD163 and TGF-β1 expression and decreased CD109 expression are associated with the risk of recurrence in CRSwNP patients. Receiver operating characteristic curves showed that TGF-β1 and CD109 had superior diagnostic performances for rCRSwNP. In vitro experiments showed that TGF-β1 promoted EMT in HNEpCs, and overexpression of CD109 reversed this effect. Functional recovery experiments confirmed that CD109 could attenuate EMT in HNEpCs by inhibiting the TGF-β1/Smad signaling pathway, attenuating EMT in epithelial cells. Our data suggested that TGF-β1 and CD109 might serve as promising predictors of rCRSwNP. The TGF-β1/Smad pathway was implicated in fostering EMT in epithelial cells, particularly those exhibiting low expression of CD109. Consequently, the absence of CD109 expression in epithelial cells could be a potential mechanism underlying rCRSwNP. [ABSTRACT FROM AUTHOR]

Abstract Reduced functionality of transforming growth factor β (TGF‐β) is a major pathogenetic component of Alzheimer's disease (AD). The reduction is caused by an ≈50% decrease in the AD brain of the TGF‐β receptor, TGFBR, causing a bottleneck effect that reduces the downstream actions of TGF‐β, which is highly disadvantageous for brain function. Degradation of TGFBR occurs in caveolae with participation by caveolin‐1 (Cav‐1) and CD109. Mechanisms for this are discussed. In the cerebral microcirculation, endothelial cells (which are rich in caveolae) carry CD109 as a surface marker that co‐precipitates with Cav‐1. Atorvastatin reduced Cav‐1 by 75% and, because Cav‐1 and CD109 co‐immunoprecipitate reciprocally, atorvastatin would also reduce the level of CD109. Administration of atorvastatin as a component of combination therapy would diminish the degradation of TGFBR and thereby benefit patients with AD.

Objective: The aim of this study was to investigate the role of CD109 in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs) and to evaluate its potential as a therapeutic target.Methods: CD109 expression was examined in synovial tissues and FLSs from RA patients and collagen-induced arthritis (CIA) model mice. CD109-deficient mice were developed to evaluate the severity of CIA. Small interfering RNAs and a neutralising antibody against CD109 (anti-CD109) were designed for functional or treatment studies in RA FLSs and CIA.Results: CD109 was found to be abundantly expressed in the synovial tissues from RA patients and CIA mice. CD109 expression in RA FLSs was upregulated by inflammatory stimuli, such as interleukin-1β and tumour necrosis factor-α. Silencing of CD109 or anti-CD109 treatment reduced proinflammatory factor production, cell migration, invasion, chemoattractive potential and osteoclast differentiation, thereby reducing the deleterious inflammatory response of RA FLSs in vitro. Mice lacking CD109 were protected against arthritis in the CIA model. Anti-CD109 treatment prevented the onset and ameliorated the severity of CIA lesions.Conclusion: Our study uncovers an antiarthritic role for CD109 and suggests that CD109 inhibition might serve as a promising novel therapeutic strategy for RA. [ABSTRACT FROM AUTHOR]

Biliary epithelial cells (BECs) can secrete bile and the epithelial‐to‐mesenchymal transition (EMT) of BECs can cause fibrosis or damage interlobular bile ducts, leading to chronic cholangiopathies, such as primary biliary cholangitis (PBC). Transforming growth factor‐β1 (TGF‐β1) is a potent inducer of the EMT while curcumin, a diarylheptanoid, can inhibit the EMT of hepatocytes in many liver diseases. However, the protection and underlying mechanisms of curcumin against the EMT of BECs have not been clarified. Herein, we show that curcumin treatment significantly mitigates the EMT of BECs in vitro and in vivo. Mechanistically, curcumin significantly attenuated the TGF‐β1‐induced Smad and Hedgehog signaling, and upregulated CD109 expression in BECs. Collectively, these findings highlighted the therapeutic potential of curcumin to counteract the EMT process in PBC. [ABSTRACT FROM AUTHOR]

