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Wang M, Chen C, Ying K, Sha L, Kuang D, Huang Y, Yang J, Yin T. Peptide-DNA conjugate-assisted DNA cyclization for highly efficient and sensitive detection of furin. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2025; 17:3570-3578. [PMID: 40259668 DOI: 10.1039/d5ay00370a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/23/2025]
Abstract
Furin, a critical regulatory protease, plays a crucial role in significant physiological processes such as oncogenic signaling pathways. Accurate detection of furin is essential for disease diagnosis and precise medical interventions. Herein, we leverage the proximity effect of the engineered peptide-DNA conjugate (PDC) to induce DNA cyclization, enabling efficient and sensitive detection of furin. The PDC is synthesized through chemical reactions that link peptides and DNA molecules, strategically structured with a peptide moiety containing the specific recognition and cleavage site for furin, sandwiched between two DNA sequences. Meanwhile, the proximity effect-mediated DNA hybridization of the PDC achieves the complementation of Padlock DNA, thereby ensuring circular DNA formation. Subsequently, the cyclized DNA serves as a template to initiate the rolling circle amplification reaction, generating numerous G-quadruplex structures that yield a fluorescence signal upon thioflavin T intercalation. While furin-catalyzed peptide cleavage disrupts the proximity effect, DNA cyclization and subsequent reactions are inhibited. The multifunctional PDC probe which can assist DNA cyclization facilitates furin recognition through peptide embedding, thus providing a new way for sensitive detection of furin, with a detection limit of 1.5 pM. Additionally, our method demonstrates efficacy in inhibitor determination, showing great potential across biomedical research, clinical diagnostics, and therapeutic development.
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Affiliation(s)
- Minghui Wang
- College of Science, Nanjing Forestry University, Nanjing, 210037, P. R. China.
| | - Cuifei Chen
- College of Science, Nanjing Forestry University, Nanjing, 210037, P. R. China.
| | - Keqin Ying
- State Key Laboratory of Analytical Chemistry for Life Science, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China
| | - Lingjun Sha
- State Key Laboratory of Analytical Chemistry for Life Science, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China
| | - Deqi Kuang
- State Key Laboratory of Analytical Chemistry for Life Science, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China
| | - Yue Huang
- Department of Food Science and Engineering, College of Light Industry and Food Engineering, Nanjing Forestry University, Nanjing 210037, P. R. China.
| | - Jie Yang
- College of Science, Nanjing Forestry University, Nanjing, 210037, P. R. China.
| | - Tingting Yin
- Department of Obstetrics and Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, P. R. China.
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Zhang D, Luo Y, Lin Y, Fang Z, Zheng H, An M, Xie Q, Wu Z, Yu C, Yang J, Yu M, Chen C, Chen R. Endosomal Trafficking Bypassed by the RAB5B-CD109 Interplay Promotes Axonogenesis in KRAS-Mutant Pancreatic Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2405092. [PMID: 39488792 DOI: 10.1002/advs.202405092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 10/13/2024] [Indexed: 11/04/2024]
Abstract
Perineural invasion (PNI) represents a unique biological feature associated with poor prognosis in pancreatic ductal adenocarcinoma (PDAC), especially in the presence of KRAS mutations. Extracellular vesicle (EV)-packaged circular RNAs (circRNAs) function as essential mediators of tumor microenvironment communication, triggering PDAC cell invasion and distant metastasis. However, the regulatory mechanisms of EV-packaged circRNAs in the PNI of KRAS-mutant PDAC have not yet been elucidated. Herein, a KRASG12D mutation-responsive EV-packaged circRNA, circPNIT, which positively correlated with PNI in PDAC patients is identified. Functionally, KRASG12D PDAC-derived EV-packaged circPNIT promoted axonogenesis and PNI both in vitro and in vivo. Mechanistically, the circPNIT-mediated Rab5B-CD109 interplay bypassed traditional endosomal trafficking to anchor Rab5B to the lipid rafts of multivesicular bodies and packaged circPNIT into CD109+ EVs. Subsequently, CD109+ EVs delivered circPNIT to neurons by binding to TRPV1 and facilitating DSCAML1 transcription-induced axonogenesis, which in turn enhanced the PNI by activating the GFRα1/RET pathway. Importantly, circPNIT-loaded CD109+ EVs are established to dramatically promote PNI in a KRASG12D/+ Trp53R172H/+ Pdx-1-Cre mouse model. Collectively, the findings highlight the mechanism underlying how EV-packaged circRNAs mediate the PNI of KRAS-mutant PDAC cells through the Rab5B endosomal bypass, identifying circPNIT as an effective target for the treatment of neuro-metastatic PDAC.
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Affiliation(s)
- Dingwen Zhang
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, P. R. China
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China
| | - Yuming Luo
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China
| | - Yan Lin
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510120, P. R. China
| | - Zhou Fang
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510080, P. R. China
| | - Hanhao Zheng
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510120, P. R. China
| | - Mingjie An
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510120, P. R. China
| | - Qingyu Xie
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510080, P. R. China
| | - Zhuo Wu
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, P. R. China
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China
| | - Chao Yu
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510080, P. R. China
| | - Jiabin Yang
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510080, P. R. China
| | - Min Yu
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China
| | - Changhao Chen
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510120, P. R. China
| | - Rufu Chen
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China
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Jensen KT, Nielsen NS, Viana Almeida A, Thøgersen IB, Enghild JJ, Harwood SL. Proteolytic cleavage of the TGFβ co-receptor CD109 changes its conformation, resulting in protease inhibition via activation of its thiol ester, and dissociation from the cell membrane. FEBS J 2024; 291:3169-3190. [PMID: 38587194 DOI: 10.1111/febs.17128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 02/14/2024] [Accepted: 03/18/2024] [Indexed: 04/09/2024]
Abstract
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.
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Affiliation(s)
| | | | - Ana Viana Almeida
- Department of Molecular Biology and Genetics, Aarhus University, Denmark
| | - Ida B Thøgersen
- Department of Molecular Biology and Genetics, Aarhus University, Denmark
| | - Jan J Enghild
- Department of Molecular Biology and Genetics, Aarhus University, Denmark
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Pan W, Yun T, Ouyang X, Ruan Z, Zhang T, An Y, Wang R, Zhu P. A blood-based multi-omic landscape for the molecular characterization of kidney stone disease. Mol Omics 2024; 20:322-332. [PMID: 38623715 DOI: 10.1039/d3mo00261f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/17/2024]
Abstract
Kidney stone disease (KSD, also named renal calculi, nephrolithiasis, or urolithiasis) is a common urological disease entailing the formation of minerals and salts that form inside the urinary tract, frequently caused by diabetes, high blood pressure, hypertension, and monogenetic components in most patients. 10% of adults worldwide are affected by KSD, which continues to be highly prevalent and with increasing incidence. For the identification of novel therapeutic targets in KSD, we adopted high-throughput sequencing and mass spectrometry (MS) techniques in this study and carried out an integrative analysis of exosome proteomic data and DNA methylation data from blood samples of normal and KSD individuals. Our research delineated the profiling of exosomal proteins and DNA methylation in both healthy individuals and those afflicted with KSD, finding that the overexpressed proteins and the demethylated genes in KSD samples are associated with immune responses. The consistency of the results in proteomics and epigenetics supports the feasibility of the comprehensive strategy. Our insights into the molecular landscape of KSD pave the way for a deeper understanding of its pathogenic mechanism, providing an opportunity for more precise diagnosis and targeted treatment strategies for KSD.
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Affiliation(s)
- Weibing Pan
- Department of Urology, Shenzhen Pingshan People's Hospital, Shenzhen, Guangdong 518118, China
| | - Tianwei Yun
- Department of Urology, Shenzhen Pingshan People's Hospital, Shenzhen, Guangdong 518118, China
| | - Xin Ouyang
- Department of Laboratory Medicine, Shenzhen Pingshan People's Hospital, Shenzhen, Guangdong 518118, China.
| | - Zhijun Ruan
- Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518020, China.
| | - Tuanjie Zhang
- Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518020, China.
| | - Yuhao An
- Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518020, China.
| | - Rui Wang
- Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518020, China.
| | - Peng Zhu
- Department of Laboratory Medicine, Shenzhen Pingshan People's Hospital, Shenzhen, Guangdong 518118, China.