CD109 is a glycosylphosphatidylinositol‐anchored glycoprotein and a member of the α2‐macroglobulin/C3,C4,C5 family of thioester‐containing proteins first identified as being expressed on blood cells, including activated T cells and platelets, and a subset of CD34 + bone marrow cells containing megakaryocyte progenitors. Although CD109 carries the biallelic platelet‐specific alloantigen Gov, the physiological functions or roles of CD109 in human disease remain largely unknown. It was recently demonstrated that CD109 is expressed in many malignant tumors, including various squamous cell carcinomas and adenocarcinomas, and plays a role as a multifunctional coreceptor. CD109 reportedly associates with transforming growth factor (TGF)‐β receptors and negatively regulates TGF‐β signaling in keratinocytes. Additionally, CD109 is potentially related to signal transducer and activator of transcription‐3 signaling and aberrant cell proliferation. In this review, we describe recent evidence of CD109‐specific significance in malignant tumors shown in mouse models and human tissues. Furthermore, we discuss the physiological functions of CD109 in vitro and in vivo, including results of phenotype analyses of CD109‐deficient mice exhibiting epidermal hyperplasia and osteopenia. [ABSTRACT FROM AUTHOR]

Metastasis is the leading cause of death in lung adenocarcinomas. Identifying potential prognostic biomarkers and exploiting regulatory mechanisms could improve the diagnosis and treatment of lung cancer patients. We previously found that cluster of differentiation 109 (CD109) was upregulated in lung tumor tissues, and CD109 overexpression was correlated with the invasive and metastatic capacities of lung adenocarcinoma cells. However, the contribution of CD109 to lung tumorigenesis remains to be elucidated. In the present study, we identified that CD109 was upregulated in metastatic lung adenocarcinoma cells, and elevation of CD109 was correlated with epithelial-to-mesenchymal transition (EMT) traits in patients with lung adenocarcinoma. Functionally, CD109 expression was crucial for EMT gene expressions, tumor invasiveness, and cancer stemness properties. Moreover, elevation of CD109 was accompanied by upregulation of the yes-associated protein (YAP) signature in metastatic lung cancer cells and lung cancer patients, and activation of YAP was demonstrated to participate in CD109-elicited EMT gene expressions and tumor invasiveness. Our study reveals the molecular mechanism underlying CD109 in lung tumor aggressiveness, and CD109 could be a potential diagnostic and therapeutic target for lung cancer patients.

Osteoporosis is a global public health problem that is increasing along with an aging population. A major determinant of osteoporosis is high bone turnover, which results from osteoclast activation. CD109 is a glycosylphosphatidylinositol‐anchored glycoprotein, a deficiency that leads to a psoriasis‐like skin inflammation in mice. Although the expression of CD109 has been reported in mouse pre‐osteoclast cells, its function in osteoclasts in vivo remains largely unknown. To investigate the physiological role of CD109 in bone metabolism, we analyzed bones from wild‐type and CD109‐deficient adult mice. Micro‐computed tomography analysis of the femur (thigh bone) showed that bone volume was lower in CD109‐deficient mice than in wild‐type mice. Bone histomorphometric analysis showed not only a reduction in bone volume but also an increase in bone turnover in CD109‐deficient mice as compared with wild‐type mice. Additionally, we measured serum levels of several markers of bone turnover and found a significant increase in the N‐terminal telopeptide of type I collagen, a bone resorption marker, as well as alkaline phosphatase, a bone formation marker, in CD109‐deficient mice. These results indicate that CD109 deficiency induces a high‐turnover, osteoporosis‐like phenotype, which suggests that CD109 plays a role in bone metabolism in vivo. [ABSTRACT FROM AUTHOR]