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Saito T, Fujino N, Kyogoku Y, Yamada M, Okutomo K, Ono Y, Konno S, Endo T, Itakura K, Matsumoto S, Sano H, Aizawa H, Numakura T, Onodera K, Okada Y, Hussell T, Ichinose M, Sugiura H. Identification of Siglec-1-negative alveolar macrophages with proinflammatory phenotypes in chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol 2024; 326:L672-L686. [PMID: 38530936 DOI: 10.1152/ajplung.00303.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 03/21/2024] [Accepted: 03/21/2024] [Indexed: 03/28/2024] Open
Abstract
Alveolar macrophages (AMs) in patients with chronic obstructive pulmonary disease (COPD) orchestrate persistent inflammation in the airway. However, subpopulations of AMs participating in chronic inflammation have been poorly characterized. We previously reported that Siglec-1 expression on AMs, which is important for bacteria engulfment, was decreased in COPD. Here, we show that Siglec-1-negative AMs isolated from COPD lung tissues exhibit a proinflammatory phenotype and are associated with poor clinical outcomes in patients with COPD. Using flow cytometry, we segregated three subsets of AMs based on the expression of Siglec-1 and their side scattergram (SSC) and forward scattergram (FSC) properties: Siglec-1+SSChiFSChi, Siglec-1-SSChiFSChi, and Siglec-1-SSCloFSClo subsets. The Siglec-1-SSCloFSClo subset number was increased in COPD. RNA sequencing revealed upregulation of multiple proinflammatory signaling pathways and emphysema-associated matrix metalloproteases in the Siglec-1-SSCloFSClo subset. Gene set enrichment analysis indicated that the Siglec-1-SSCloFSClo subset adopted intermediate phenotypes between monocytes and mature alveolar macrophages. Functionally, these cells produced TNF-α, IL-6, and IL-8 at baseline, and these cytokines were significantly increased in response to viral RNA. The increase in Siglec-1-negative AMs in induced sputum is associated with future exacerbation risk and lung function decline in patients with COPD. Collectively, the novel Siglec-1-SSCloFSClo subset of AMs displays proinflammatory properties, and their emergence in COPD airways may be associated with poor clinical outcomes.NEW & NOTEWORTHY Alveolar macrophages (AMs) in patients with chronic obstructive pulmonary disease (COPD) orchestrate persistent inflammation in the airway. We find that Siglec-1-negative alveolar macrophages have a wide range of proinflammatory landscapes and a protease-expressing phenotype. Moreover, this subset is associated with the pathogenesis of COPD and responds to viral stimuli.
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Affiliation(s)
- Takuya Saito
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Naoya Fujino
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yorihiko Kyogoku
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mitsuhiro Yamada
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Koji Okutomo
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshinao Ono
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shuichi Konno
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takuto Endo
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Koji Itakura
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shuichiro Matsumoto
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hirohito Sano
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroyuki Aizawa
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tadahisa Numakura
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Katsuhiro Onodera
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshinori Okada
- Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Tracy Hussell
- Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, United Kingdom
| | | | - Hisatoshi Sugiura
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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Naoi H, Suzuki Y, Miyagi A, Horiguchi R, Aono Y, Inoue Y, Yasui H, Hozumi H, Karayama M, Furuhashi K, Enomoto N, Fujisawa T, Inui N, Mii S, Ichihara M, Takahashi M, Suda T. CD109 Attenuates Bleomycin-induced Pulmonary Fibrosis by Inhibiting TGF-β Signaling. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1221-1231. [PMID: 38334455 DOI: 10.4049/jimmunol.2300285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 01/23/2024] [Indexed: 02/10/2024]
Abstract
Pulmonary fibrosis is a fatal condition characterized by fibroblast and myofibroblast proliferation and collagen deposition. TGF-β plays a pivotal role in the development of pulmonary fibrosis. Therefore, modulation of TGF-β signaling is a promising therapeutic strategy for treating pulmonary fibrosis. To date, however, interventions targeting TGF-β have not shown consistent efficacy. CD109 is a GPI-anchored glycoprotein that binds to TGF-β receptor I and negatively regulates TGF-β signaling. However, no studies have examined the role and therapeutic potential of CD109 in pulmonary fibrosis. The purpose of this study was to determine the role and therapeutic value of CD109 in bleomycin-induced pulmonary fibrosis. CD109-transgenic mice overexpressing CD109 exhibited significantly attenuated pulmonary fibrosis, preserved lung function, and reduced lung fibroblasts and myofibroblasts compared with wild-type (WT) mice. CD109-/- mice exhibited pulmonary fibrosis comparable to WT mice. CD109 expression was induced in variety types of cells, including lung fibroblasts and macrophages, upon bleomycin exposure. Recombinant CD109 protein inhibited TGF-β signaling and significantly decreased ACTA2 expression in human fetal lung fibroblast cells in vitro. Administration of recombinant CD109 protein markedly reduced pulmonary fibrosis in bleomycin-treated WT mice in vivo. Our results suggest that CD109 is not essential for the development of pulmonary fibrosis, but excess CD109 protein can inhibit pulmonary fibrosis development, possibly through suppression of TGF-β signaling. CD109 is a novel therapeutic candidate for treating pulmonary fibrosis.
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Affiliation(s)
- Hyogo Naoi
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yuzo Suzuki
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Asuka Miyagi
- Advanced Research Facilities and Services, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Ryo Horiguchi
- Advanced Research Facilities and Services, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yuya Aono
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yusuke Inoue
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hideki Yasui
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hironao Hozumi
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Masato Karayama
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kazuki Furuhashi
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Noriyuki Enomoto
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Tomoyuki Fujisawa
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Naoki Inui
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Shinji Mii
- Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masatoshi Ichihara
- Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Biomedical Science, Chubu University Graduate School of Life and Health Science, Kasugai, Japan
| | - Masahide Takahashi
- Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- International Center for Cell and Gene Therapy, Fujita Health University, Toyoake, Japan
| | - Takafumi Suda
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
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Yuan Y, Li P, Li J, Zhao Q, Chang Y, He X. Protein lipidation in health and disease: molecular basis, physiological function and pathological implication. Signal Transduct Target Ther 2024; 9:60. [PMID: 38485938 PMCID: PMC10940682 DOI: 10.1038/s41392-024-01759-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/31/2023] [Accepted: 01/24/2024] [Indexed: 03/18/2024] Open
Abstract
Posttranslational modifications increase the complexity and functional diversity of proteins in response to complex external stimuli and internal changes. Among these, protein lipidations which refer to lipid attachment to proteins are prominent, which primarily encompassing five types including S-palmitoylation, N-myristoylation, S-prenylation, glycosylphosphatidylinositol (GPI) anchor and cholesterylation. Lipid attachment to proteins plays an essential role in the regulation of protein trafficking, localisation, stability, conformation, interactions and signal transduction by enhancing hydrophobicity. Accumulating evidence from genetic, structural, and biomedical studies has consistently shown that protein lipidation is pivotal in the regulation of broad physiological functions and is inextricably linked to a variety of diseases. Decades of dedicated research have driven the development of a wide range of drugs targeting protein lipidation, and several agents have been developed and tested in preclinical and clinical studies, some of which, such as asciminib and lonafarnib are FDA-approved for therapeutic use, indicating that targeting protein lipidations represents a promising therapeutic strategy. Here, we comprehensively review the known regulatory enzymes and catalytic mechanisms of various protein lipidation types, outline the impact of protein lipidations on physiology and disease, and highlight potential therapeutic targets and clinical research progress, aiming to provide a comprehensive reference for future protein lipidation research.
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Affiliation(s)
- Yuan Yuan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peiyuan Li
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianghui Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China.
| | - Ying Chang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China.
| | - Xingxing He
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China.
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8
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Al‐kuraishy HM, Al‐Maiahy TJ, Al‐Gareeb AI, Alexiou A, Papadakis M, Saad HM, Batiha GE. The possible role furin and furin inhibitors in endometrial adenocarcinoma: A narrative review. Cancer Rep (Hoboken) 2024; 7:e1920. [PMID: 38018319 PMCID: PMC10809206 DOI: 10.1002/cnr2.1920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/29/2023] [Accepted: 10/09/2023] [Indexed: 11/30/2023] Open
Abstract
BACKGROUND Endometrial adenocarcinoma (EAC) is a malignant tumor of the endometrium. EAC is the most common female malignancy following the menopause period. About 40% of patients with EAC are linked with obesity and interrelated with hypertension, diabetes mellitus, and high circulating estrogen levels. Proprotein convertase (PC) furin was involved in the progression of EAC. RECENT FINDINGS Furin is a protease enzyme belonging to the subtilisin PC family called PC subtilisin/kexin type 3 that converts precursor proteins to biologically active forms and products. Aberrant activation of furin promotes abnormal cell proliferation and the development of cancer. Furin promotes angiogenesis, malignant cell proliferation, and tissue invasion by malignant cells through its pro-metastatic and oncogenic activities. Furin activity is correlated with the malignant proliferation of EAC. Higher expression of furin may increase the development of EAC through overexpression of pro-renin receptors and disintegrin and metalloprotease 17 (ADAM17). As well, inflammatory signaling in EAC promotes the expression of furin with further propagation of malignant transformation. CONCLUSION Furin is associated with the development and progression of EAC through the induction of proliferation, invasion, and metastasis of malignant cells of EAC. Furin induces ontogenesis in EAC through activation expression of ADAM17, pro-renin receptor, CD109, and TGF-β. As well, EAC-mediated inflammation promotes the expression of furin with further propagation of neoplastic growth and invasion.
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Affiliation(s)
- Hayder M. Al‐kuraishy
- Department of Clinical Pharmacology and MedicineCollege of Medicine, Mustansiriyah UniversityBaghdadIraq
| | - Thabat J. Al‐Maiahy
- Department of Gynecology and ObstetricsCollege of Medicine, Mustansiriyah UniversityBaghdadIraq
| | - Ali I. Al‐Gareeb
- Department of Clinical Pharmacology and MedicineCollege of Medicine, Mustansiriyah UniversityBaghdadIraq
| | - Athanasios Alexiou
- University Centre for Research & DevelopmentChandigarh University, Chandigarh‐Ludhiana HighwayMohaliPunjabIndia
- Department of Research & DevelopmentFunogenAthensGreece
- Department of Research & DevelopmentAFNP MedWienAustria
- Department of Science and EngineeringNovel Global Community Educational FoundationHebershamNew South WalesAustralia
| | - Marios Papadakis
- Department of Surgery IIUniversity Hospital Witten‐Herdecke, University of Witten‐HerdeckeWuppertalGermany
| | - Hebatallah M. Saad
- Department of PathologyFaculty of Veterinary Medicine, Matrouh UniversityMatrouhEgypt
| | - Gaber El‐Saber Batiha
- Department of Pharmacology and TherapeuticsFaculty of Veterinary Medicine, Damanhour UniversityDamanhourAlBeheiraEgypt
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Yoo HB, Moon JW, Kim HR, Lee HS, Miyabayashi K, Park CH, Ge S, Zhang A, Tae YK, Sub Y, Park HW, Gee HY, Notta F, Tuveson DA, Bang S, Kim MY, Roe JS. A TEAD2-Driven Endothelial-Like Program Shapes Basal-Like Differentiation and Metastasis of Pancreatic Cancer. Gastroenterology 2023; 165:133-148.e17. [PMID: 36907523 PMCID: PMC10330865 DOI: 10.1053/j.gastro.2023.02.049] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 02/18/2023] [Accepted: 02/24/2023] [Indexed: 03/14/2023]
Abstract
BACKGROUND & AIMS Pancreatic ductal adenocarcinoma (PDA), with its highly metastatic propensity, is one of the most lethal subtypes of pancreatic cancer. Although recent large-scale transcriptomic studies have demonstrated that heterogeneous gene expressions play an essential role in determining molecular phenotypes of PDA, biological cues for and consequences of distinct transcriptional programs remain unclear. METHODS We developed an experimental model that enforces the transition of PDA cells toward a basal-like subtype. We combined epigenome and transcriptome analyses with extensive in vitro and in vivo evaluations of tumorigenicity to demonstrate the validity of basal-like subtype differentiation in association with endothelial-like enhancer landscapes via TEA domain transcription factor 2 (TEAD2). Finally, we used loss-of-function experiments to investigate the importance of TEAD2 in regulating reprogrammed enhancer landscape and metastasis in basal-like PDA cells. RESULTS Aggressive characteristics of the basal-like subtype are faithfully recapitulated in vitro and in vivo, demonstrating the physiological relevance of our model. Further, we showed that basal-like subtype PDA cells acquire a TEAD2-dependent proangiogenic enhancer landscape. Genetic and pharmacologic inhibitions of TEAD2 in basal-like subtype PDA cells impair their proangiogenic phenotypes in vitro and cancer progression in vivo. Last, we identify CD109 as a critical TEAD2 downstream mediator that maintains constitutively activated JAK-STAT signaling in basal-like PDA cells and tumors. CONCLUSIONS Our findings implicate a TEAD2-CD109-JAK/STAT axis in the basal-like differentiated pancreatic cancer cells and as a potential therapeutic vulnerability.
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Affiliation(s)
- Hye-Been Yoo
- Department of Biochemistry, Yonsei University, Seoul, Korea
| | - Jin Woo Moon
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea
| | - Hwa-Ryeon Kim
- Department of Biochemistry, Yonsei University, Seoul, Korea
| | - Hee Seung Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Koji Miyabayashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Chan Hee Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Sabrina Ge
- Princess Margaret Cancer Center, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Amy Zhang
- Princess Margaret Cancer Center, Toronto, Ontario, Canada; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Yoo Keung Tae
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Yujin Sub
- Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea
| | - Hyun-Woo Park
- Department of Biochemistry, Yonsei University, Seoul, Korea
| | - Heon Yung Gee
- Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea
| | - Faiyaz Notta
- Princess Margaret Cancer Center, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - David A Tuveson
- Lustgarten Foundation Dedicated Laboratory at Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
| | - Seungmin Bang
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Mi-Young Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
| | - Jae-Seok Roe
- Department of Biochemistry, Yonsei University, Seoul, Korea.
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10
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Mori N, Esaki N, Shimoyama Y, Shiraki Y, Asai N, Sakai T, Nishida Y, Takahashi M, Enomoto A, Mii S. Significance of expression of CD109 in osteosarcoma and its involvement in tumor progression via BMP signaling. Pathol Res Pract 2023; 245:154443. [PMID: 37030166 DOI: 10.1016/j.prp.2023.154443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/30/2023] [Accepted: 04/03/2023] [Indexed: 04/09/2023]
Abstract
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.
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11
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Kummola L, Salomaa T, Ortutay Z, Savan R, Young HA, Junttila IS. IL-4, IL-13 and IFN-γ -induced genes in highly purified human neutrophils. Cytokine 2023; 164:156159. [PMID: 36809715 DOI: 10.1016/j.cyto.2023.156159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/27/2023] [Accepted: 02/10/2023] [Indexed: 02/21/2023]
Abstract
Interleukin (IL)-4 and IL-13 are related cytokines with well-known specific roles in type 2 immune response. However, their effects on neutrophils are not completely understood. For this, we studied human primary neutrophil responses to IL-4 and IL-13. Neutrophils are dose-dependently responsive to both IL-4 and IL-13 as indicated by signal transducer and activator of transcription 6 (STAT6) phosphorylation upon stimulation, with IL-4 being more potent inducer of STAT6. IL-4-, IL-13- and Interferon (IFN)-γ-stimulated gene expression in highly purified human neutrophils induced both overlapping and unique gene expression in highly purified human neutrophils. IL-4 and IL-13 specifically regulate several immune-related genes, including IL-10, tumor necrosis factor (TNF) and leukemia inhibitory factor (LIF), while type1 immune response-related IFN-γ induced gene expression related for example, to intracellular infections. In analysis of neutrophil metabolic responses, oxygen independent glycolysis was specifically regulated by IL-4, but not by IL-13 or IFN-γ, suggesting specific role for type I IL-4 receptor in this process. Our results provide a comprehensive analysis of IL-4, IL-13 and IFN-γ -induced gene expression in neutrophils while also addressing cytokine-mediated metabolic changes in neutrophils.
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Affiliation(s)
- Laura Kummola
- Biodiversity Interventions for Well-being, Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland
| | - Tanja Salomaa
- Cytokine Biology Research Group, Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland; Fimlab Laboratories, 33520 Tampere, Finland
| | | | - Ram Savan
- Department of Immunology, School of Medicine, University of Washington, 98195 Seattle, WA, USA
| | - Howard A Young
- Center for Cancer Research, National Cancer Institute, 21702 Frederick, MD, USA
| | - Ilkka S Junttila
- Cytokine Biology Research Group, Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland; Fimlab Laboratories, 33520 Tampere, Finland; Northern Finland Laboratory Centre (NordLab), 90220 Oulu, Finland; Research Unit of Biomedicine, University of Oulu, 90570 Oulu, Finland.
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12
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Aono Y, Suzuki Y, Horiguchi R, Inoue Y, Karayama M, Hozumi H, Furuhashi K, Enomoto N, Fujisawa T, Nakamura Y, Inui N, Mii S, Takahashi M, Suda T. CD109 on Dendritic Cells Regulates Airway Hyperreactivity and Eosinophilic Airway Inflammation. Am J Respir Cell Mol Biol 2023; 68:201-212. [PMID: 36215676 DOI: 10.1165/rcmb.2022-0109oc] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
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.
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Affiliation(s)
- Yuya Aono
- Second Division, Department of Internal Medicine, and
| | - Yuzo Suzuki
- Second Division, Department of Internal Medicine, and
| | - Ryo Horiguchi
- Advanced Research Facilities and Services, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yusuke Inoue
- Second Division, Department of Internal Medicine, and
| | | | | | | | | | | | | | - Naoki Inui
- Second Division, Department of Internal Medicine, and
| | - Shinji Mii
- Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; and
| | - Masahide Takahashi
- Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; and.,International Center for Cell and Gene Therapy, Fujita Health University, Toyoake, Japan
| | - Takafumi Suda
- Second Division, Department of Internal Medicine, and
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13
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Hosokawa K, Nakao S. Somatic mutations and clonal expansions in paroxysmal nocturnal hemoglobinuria. Semin Hematol 2022; 59:143-149. [DOI: 10.1053/j.seminhematol.2022.08.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/17/2022] [Accepted: 08/17/2022] [Indexed: 01/02/2023]
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14
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CD109 Is a Critical Determinant of EGFR Expression and Signaling, and Tumorigenicity in Squamous Cell Carcinoma Cells. Cancers (Basel) 2022; 14:cancers14153672. [PMID: 35954339 PMCID: PMC9367592 DOI: 10.3390/cancers14153672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/13/2022] [Accepted: 07/19/2022] [Indexed: 11/16/2022] Open
Abstract
(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.