Abstract: Glioblastoma (GBM) cancer stem cells (CSCs) are insidious. They extensively infiltrate brain tissue, resist radiotherapy and chemotherapy, and are thought to represent the ultimate drivers of disease progression. New research has identified CD109, a GPI‐anchored protein, on a population of perivascular CSCs. Investigation of primary human tumour tissue suggests a role for CD109‐expressing CSCs in the progression from low‐grade to high‐grade glioma, and animal modelling reveals a critical role for CD109 in the maintenance of the GBM CSC phenotype. Furthermore, CD109‐expressing CSCs appear to drive the proliferation of adjacent non‐stem tumour cells (NSTCs) in a rare example of CSC–NSTC cooperative interaction. With this Commentary, we highlight the newly revealed biology of CD109, and offer a synthesis of the published information on glioma CSCs in a variety of anatomical growth zones. We also discuss the landscape of interacting cells within GBM tumours, emphasizing the few reported examples of pro‐tumourigenic, interactive tumour cell partnerships, as well as a variety of tumour cell–non‐transformed neural cell interactions. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: In the progression of glioma, tumour cells often exploit the perivascular microenvironment to promote their survival and resistance to conventional therapies. Some of these cells are considered to be brain tumour stem cells (BTSCs); however, the molecular nature of perivascular tumour cells has not been specifically clarified because of the complexity of glioma. Here, we identified CD109, a glycosylphosphatidylinositol‐anchored protein and regulator of multiple signalling pathways, as a critical regulator of the progression of lower‐grade glioma (World Health Organization grade II/III) by clinicopathological and whole‐genome sequencing analysis of tissues from human glioma. The importance of CD109‐positive perivascular tumour cells was confirmed not only in human lower‐grade glioma tissues but also in a mouse model that recapitulated human glioma. Intriguingly, BTSCs isolated from mouse glioma expressed high levels of CD109. CD109‐positive BTSCs exerted a proliferative effect on differentiated glioma cells treated with temozolomide. These data reveal the significance of tumour cells that populate perivascular regions during glioma progression, and indicate that CD109 is a potential therapeutic target for the disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Myxofibrosarcoma (MFS), formerly considered as a myxoid variant of malignant fibrous histiocytoma, is the most common sarcoma of the extremities in adults and is characterized by a high frequency of local recurrence. The clinical behavior of MFS is unpredictable and the efficacy of chemotherapy is still not well documented. Furthermore, given the relatively recent recognition of MFS as a distinct pathologic entity its cellular and molecular biology has still not been extensively studied in patient-derived preclinical models. We examined the molecular biology and treatment outcomes of high-grade, patient-derived MFS primary cultures. Methods: A total of three patient-derived MFS primary cultures were analyzed. We evaluated the role of CD109 expression and also looked for a correlation between transforming growth factor-beta (TGF-β) expression and sensitivity of the primary cultures to different drugs. Results: CD109 was a promising marker for the identification of more aggressive high-grade MFS and a potential therapeutic target. The results also highlighted the potential role of TGF-β in chemoresistance. Pharmacological analysis confirmed the sensitivity of the cultures to chemotherapy. The most active treatments were epirubicin alone and epirubicin in combination with ifosfamide, the latter representing the current standard of care for soft tissue sarcomas (STSs), including MFS. Conclusions: Our results provide a starting point for further research aimed at improving the management of MFS patients undergoing chemotherapy. [ABSTRACT FROM AUTHOR]

Cluster of differentiation (CD) 109 is a glycosylphosphatidylinositol- anchored cell surface glycoprotein and a co-receptor for transforming growth factor β. The expression of CD109 has been detected in squamous cell carcinoma of the lung, esophagus, skin and gallbladder. The aim of the present study was to evaluate CD109 expression in penile squamous cell carcinoma (PSCC). CD109 expression in PSCC tumor and adjacent tissues from 45 specimens in tissue microarrays was examined by immunohistochemical analyses. In addition, 3 fresh surgical samples of PSCC were collected and examined for their CD109 mRNA and protein levels by reverse transcription-quantitative polymerase chain reaction, western blotting and immunofluorescence staining. CD109 transcription and expression were significantly higher in the PSCC tissues compared with adjacent normal penile tissues, and its expression was restricted to squamous cells. However, CD109 expression level was not associated with the PSCC differentiation grade. These results suggest that CD109 may be associated with the pathogenesis of PSCC, and may therefore be a potential therapeutic target. [ABSTRACT FROM AUTHOR]