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15
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Adachi K, Sakurai Y, Ichinoe M, Tadehara M, Tamaki A, Kesen Y, Kato T, Mii S, Enomoto A, Takahashi M, Koizumi W, Murakumo Y. CD109 expression in tumor cells and stroma correlates with progression and prognosis in pancreatic cancer. Virchows Arch 2022; 480:819-829. [PMID: 34762199 DOI: 10.1007/s00428-021-03230-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/20/2021] [Accepted: 10/30/2021] [Indexed: 10/19/2022]
Abstract
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.
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Affiliation(s)
- Kai Adachi
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Japan
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yasutaka Sakurai
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Japan
| | - Masaaki Ichinoe
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Japan
| | - Masayoshi Tadehara
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Japan
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Akihiro Tamaki
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Japan
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yurika Kesen
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Japan
| | - Takuya Kato
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Japan
| | - Shinji Mii
- Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Atsushi Enomoto
- Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahide Takahashi
- Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- International Center for Cell and Gene Therapy, Fujita Health University, Toyoake, Japan
| | - Wasaburo Koizumi
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yoshiki Murakumo
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Japan.
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16
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Kuroishi A, Takihara Y, Hirayama F. Current understanding and future perspectives for anti-human platelet antigen-15 antibodies in patients with alloimmune thrombocytopenia: History, laboratory testing, and clinical impact. Transfusion 2022; 62:1128-1141. [PMID: 35266549 DOI: 10.1111/trf.16845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 02/02/2022] [Accepted: 02/11/2022] [Indexed: 11/30/2022]
Affiliation(s)
- Ayumu Kuroishi
- Laboratory, Japanese Red Cross Kinki Block Blood Center, Ibaraki-shi, Osaka, Japan
| | | | - Fumiya Hirayama
- Japanese Red Cross Kinki Block Blood Center, Ibaraki-shi, Osaka, Japan
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17
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Pawlak JB, Blobe GC. TGF-β superfamily co-receptors in cancer. Dev Dyn 2022; 251:137-163. [PMID: 33797167 PMCID: PMC8484463 DOI: 10.1002/dvdy.338] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/17/2021] [Accepted: 03/22/2021] [Indexed: 01/03/2023] Open
Abstract
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.
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Affiliation(s)
| | - Gerard C. Blobe
- Department of Medicine, Duke University Medical Center,Department of Pharmacology and Cancer Biology, Duke University Medical Center,Corresponding author: Gerard Blobe, B354 LSRC, Box 91004 DUMC, Durham, NC 27708, , 919-668-1352
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18
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The GPI-anchored protein CD109 protects hematopoietic progenitor cells from undergoing erythroid differentiation induced by TGF-β. Leukemia 2021; 36:847-855. [PMID: 34743190 DOI: 10.1038/s41375-021-01463-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 10/09/2021] [Accepted: 10/21/2021] [Indexed: 12/20/2022]
Abstract
Although a glycosylphosphatidylinositol-anchored protein (GPI-AP) CD109 serves as a TGF-β co-receptor and inhibits TGF-β signaling in keratinocytes, the role of CD109 on hematopoietic stem progenitor cells (HSPCs) remains unknown. We studied the effect of CD109 knockout (KO) or knockdown (KD) on TF-1, a myeloid leukemia cell line that expresses CD109, and primary human HSPCs. CD109-KO or KD TF-1 cells underwent erythroid differentiation in the presence of TGF-β. CD109 was more abundantly expressed in hematopoietic stem cells (HSCs) than in multipotent progenitors and HSPCs of human bone marrow (BM) and cord blood but was not detected in mouse HSCs. Erythroid differentiation was induced by TGF-β to a greater extent in CD109-KD cord blood or iPS cell-derived megakaryocyte-erythrocyte progenitor cells (MEPs) than in wild-type MEPs. When we analyzed the phenotype of peripheral blood MEPs of patients with paroxysmal nocturnal hemoglobinuria who had both GPI(+) and GPI(-) CD34+ cells, the CD36 expression was more evident in CD109- MEPs than CD109+ MEPs. In summary, CD109 suppresses TGF-β signaling in HSPCs, and the lack of CD109 may increase the sensitivity of PIGA-mutated HSPCs to TGF-β, thus leading to the preferential commitment of erythroid progenitor cells to mature red blood cells in immune-mediated BM failure.
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19
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Li W, Lückstädt W, Wöhner B, Bub S, Schulz A, Socher E, Arnold P. Structural and functional properties of meprin β metalloproteinase with regard to cell signaling. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1869:119136. [PMID: 34626678 DOI: 10.1016/j.bbamcr.2021.119136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/05/2021] [Accepted: 09/06/2021] [Indexed: 10/20/2022]
Abstract
The metalloproteinase meprin β plays an important role during collagen I deposition in the skin, mucus detachment in the small intestine and also regulates the abundance of different cell surface proteins such as the interleukin-6 receptor (IL-6R), the triggering receptor expressed on myeloid cells 2 (TREM2), the cluster of differentiation 99 (CD99), the amyloid precursor protein (APP) and the cluster of differentiation 109 (CD109). With that, regulatory mechanisms that control meprin β activity and regulate its release from the cell surface to enable access to distant substrates are increasingly important. Here, we will summarize factors that alternate meprin β activity and thereby regulate its proteolytic activity on the cell surface or in the supernatant. We will also discuss cleavage of the IL-6R and TREM2 on the cell surface and compare it to CD109. CD109, as a substrate of meprin β, is cleaved within the protein core, thereby releasing defined fragments from the cell surface. At last, we will also summarize the role of proteases in general and meprin β in particular in substrate release on extracellular vesicles.
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Affiliation(s)
- Wenjia Li
- Institute of Functional and Clinical Anatomy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Wiebke Lückstädt
- Institute of Anatomy, Christian-Albrechts-Universität zu Kiel (CAU), Kiel, Germany
| | - Birte Wöhner
- Institute of Anatomy, Christian-Albrechts-Universität zu Kiel (CAU), Kiel, Germany
| | - Simon Bub
- Department of Molecular-Neurology, University Hospital Erlangen, Erlangen, Germany
| | - Antonia Schulz
- Institute of Anatomy, Christian-Albrechts-Universität zu Kiel (CAU), Kiel, Germany
| | - Eileen Socher
- Institute of Functional and Clinical Anatomy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Philipp Arnold
- Institute of Functional and Clinical Anatomy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
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20
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Kwon W, Choi SK, Kim D, Kim HG, Park JK, Han JE, Cho GJ, Yun S, Yu W, Han SH, Ha YS, Lee JN, Kwon TG, Cho DH, Yi JK, Kim MO, Ryoo ZY, Park S. ZNF507 affects TGF-β signaling via TGFBR1 and MAP3K8 activation in the progression of prostate cancer to an aggressive state. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:291. [PMID: 34537073 PMCID: PMC8449443 DOI: 10.1186/s13046-021-02094-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 09/03/2021] [Indexed: 12/31/2022]
Abstract
Background The progression of prostate cancer (PC) to the highly aggressive metastatic castration-resistant prostate cancer (mCRPC) or neuroendocrine prostate cancer (NEPC) is a fatal condition and the underlying molecular mechanisms are poorly understood. Here, we identified the novel transcriptional factor ZNF507 as a key mediator in the progression of PC to an aggressive state. Methods We analyzed ZNF507 expression in the data from various human PC database and high-grade PC patient samples. By establishment of ZNF507 knockdown and overexpression human PC cell lines, we assessed in vitro PC phenotype changes including cell proliferation, survival, migration and invasion. By performing microarray with ZNF507 knockdown PC cells, we profiled the gene clusters affected by ZNF507 knockdown. Moreover, ZNF507 regulated key signal was evaluated by dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays. Finally, we performed xenograft and in vivo metastasis assay to confirm the effect of ZNF507 knockdown in PC cells. Results We found that ZNF507 expression was increased, particularly in the highly graded PC. ZNF507 was also found to be associated with metastatic PC of a high grade. Loss- or gain-of-function–based analysis revealed that ZNF507 promotes the growth, survival, proliferation, and metastatic properties of PC (e.g., epithelial-mesenchymal transition) by upregulating TGF-β signaling. Profiling of gene clusters affected by ZNF507 knockdown revealed that ZNF507 positively regulated the transcription of TGFBR1, MAP3K8, and FURIN, which in turn promoted the progression of PC to highly metastatic and aggressive state. Conclusions Our findings suggest that ZNF507 is a novel key regulator of TGF-β signaling in the progression of malignant PC and could be a promising target for studying the development of advanced metastatic PCs. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02094-3.