CD109 is a glycosylphosphatidylinositol-anchored glycoprotein that negatively regulates TGF-β signaling. CD109 was originally identified in hematopoietic tumors; however, the significance of CD109 in hematopoietic malignancies remains unclear. Here, we study the association of CD109 with diffuse large B-cell lymphoma (DLBCL) prognosis. Eighty-four DLBCL specimens were immunohistochemically analyzed for CD109 expression, and 31 and 53 cases were classified into low- and high-CD109 expression groups, respectively. CD109 expression was not associated with overall survival using the Kaplan-Meier analysis and log-rank tests (P = 0.17); however, a significant association was observed between high-CD109 expression and low-1-year survival (P = 0.01). Moreover, in combination with the revised International Prognostic Index (R-IPI), R-IPI-poor/CD109-high was associated with poorer prognosis compared with R-IPI-poor alone. We assessed TGF-β signaling in CD109-depleted Nalm6 cells (a human B-lymphoblastic leukemia/lymphoma cell line), and found prolonged Smad2 phosphorylation compared with control cells after TGF-β1 stimulation, suggesting that CD109 attenuates TGF-β1 signaling in human B-cell tumors. These results suggest that CD109 is a putative biomarker for identifying a high-risk group among DLBCL patients. [ABSTRACT FROM AUTHOR]

Osteosarcoma, the most common primary malignant bone tumor, is defined by the formation of neoplastic osteoid and/or bone. This sarcoma is a highly heterogeneous disease with a wide range of patient outcomes. CD109 is a glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed in various types of malignant tumors. We previously reported that CD109 is expressed in osteoblasts and osteoclasts in normal human tissues and plays a role in bone metabolism in vivo. While CD109 has been shown to promote various carcinomas through the downregulation of TGF-β signaling, the role and mechanism of CD109 in sarcomas remain largely unknown. In this study, we investigated the molecular function of CD109 in sarcomas using osteosarcoma cell lines and tissue. Semi-quantitative immunohistochemical analysis using human osteosarcoma tissue revealed a significantly worse prognosis in the CD109-high group compared with the CD109-low group. We found no association between CD109 expression and TGF-β signaling in osteosarcoma cells. However, enhancement of SMAD1/5/9 phosphorylation was observed in CD109 knockdown cells under bone morphogenetic protein-2 (BMP-2) stimulation. We also performed immunohistochemical analysis for phospho-SMAD1/5/9 using human osteosarcoma tissue and found a negative correlation between CD109 expression and SMAD1/5/9 phosphorylation. In vitro wound healing assay showed that osteosarcoma cell migration was significantly attenuated in CD109-knockdown cells compared with control cells in the presence of BMP. These results suggest that CD109 is a poor prognostic factor in osteosarcoma and affects tumor cell migration via BMP signaling. • CD109 is highly expressed in osteosarcoma cells and tissue. • CD109 is a statistically significant poor prognostic factor in human osteosarcoma. • CD109 negatively regulates BMP signaling in osteosarcoma cells. • CD109 suppresses BMP-2-mediated cell migration in osteosarcoma. [ABSTRACT FROM AUTHOR]

Myxofibrosarcoma (MFS) belongs to the group of sarcoma tumors, which represent only 1% of the totality of adult tumors worldwide. Thus, given the rare nature of this cancer, this makes the availability of MFS cell lines difficult. In an attempt to partially fill this gap, we immortalized a primary culture of MFS (IM-MFS-1) and compared the cell morphology with patient’s tumor tissue. IM-MFS-1 was genetically characterized through a Comparative Genomic Hybridization (CGH) array and the mesenchymal phenotype was evaluated using Polymerase chain reaction (PCR) and immunofluorescence staining. Drug sensitivity for MFS therapies was monitored over time in cultures. We confirmed the conservation of the patient’s tumor cell morphology and of the mesenchymal phenotype. Conversely, the synthesis and expression of CD109, a TGFβ co-receptor used to facilitate the diagnosis of high-grade MFS diagnosis, was maintained constant until high cancer cell line passages. The CGH array revealed a complex karyotype with cytogenetic alterations that include chromosome regions associated with genes involved in tumor processes. Cytotoxicity assays show drug sensitivity constantly increased during the culture passages until a plateau was reached. In conclusion, we established and characterized a new MFS cell line that can be used for future preclinical and molecular studies on soft tissue sarcomas.