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Affiliation(s)
- Wookbong Kwon
- Core Protein Resources Center, DGIST, Daegu, Republic of Korea.,Division of Biotechnology, DGIST, Daegu, Republic of Korea
| | - Seong-Kyoon Choi
- Core Protein Resources Center, DGIST, Daegu, Republic of Korea. .,Division of Biotechnology, DGIST, Daegu, Republic of Korea.
| | - Daehwan Kim
- Core Protein Resources Center, DGIST, Daegu, Republic of Korea.,Division of Biotechnology, DGIST, Daegu, Republic of Korea.,School of Life Science, BK21 FOUR KNU Creative Bioresearch, Kyungpook National University, Daegu, Korea
| | - Hyeon-Gyeom Kim
- Core Protein Resources Center, DGIST, Daegu, Republic of Korea
| | - Jin-Kyu Park
- College of Veterinary Medicine, Kyungpook National University, 41566, Daegu, Korea
| | - Jee Eun Han
- College of Veterinary Medicine, Kyungpook National University, 41566, Daegu, Korea
| | - Gil-Jae Cho
- College of Veterinary Medicine, Kyungpook National University, 41566, Daegu, Korea
| | - Sungho Yun
- College of Veterinary Medicine, Kyungpook National University, 41566, Daegu, Korea
| | - Wookyung Yu
- Department of Brain and Cognitive Sciences, DGIST, Daegu, Republic of Korea
| | - Se-Hyeon Han
- School of Media Communication, Hanyang University, Wangsimni-ro 222, Seongdong- gu, Seoul, South Korea.,Department of News-team, SBS (Seoul Broadcasting System), Mokdongseo-ro 161, Yangcheon-gu, Seoul, South Korea
| | - Yun-Sok Ha
- Department of Urology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Jun Nyung Lee
- Department of Urology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Tae Gyun Kwon
- Department of Urology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Dong-Hyung Cho
- School of Life Science, BK21 FOUR KNU Creative Bioresearch, Kyungpook National University, Daegu, Korea.,Brain Science and Engineering Institute, Kyungpook National University, 41566, Daegu, Republic of Korea
| | - Jun-Koo Yi
- Gyeongsangbuk-do Livestock Research institute, Yeongju, South Korea
| | - Myoung Ok Kim
- Department of Animal Science and Biotechnology, ITRD, Kyungpook National University, 37224, Sangju, Republic of Korea
| | - Zae Young Ryoo
- School of Life Science, BK21 FOUR KNU Creative Bioresearch, Kyungpook National University, Daegu, Korea.
| | - Song Park
- Core Protein Resources Center, DGIST, Daegu, Republic of Korea. .,Department of Brain and Cognitive Sciences, DGIST, Daegu, Republic of Korea.
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21
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Filppu P, Tanjore Ramanathan J, Granberg KJ, Gucciardo E, Haapasalo H, Lehti K, Nykter M, Le Joncour V, Laakkonen P. CD109-GP130 interaction drives glioblastoma stem cell plasticity and chemoresistance through STAT3 activity. JCI Insight 2021; 6:141486. [PMID: 33986188 PMCID: PMC8262342 DOI: 10.1172/jci.insight.141486] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 04/01/2021] [Indexed: 12/21/2022] Open
Abstract
Glioma stem cells (GSCs) drive propagation and therapeutic resistance of glioblastomas, the most aggressive diffuse brain tumors. However, the molecular mechanisms that maintain the stemness and promote therapy resistance remain poorly understood. Here we report CD109/STAT3 axis as crucial for the maintenance of stemness and tumorigenicity of GSCs and as a mediator of chemoresistance. Mechanistically, CD109 physically interacts with glycoprotein 130 to promote activation of the IL-6/STAT3 pathway in GSCs. Genetic depletion of CD109 abolished the stemness and self-renewal of GSCs and impaired tumorigenicity. Loss of stemness was accompanied with a phenotypic shift of GSCs to more differentiated astrocytic-like cells. Importantly, genetic or pharmacologic targeting of CD109/STAT3 axis sensitized the GSCs to chemotherapy, suggesting that targeting CD109/STAT3 axis has potential to overcome therapy resistance in glioblastoma.
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Affiliation(s)
- Pauliina Filppu
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | | | - Kirsi J. Granberg
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Science Center, Tampere University Hospital, Tampere, Finland
| | - Erika Gucciardo
- Individualized Drug Therapy Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Hannu Haapasalo
- Department of Pathology, Fimlab Laboratories, Tampere University Hospital and University of Tampere, Tampere, Finland
| | - Kaisa Lehti
- Individualized Drug Therapy Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
- Department of Biomedical Laboratory Science, Faculty of Natural Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Matti Nykter
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Vadim Le Joncour
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Pirjo Laakkonen
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Laboratory Animal Centre, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
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22
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Koh HM, Lee HJ, Kim DC. Usefulness of CD109 expression as a prognostic biomarker in patients with cancer: A systematic review and meta-analysis. Medicine (Baltimore) 2021; 100:e25006. [PMID: 33725975 PMCID: PMC7982172 DOI: 10.1097/md.0000000000025006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 02/11/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND It has been revealed that CD109 expression is associated with prognosis in cancer patients, but it remains unclear thus far. Therefore, we performed a meta-analysis in the present study for a better assessment of the prognostic role of CD109 expression in cancer patients. METHODS Eligible studies were collected through a search of the PubMed, Embase, Cochrane Library, and Scopus databases. The pooled hazard ratio (HR) with 95% confidence interval (CI) was evaluated to reveal the association between CD109 expression and overall survival (OS) in cancer patients. RESULTS Seven studies with 1583 patients were enrolled. The pooled HR with 95% CI was calculated as 2.31 (95% CI 1.93-2.76, P < .001), suggesting an association between high expression of CD109 and unfavorable OS in cancer patients. CONCLUSION This analysis indicated that CD109 expression could be used as a prognostic biomarker in cancer patients. This is the first meta-analysis to report the relationship between CD109 expression and prognosis in cancer patients.
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Affiliation(s)
- Hyun Min Koh
- Department of Pathology, Gyeongsang National University Changwon Hospital, Changwon
| | - Hyun Ju Lee
- Department of Pathology, Soonchunhyang University College of Medicine
- Department of Pathology, Soonchunhyang University Cheonan Hospital, Cheonan
| | - Dong Chul Kim
- Department of Pathology, Gyeongsang National University School of Medicine
- Department of Pathology, Gyeongsang National University Hospital
- Gyeongsang Institute of Health Science, Jinju, Republic of Korea
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23
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Lückstädt W, Bub S, Koudelka T, Pavlenko E, Peters F, Somasundaram P, Becker-Pauly C, Lucius R, Zunke F, Arnold P. Cell Surface Processing of CD109 by Meprin β Leads to the Release of Soluble Fragments and Reduced Expression on Extracellular Vesicles. Front Cell Dev Biol 2021; 9:622390. [PMID: 33738281 PMCID: PMC7960916 DOI: 10.3389/fcell.2021.622390] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 01/29/2021] [Indexed: 12/21/2022] Open
Abstract
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.
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Affiliation(s)
- Wiebke Lückstädt
- Anatomical Institute, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Simon Bub
- Anatomical Institute, Christian-Albrechts-University Kiel, Kiel, Germany
- Department of Molecular Neurology, University Hospital Erlangen, Erlangen, Germany
| | - Tomas Koudelka
- Systematic Proteomics and Bioanalytics, Institute for Experimental Medicine, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Egor Pavlenko
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Florian Peters
- Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland
| | - Prasath Somasundaram
- Systematic Proteomics and Bioanalytics, Institute for Experimental Medicine, Christian-Albrechts-University Kiel, Kiel, Germany
| | | | - Ralph Lucius
- Anatomical Institute, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Friederike Zunke
- Department of Molecular Neurology, University Hospital Erlangen, Erlangen, Germany
| | - Philipp Arnold
- Anatomical Institute, Christian-Albrechts-University Kiel, Kiel, Germany
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24
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Hagiwara S, Sasaki E, Hasegawa Y, Suzuki H, Nishikawa D, Beppu S, Terada H, Sawabe M, Takahashi M, Hanai N. Serum CD109 levels reflect the node metastasis status in head and neck squamous cell carcinoma. Cancer Med 2021; 10:1335-1346. [PMID: 33565282 PMCID: PMC7926025 DOI: 10.1002/cam4.3737] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 12/12/2020] [Accepted: 12/13/2020] [Indexed: 12/14/2022] Open
Abstract
Background Various biomarkers are being developed for the early diagnosis of cancer and for predicting its prognosis. The aim of this study is to evaluate the diagnostic significance of serum CD109 in head and neck squamous cell carcinoma (HNSCC). Methods The serum CD109 levels in a total of 112 serum samples collected before and after surgery from 56 HNSCC patients were analyzed with an enzyme‐linked immunosorbent assay (ELISA). The clinical factor that showed a statistically significant association with both the preoperative serum CD109 level, and the CD109 index: which was defined as the ratio of the preoperative serum CD109 level to the postoperative serum CD109 level, were assessed. The correlations between the serum CD109 levels and lymph node density (LND), pathological features such as lymphatic invasion, and serum SCC antigen levels were also assessed. Results The ELISA measurement revealed that preoperative serum CD109 levels were elevated in patients with node metastasis‐positive and stage IV disease, in comparison to those with node metastasis‐negative and Stage I+II+III disease, respectively. A multiple regression analysis indicated that serum CD109 level was significantly associated with the node metastasis status. A Spearman's rank correlation analysis also revealed a positive correlation between the preoperative serum CD109 level and LND. Furthermore, the probabilities of the overall and relapse‐free survival were significantly lower in patients with a preoperative serum CD109 level of ≥38.0 ng/ml and a CD109 index of ≥1.6, respectively, than in others. There was no significant correlation between the serum CD109 and SCC antigen levels. Conclusions The serum CD109 levels were elevated in patients with advanced stage disease, reflecting the node metastasis status. CD109 in sera could be a novel prognostic marker for HNSCC involving lymph node metastasis.
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Affiliation(s)
- Sumitaka Hagiwara
- Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Eiichi Sasaki
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Yasuhisa Hasegawa
- Department of Head and Neck Surgery - Otolaryngology, Asahi University Hospital, Gifu, Japan
| | - Hidenori Suzuki
- Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Daisuke Nishikawa
- Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Shintaro Beppu
- Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Hoshino Terada
- Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Michi Sawabe
- Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Masahide Takahashi
- International Center for Cell and Gene Therapy, Fujita Health University, Toyoake, Japan
| | - Nobuhiro Hanai
- Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
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25
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Lee KY, Kuo TC, Chou CM, Hsu WJ, Lee WC, Dai JZ, Wu SM, Lin CW. Upregulation of CD109 Promotes the Epithelial-to-Mesenchymal Transition and Stemness Properties of Lung Adenocarcinomas via Activation of the Hippo-YAP Signaling. Cells 2020; 10:cells10010028. [PMID: 33375719 PMCID: PMC7823273 DOI: 10.3390/cells10010028] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/17/2020] [Accepted: 12/22/2020] [Indexed: 12/12/2022] Open
Abstract
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.
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Affiliation(s)
- Kang-Yun Lee
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei 23561, Taiwan; (K.-Y.L.); (S.-M.W.)
- Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Tai-Chih Kuo
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Xing Street, Taipei 11031, Taiwan; (T.-C.K.); (C.-M.C.); (W.-J.H.); (W.-C.L.); (J.-Z.D.)
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Chih-Ming Chou
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Xing Street, Taipei 11031, Taiwan; (T.-C.K.); (C.-M.C.); (W.-J.H.); (W.-C.L.); (J.-Z.D.)
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Wen-Jing Hsu
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Xing Street, Taipei 11031, Taiwan; (T.-C.K.); (C.-M.C.); (W.-J.H.); (W.-C.L.); (J.-Z.D.)
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Wei-Cheng Lee
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Xing Street, Taipei 11031, Taiwan; (T.-C.K.); (C.-M.C.); (W.-J.H.); (W.-C.L.); (J.-Z.D.)
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Jia-Zih Dai
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Xing Street, Taipei 11031, Taiwan; (T.-C.K.); (C.-M.C.); (W.-J.H.); (W.-C.L.); (J.-Z.D.)
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Sheng-Ming Wu
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei 23561, Taiwan; (K.-Y.L.); (S.-M.W.)
| | - Cheng-Wei Lin
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Xing Street, Taipei 11031, Taiwan; (T.-C.K.); (C.-M.C.); (W.-J.H.); (W.-C.L.); (J.-Z.D.)
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Correspondence: ; Tel.: +886-2-27361661 (ext. 3160); Fax: +886-2-27356689
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26
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Taki T, Shiraki Y, Enomoto A, Weng L, Chen C, Asai N, Murakumo Y, Yokoi K, Takahashi M, Mii S. CD109 regulates in vivo tumor invasion in lung adenocarcinoma through TGF-β signaling. Cancer Sci 2020; 111:4616-4628. [PMID: 33007133 PMCID: PMC7734007 DOI: 10.1111/cas.14673] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 09/09/2020] [Accepted: 09/23/2020] [Indexed: 12/15/2022] Open
Abstract
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.
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Affiliation(s)
- Tetsuro Taki
- Department of PathologyNagoya University Graduate School of MedicineNagoyaJapan
| | - Yukihiro Shiraki
- Department of PathologyNagoya University Graduate School of MedicineNagoyaJapan
- Division of Molecular Pathology, Center for Neurological Disease and CancerNagoya University Graduate School of MedicineNagoyaJapan
| | - Atsushi Enomoto
- Department of PathologyNagoya University Graduate School of MedicineNagoyaJapan
| | - Liang Weng
- Department of PathologyNagoya University Graduate School of MedicineNagoyaJapan
| | - Chen Chen
- Department of PathologyNagoya University Graduate School of MedicineNagoyaJapan
| | - Naoya Asai
- Department of Molecular Pathology, Graduate School of MedicineFujita Health UniversityToyoakeJapan
| | - Yoshiki Murakumo
- Department of PathologyKitasato University School of MedicineSagamiharaJapan
| | - Kohei Yokoi
- Department of Thoracic SurgeryNagoya University Graduate School of MedicineNagoyaJapan
| | - Masahide Takahashi
- Department of PathologyNagoya University Graduate School of MedicineNagoyaJapan
- Division of Molecular Pathology, Center for Neurological Disease and CancerNagoya University Graduate School of MedicineNagoyaJapan
| | - Shinji Mii
- Department of PathologyNagoya University Graduate School of MedicineNagoyaJapan
- Division of Molecular Pathology, Center for Neurological Disease and CancerNagoya University Graduate School of MedicineNagoyaJapan
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27
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Mo XT, Leung THY, Tang HWM, Siu MKY, Wan PKT, Chan KKL, Cheung ANY, Ngan HYS. CD109 mediates tumorigenicity and cancer aggressiveness via regulation of EGFR and STAT3 signalling in cervical squamous cell carcinoma. Br J Cancer 2020; 123:833-843. [PMID: 32507856 PMCID: PMC7463003 DOI: 10.1038/s41416-020-0922-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 04/07/2020] [Accepted: 05/14/2020] [Indexed: 12/13/2022] Open
Abstract
Background CD109 was involved in the tumorigenesis and progression of various cancers via TGF-β1 signalling and STAT3 activation. As CD109 is strongly expressed in cervical squamous cell carcinoma, this study was conducted to investigate its functional characteristics in cervical cancer. Methods CD109 expression was examined by immunohistochemistry (IHC) with cervical tissue microarray. The effects of CD109 expression were examined on migration, cell proliferation, spheroid formation and soft-agar colony-formation assay. Meanwhile, cervical cancer cell lines with high CD109 expression were chosen for the functional study using siRNA knockdown and CRISPR/Cas9 knockout. Results IHC demonstrated an upregulation of CD109 in the cell membrane of cervical squamous cell carcinoma. CD109( + ) cells isolated by flow-cytometric sorting displayed enhanced migration, cell proliferation, sphere-forming and anchorage-independent cell growth ability. In contrast, silencing of CD109 expression could reverse the in vitro and in vivo tumorigenic and aggressive properties. Furthermore, CD109 induced EGFR-mediated STAT3 phosphorylation known to be responsible for cell migration, proliferation and maintenance of CSC phenotype. Conclusion Abundant CD109( + ) populations in cervical cancer cells potentially contributed to carcinogenesis and aggressiveness, whereas silencing of CD109 expression could reverse those properties. CD109 mediates cervical tumorigenicity and aggressiveness via CD109/EGFR/STAT3 signalling.
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Affiliation(s)
- Xue-Tang Mo
- Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region of China
| | - Thomas Ho-Yin Leung
- Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region of China
| | - Hermit Wai-Man Tang
- Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region of China
| | - Michelle Kwan-Yee Siu
- Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region of China
| | - Peter Kok-Ting Wan
- Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region of China
| | - Karen Kar-Loen Chan
- Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region of China
| | - Annie Nga-Yin Cheung
- Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region of China
| | - Hextan Yuen-Sheung Ngan
- Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region of China.