CD109 antigen on the endothelial cell surface plays an important role in vascular pathology. The aim of the work was to investigate the effect of the immobilization of CD109 antigen with specific antibodies on nanomechanical properties of human umbilical endothelial cells (HUVECs) using atomic force microscopy in quantitative nanomechanical property mapping mode (PeakForce QNM). Anti-CD109 antibodies induced significant stiffening of the cell surface Me(LQ; UQ): in 1.45(1.07;2.29) times with respect to control cells for fixed cells and in 4.9(3.6;5.9) times with respect to control cells for living cells, and changes in the spatial distribution of cell surface mechanical properties. The changes in the HUVEC's mechanical properties were accompanied by the activation of the TGF-/Smad2/3 signaling pathway and reorganization of the vimentin and actin cytoskeletal elements. Our findings show that blocking CD109 antigen using anti-CD109 antibodies leads in HUVECs to the processes similar to that occur after cell TGF-β-signaling activation. Therefore, we suggest that CD109 antigen may be involved in regulating the mechanical behavior of endothelial cells., (© 2023 The Authors. Cytoskeleton published by Wiley Periodicals LLC.)

Background: Hepatocellular carcinoma (HCC) accounts for 75-80 % of primary liver cancer, and usually arises after years of liver disease. Thus it is important to understand the molecular mechanisms which drive or mediate the development of HCC.Aim: In this work, we examined whether CD109 was associated with a poor prognosis in HCC and explored possible underlying mechanisms.Methods: We examined the CD109 and Ki67 expression levels in 97 patients with HCC using immunohistochemistry. CD109 levels in HCC cells were down-regulated by shRNA transfection. The cycle progression and cell proliferation status of HCC cells were evaluated by flow cytometry and CCK-8 assay. The effect of CD109 on proliferation and apoptosis was investigated by western blot and TUNEL activity assays.Results: The CD109 protein was up-regulated in HCC tissue compared with adjacent noncancerous tissue. CD109 expression levels in the 97 patients with HCC were positively correlated with histological grade. Univariate and multivariate survival analysis revealed that CD109 was a significant predictor of overall survival among HCC patients. CD109 shRNA knockdown delayed the G1-S phase transition, abrogated cell proliferation, and increased cell apoptosis. Furthermore, CD109 impaired TGF-β/Smad signaling through control of p-smad2.Conclusions: CD109 promoted HCC proliferation and predicted poor prognosis. In addition, CD109 expression was associated with anti-apoptosis in HCC cells. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β (TGF-β) is a multifunctional cytokine implicated in many diseases, including tissue fibrosis and cancer. TGF-β mediates diverse biological responses by signalling through type I and II TGF-β receptors (TβRI and TβRII). We have previously identified CD109, a glycosylphosphatidylinositol (GPI)-anchored protein, as a novel TGF-β co-receptor that negatively regulates TGF-β signalling and responses and demonstrated that membrane-anchored CD109 promotes TGF-β receptor degradation via a SMAD7/Smurf2- mediated mechanism. To determine whether CD109 released from the cell surface (soluble CD109 or sCD109) also acts as a TGF-β antagonist, we determined the efficacy of recombinant sCD109 to interact with TGF-β and inhibit TGF-β signalling and responses. Our results demonstrate that sCD109 binds TGF-β with high affinity as determined by surface plasmon resonance (SPR) and cell-based radioligand binding and affinity labelling competition assays. SPR detected slow dissociation kinetics between sCD109 and TGF-β at low concentrations, indicating a stable and effective interaction. In addition, sCD109 antagonizes TGF-β-induced Smad2/3 phosphorylation, transcription and cell migration. Together, our results suggest that sCD109 can bind TGF-β, inhibit TGF-β binding to its receptors and decrease TGF- β signalling and TGF-β-induced cellular responses. [ABSTRACT FROM AUTHOR]