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28
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Gularyan SK, Gulin AA, Anufrieva KS, Shender VO, Shakhparonov MI, Bastola S, Antipova NV, Kovalenko TF, Rubtsov YP, Latyshev YA, Potapov AA, Pavlyukov MS. Investigation of Inter- and Intratumoral Heterogeneity of Glioblastoma Using TOF-SIMS. Mol Cell Proteomics 2020; 19:960-970. [PMID: 32265293 PMCID: PMC7261812 DOI: 10.1074/mcp.ra120.001986] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 04/06/2020] [Indexed: 11/06/2022] Open
Abstract
Glioblastoma (GBM) is one of the most aggressive human cancers with a median survival of less than two years. A distinguishing pathological feature of GBM is a high degree of inter- and intratumoral heterogeneity. Intertumoral heterogeneity of GBM has been extensively investigated on genomic, methylomic, transcriptomic, proteomic and metabolomics levels, however only a few studies describe intratumoral heterogeneity because of the lack of methods allowing to analyze GBM samples with high spatial resolution. Here, we applied TOF-SIMS (Time-of-flight secondary ion mass spectrometry) for the analysis of single cells and clinical samples such as paraffin and frozen tumor sections obtained from 57 patients. We developed a technique that allows us to simultaneously detect the distribution of proteins and metabolites in glioma tissue with 800 nm spatial resolution. Our results demonstrate that according to TOF-SIMS data glioma samples can be subdivided into clinically relevant groups and distinguished from the normal brain tissue. In addition, TOF-SIMS was able to elucidate differences between morphologically distinct regions of GBM within the same tumor. By staining GBM sections with gold-conjugated antibodies against Caveolin-1 we could visualize border between zones of necrotic and cellular tumor and subdivide glioma samples into groups characterized by different survival of the patients. Finally, we demonstrated that GBM contains cells that are characterized by high levels of Caveolin-1 protein and cholesterol. This population may partly represent a glioma stem cells. Collectively, our results show that the technique described here allows to analyze glioma tissues with a spatial resolution beyond reach of most of other omics approaches and the obtained data may be used to predict clinical behavior of the tumor.
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Affiliation(s)
- Samvel K Gularyan
- N.N. Semenov Federal Research Center for Chemical Physics, Moscow, Russia
| | - Alexander A Gulin
- N.N. Semenov Federal Research Center for Chemical Physics, Moscow, Russia; Department of Chemistry, Lomonosov Moscow State University, Moscow Russia
| | - Ksenia S Anufrieva
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia; Moscow Institute of Physics and Technology, Moscow Region, Russia
| | - Victoria O Shender
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
| | | | - Soniya Bastola
- Department of Neurosurgery, University of Alabama at Birmingham, Wallace Tumor Institute, Birmingham, Alabama
| | | | | | - Yury P Rubtsov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
| | - Yaroslav A Latyshev
- Federal State Autonomous Institution, N.N. Burdenko National Medical Research Center of Neurosurgery, Moscow, Russia
| | - Alexander A Potapov
- Federal State Autonomous Institution, N.N. Burdenko National Medical Research Center of Neurosurgery, Moscow, Russia
| | - Marat S Pavlyukov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
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29
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Hatsuzawa Y, Yamaguchi K, Takanashi T, Sato I, Tamai K, Mochizuki M, Iwai W, Wakui Y, Abue M, Yamamoto K, Yasuda J, Mizuma M, Unno M, Sugamura K. CD109 promotes the tumorigenic ability and metastatic motility of pancreatic ductal adenocarcinoma cells. Pancreatology 2020; 20:493-500. [PMID: 32007357 DOI: 10.1016/j.pan.2020.01.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 12/18/2019] [Accepted: 01/18/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND 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). METHODS 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. RESULTS 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. CONCLUSIONS CD109 plays a critical role in the promotion of tumorigenic ability and cellular motility relating to metastasis of PDAC cells.
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Affiliation(s)
- Yuuri Hatsuzawa
- Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, 9811293, Japan; Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, 9808575, Japan
| | - Kazunori Yamaguchi
- Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, 9811293, Japan; Department of Cancer Science, Tohoku University Graduate School of Medicine, Sendai, 9808575, Japan.
| | - Tomoka Takanashi
- Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, 9811293, Japan
| | - Ikuro Sato
- Department of Cancer Science, Tohoku University Graduate School of Medicine, Sendai, 9808575, Japan; Division of Pathology, Miyagi Cancer Center, Natori, 9811293, Japan
| | - Keiichi Tamai
- Department of Cancer Science, Tohoku University Graduate School of Medicine, Sendai, 9808575, Japan; Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, 9811293, Japan
| | - Mai Mochizuki
- Department of Cancer Science, Tohoku University Graduate School of Medicine, Sendai, 9808575, Japan; Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, 9811293, Japan
| | - Wataru Iwai
- Department of Gastroenterology, Miyagi Cancer Center, Natori, 9811293, Japan
| | - Yuta Wakui
- Department of Gastroenterology, Miyagi Cancer Center, Natori, 9811293, Japan
| | - Makoto Abue
- Department of Gastroenterology, Miyagi Cancer Center, Natori, 9811293, Japan
| | - Kuniharu Yamamoto
- Department of Surgery, Tohoku Medical and Pharmaceutical University, Sendai, 9838536, Japan
| | - Jun Yasuda
- Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, 9811293, Japan
| | - Masamichi Mizuma
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, 9808575, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, 9808575, Japan
| | - Kazuo Sugamura
- Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, 9811293, Japan
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Lee KY, Shueng PW, Chou CM, Lin BX, Lin MH, Kuo DY, Tsai IL, Wu SM, Lin CW. Elevation of CD109 promotes metastasis and drug resistance in lung cancer via activation of EGFR-AKT-mTOR signaling. Cancer Sci 2020; 111:1652-1662. [PMID: 32133706 PMCID: PMC7226182 DOI: 10.1111/cas.14373] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 02/19/2020] [Accepted: 02/28/2020] [Indexed: 12/15/2022] Open
Abstract
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.
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Affiliation(s)
- Kang-Yun Lee
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.,Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Pei-Wei Shueng
- Division of Radiation Oncology, Far Eastern Memorial Hospital, New Taipei City, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chih-Ming Chou
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Bo-Xing Lin
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Mei-Hsiang Lin
- Graduate Institute of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Deng-Yu Kuo
- Division of Radiation Oncology, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - I-Lin Tsai
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan
| | - Sheng-Ming Wu
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.,Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Cheng-Wei Lin
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan.,Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
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Zhu J, Li B, Xu M, Liu R, Xia T, Zhang Z, Xu Y, Liu S. Graphene Oxide Promotes Cancer Metastasis through Associating with Plasma Membrane To Promote TGF-β Signaling-Dependent Epithelial-Mesenchymal Transition. ACS NANO 2020; 14:818-827. [PMID: 31877027 DOI: 10.1021/acsnano.9b07891] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Nanomedicines are being developed to treat diverse diseases; however, inadvertent or unintended health effects have to be considered, especially for those targeting cancers. For cancers, occurrence of metastasis hints an advanced phase of cancer progression, and nanomedicines per se should be evaluated for their effects on existing metastatic tumors and triggering metastases. Graphene-based 2D nanomaterials, such as graphene oxide (GO), due to its unique characteristics, have been extensively studied for biomedical applications including cancer therapy. However, the potential effect of GO on metastasis has not been determined yet. Herein, we found that low-dose GO could induce significant morphological and structural changes of the cellular membrane within cancer cells, suggesting an epithelial-mesenchymal transition (EMT), with enhanced invasion/migration and the alterations of representative EMT indicators in GO-treated cells. These changes resulted in enhanced lung metastasis of cancer cells in various metastasis models. The mechanistic investigations unveiled that GO increased the protein levels of the TGF-β receptor, leading to a constitutively activated TGF-β-Smad2/3 signaling pathway that drives the EMT. Collectively, our findings enhance the understanding of the unintended side and detrimental effects of GO nanosheets in increasing the progression of metastatic tumors. Thus, the likelihood of pro-EMT effects upon low-dose GO exposure should be considered when developing GO nanomedicines.
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Affiliation(s)
- Jianqiang Zhu
- Department of Urology, The Second Hospital of Tianjin Medical University , Tianjin Institute of Urology , Tianjin 300211 , China
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences , Chinese Academy of Sciences , Beijing 100085 , China
| | - Bin Li
- Department of Urology, The Second Hospital of Tianjin Medical University , Tianjin Institute of Urology , Tianjin 300211 , China
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences , Chinese Academy of Sciences , Beijing 100085 , China
| | - Ming Xu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences , Chinese Academy of Sciences , Beijing 100085 , China
- University of Chinese Academy of Sciences , Beijing 100049 , China
| | - Rui Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences , Chinese Academy of Sciences , Beijing 100085 , China
- University of Chinese Academy of Sciences , Beijing 100049 , China
| | - Tian Xia
- Division of Nano Medicine, Department of Medicine , University of California Los Angeles , 10833 Le Conte Avenue , Los Angeles , California 90095 , United States
| | - Zhihong Zhang
- Department of Urology, The Second Hospital of Tianjin Medical University , Tianjin Institute of Urology , Tianjin 300211 , China
| | - Yong Xu
- Department of Urology, The Second Hospital of Tianjin Medical University , Tianjin Institute of Urology , Tianjin 300211 , China
| | - Sijin Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences , Chinese Academy of Sciences , Beijing 100085 , China
- University of Chinese Academy of Sciences , Beijing 100049 , China
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Siegfried G, Descarpentrie J, Evrard S, Khatib AM. Proprotein convertases: Key players in inflammation-related malignancies and metastasis. Cancer Lett 2019; 473:50-61. [PMID: 31899298 PMCID: PMC7115805 DOI: 10.1016/j.canlet.2019.12.027] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 12/17/2019] [Accepted: 12/18/2019] [Indexed: 12/19/2022]
Abstract
Many cancers occur from locations of inflammation due to chronic irritation and/or infection. Tumor microenvironment contains various different inflammatory cells and mediators that orchestrate diverse neoplastic processes, including proliferation, survival, adhesion and migration. In parallel, tumor cells have adapted some of the signaling molecules used by inflammatory cells, such as selectins and chemokines as well as their receptors for invasion, extravasation and subsequently metastasis. Expression and/or activation of the majority of these molecules is mediated by the proprotein convertases (PCs); proteases expressed by both tumor cells and inflammatory cells. This review analyzes the potential role of these enzymatic system in inflammation-associated cancer impacting on the malignant and metastatic potential of cancer cells, describing the possible use of PCs as a new anti-inflammatory therapeutic approach to tumor progression and metastasis.