Transforming growth factor (TGF)-β signaling plays an important role in the pathogenesis of psoriasis. CD109, a novel TGF-β co-receptor, which inhibits TGF-β signaling by enhancing Smad7-dependent degradation of TGF-β type I receptor (TGF-β RI), is abnormally expreβsed in psoriasis. To date, the expreβsion of Smad7 and the correlation between CD109 and Smad7 expreβsion in psoriasis have not been fully elucidated. This study was designed to investigate the expreβsion and the correlation of CD109 and TGF-β signaling aβsociated proteins in psoriasis and their roles in the pathogenesis of psoriasis. Thirty-two psoriasis specimens were subjected to immunohistochemical staining for CD109, Smad7, TGF-β RI and Ki67. Ten normal skin (NS) specimens served as controls. The positive expression rate (% positive cells) of Smad7 and Ki67 in psoriasis was significantly higher than in NS (62.6%±19.9% vs. 17.2%±4.4%, and 50.7%±14.3% vs. 19.5%±3.2%, respectively, P<0.001), and the expression levels of CD109 and TGF-β R? were reduced significantly in psoriasis as compared with NS (8.1%±6.7% vs. 35.8%±6.7% and 27.3%±3.4% vs. 3.0%±3.4%, respectively, P<0.001). There were significantly negative correlations between CD109 and Smad7 ( r=-0.831, P<0.01). These findings indicated that CD109 might play a certain role in the pathogenesis of psoriasis. Lower expression of CD109 and TGF-β RI was highly correlated with higher expression of Smad7 and Ki67, suggesting that CD109 may induce the pathogenesis of psoriasis through Smad7-mediated degradation of TGF-β RI, and lead to the termination of TGF-β signaling. [ABSTRACT FROM AUTHOR]

Asthma is a chronic airway inflammatory disease characterized by airway hyperreactivity (AHR) and eosinophilic airway inflammation. Dendritic cells (DCs) are essential for the development of asthma via presenting allergens, causing T-helper cell type 2 (Th2) skewing and eosinophil inflammation. Recent studies have revealed that CD109, a glycosylphosphatidylinositol-anchored glycoprotein, is involved in the pathogenesis of inflammatory diseases such as rheumatoid arthritis and psoriasis. However, no study has addressed the role of CD109 in asthma. This study sought to address the role of CD109 on DCs in the development of AHR and allergic inflammation. CD109-deficient mice ( CD109 -/- ) were sensitized with house dust mite or ovalbumin and compared with wild-type mice for induction of AHR and allergic inflammation. CD109-deficient mice had reduced AHR and eosinophilic inflammation together with lower Th2 cytokine expression compared with wild-type mice. Interestingly, CD109 expression was induced in lung conventional DC2s (cDC2s), but not lung cDC1s, upon allergic challenge. Lung cDC2s from CD109 -/- mice had a poor ability to induce cytokine production in ex vivo DC-T cell cocultures with high expression of RUNX3 (runt-related transcription factor 3), resulting in suppression of Th2 differentiation. Adoptive transfer of bone marrow-derived CD109 -/- DCs loaded with house dust mite failed to develop AHR and eosinophilic inflammation. Finally, administration of monoclonal anti-CD109 antibody reduced airway eosinophils and significantly decreased AHR. Our results suggest the involvement of CD109 in asthma pathogenesis. CD109 is a novel therapeutic target for asthma.

Exosomes are 50–100-nm-diameter membrane vesicles released from various types of cells. Exosomes retain proteins, mRNAs and miRNAs, which can be transported to surrounding cells. CD109 is a glycosylphosphatidylinositol-anchored glycoprotein, and is released from the cell surface to the culture medium in vitro . Recently, it was reported that secreted CD109 from the cell surface downregulates transforming growth factor-β signaling in human keratinocytes. In this study, we revealed that CD109 is a component of the exosome in conditioned medium. FLAG-tagged human CD109 (FLAG-CD109) in conditioned medium secreted from HEK293 cells expressing FLAG-CD109 (293/FLAG-CD109) was immunoprecipitated with anti-FLAG affinity gel, and the co-precipitated proteins were analyzed by mass spectrometry and western blotting. Exosomal proteins were associated with CD109. We revealed the presence of CD109 in exosome fractions from conditioned medium of 293/FLAG-CD109. Moreover, the localization of CD109 in the exosome was demonstrated using immuno-electron microscopy. When we used HEK293 cells expressing FLAG-tagged truncated CD109, which does not contain the C-terminal region, the association of truncated CD109 with exosomes was not detected in conditioned medium. These findings indicate that CD109 is an exosomal protein and that the C-terminal region of CD109 is required for its presence in the exosome. [ABSTRACT FROM AUTHOR]