Proteins maturation by the proprotein convertases plays important role in inflammation-related cancer and metastasis. Protein precursors require the proprotein convertases for the induction of inflammation. Understanding of the molecular mechanism linking the proprotein convertases to inflammation will allow novel therapies. Inhibitors of the proprotein convertases constitute great potential for cancer treatment.
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Affiliation(s)
- Geraldine Siegfried
- Univ. Bordeaux, 33000, Bordeaux, France; INSERM UMR1029, 33400, Pessac, France.
| | - Jean Descarpentrie
- Univ. Bordeaux, 33000, Bordeaux, France; INSERM UMR1029, 33400, Pessac, France.
| | - Serge Evrard
- Univ. Bordeaux, 33000, Bordeaux, France; Institut Bergonié, 33076, Bordeaux, France.
| | - Abdel-Majid Khatib
- Univ. Bordeaux, 33000, Bordeaux, France; INSERM UMR1029, 33400, Pessac, France.
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Jin S, Zhang L, Wei YF, Zhang HJ, Wang CY, Zou H, Hu JM, Jiang JF, Pang LJ. Pure squamous cell carcinoma of the gallbladder locally invading the liver and abdominal cavity: A case report and review of the literature. World J Clin Cases 2019; 7:4163-4171. [PMID: 31832423 PMCID: PMC6906552 DOI: 10.12998/wjcc.v7.i23.4163] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 09/30/2019] [Accepted: 10/15/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gallbladder squamous cell carcinoma (GBSCC) is a rare subtype of malignancy and accounts for only 2%-3% of gallbladder malignancies. Due to its rapid development, most patients with GBSCC initially present with an advanced stage of the disease and hence a poor prognosis. The clinicopathological and biological features of SCC remain to be fully elucidated, owing to its uncommon occurrence. The majority of currently available data only described individual case reports or series analyses of trivial cases.
CASE SUMMARY A 64-year-old man was admitted for progressively poor abdominal distension and pain. Liver computed tomography (CT) showed infiltration of gallbladder carcinoma into the adjacent liver, and enlarged retroperitoneal lymph nodes. The patient underwent radical cholecystectomy. Part of the mass was grey and soft, and the neoplastic section showed a purulent-necrotic lesion. Hematoxylin and eosin staining revealed a moderately differentiated SCC. Immunohistochemical studies showed strong staining of the tumor for AE1/3 and CK5/6. Staining for CK19, CK7, and CAM5.2 was positive in the cytoplasm. Systemic chemotherapy was not administered because of the patient’s poor physical condition. After five months, CT and magnetic resonance cholangiopancreatography showed multiple metastases in the liver and abdominal cavity.
CONCLUSION Squamous components of GBSCC may explain the complex biological behavior, and CD109 may be involved in the pathogenesis.
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Affiliation(s)
- Shan Jin
- Department of Pathology, the First Affiliated Hospital to Shihezi University School of Medicine and Shihezi University School of Medicine, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Lu Zhang
- Department of Pathology, the First Affiliated Hospital to Shihezi University School of Medicine and Shihezi University School of Medicine, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Yuan-Feng Wei
- Department of Pathology, the First Affiliated Hospital to Shihezi University School of Medicine and Shihezi University School of Medicine, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Hai-Jun Zhang
- Department of Pathology, the First Affiliated Hospital to Shihezi University School of Medicine and Shihezi University School of Medicine, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Cheng-Yan Wang
- Department of Pathology, the First Affiliated Hospital to Shihezi University School of Medicine and Shihezi University School of Medicine, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Hong Zou
- Department of Pathology, the First Affiliated Hospital to Shihezi University School of Medicine and Shihezi University School of Medicine, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Jian-Ming Hu
- Department of Pathology, the First Affiliated Hospital to Shihezi University School of Medicine and Shihezi University School of Medicine, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Jin-Fang Jiang
- Department of Pathology, the First Affiliated Hospital to Shihezi University School of Medicine and Shihezi University School of Medicine, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Li-Juan Pang
- Department of Pathology, the First Affiliated Hospital to Shihezi University School of Medicine and Shihezi University School of Medicine, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
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Song G, Feng T, Zhao R, Lu Q, Diao Y, Guo Q, Wang Z, Zhang Y, Ge L, Pan J, Wang L, Han J. CD109 regulates the inflammatory response and is required for the pathogenesis of rheumatoid arthritis. Ann Rheum Dis 2019; 78:1632-1641. [PMID: 31455659 PMCID: PMC6900259 DOI: 10.1136/annrheumdis-2019-215473] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 07/31/2019] [Accepted: 08/06/2019] [Indexed: 12/20/2022]
Abstract
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.
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Affiliation(s)
- Guanhua Song
- Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Tingting Feng
- Department of Pathology, Shandong University Medical School, Jinan, China
| | - Ru Zhao
- Department of Pathology, Shandong University Medical School, Jinan, China
| | - Qiqi Lu
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
| | - Yutao Diao
- Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Qingwei Guo
- Department of Hematology, Qilu Children's Hospital of Shandong University, Jinan, China
| | - Zhaoxia Wang
- Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Yuang Zhang
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
| | - Luna Ge
- Shandong Medicinal Biotechnology Centre, Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Key Lab for Biotechnology Drugs of Ministry of Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Jihong Pan
- Shandong Medicinal Biotechnology Centre, Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Key Lab for Biotechnology Drugs of Ministry of Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Lin Wang
- Shandong Medicinal Biotechnology Centre, Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Key Lab for Biotechnology Drugs of Ministry of Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Jinxiang Han
- Shandong Medicinal Biotechnology Centre, Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Key Lab for Biotechnology Drugs of Ministry of Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
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CD109 acts as a gatekeeper of the epithelial trait by suppressing epithelial to mesenchymal transition in squamous cell carcinoma cells in vitro. Sci Rep 2019; 9:16317. [PMID: 31695056 PMCID: PMC6834570 DOI: 10.1038/s41598-019-50694-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 01/31/2019] [Indexed: 02/07/2023] Open
Abstract
There is increasing evidence that the expression of CD109, a GPI-anchored cell surface protein is dysregulated in squamous cell carcinoma (SCC). However, the functional role of CD109 in SCC progression is poorly understood. In current study, we demonstrate that CD109 is a critical regulator of epithelial phenotype in SSC cells. CD109 levels inversely correlate with TGF-β signaling, EMT, migration, and invasion in cultured SCC cells. CRISPR/Cas9-mediated knockout CD109 (CD109 KO) in SCC cells represses epithelial traits and promotes the mesenchymal phenotype, as evidenced by elevated expression of mesenchymal proteins and markers of epithelial to mesenchymal transition. Treatment with recombinant CD109 protein causes CD109 KO cells to regain their epithelial traits. CD109 loss results in pronounced alterations of gene expression as detected by microarray analysis and in dysregulation of 15 important signalling pathways as shown by KEGG pathway cluster analysis. Validation using 52 human oral SCC tumor samples show that CD109 levels inversely correlate with tumor grade and the activation state of one such pathway, the TGF-β signaling pathway. Taken together, our findings highlight a novel role for CD109 as a gatekeeper of the epithelial phenotype by regulating TGF-β pathway in SCC cells.
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Fan J, Wang Q, Zhang Z, Sun L. Curcumin mitigates the epithelial‐to‐mesenchymal transition in biliary epithelial cells through upregulating CD109 expression. Drug Dev Res 2019; 80:992-999. [PMID: 31403228 DOI: 10.1002/ddr.21580] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 07/16/2019] [Accepted: 07/17/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Junyu Fan
- Department of Integrated Traditional Chinese and Western MedicineHuashan Hospital Affiliated to Fudan University Shanghai China
| | - Qian Wang
- Department of Rheumatology and ImmunologySixth People's Hospital Affiliated to Shanghai Jiao Tong University Shanghai China
| | - Zhuoya Zhang
- Department of Rheumatology and ImmunologyDrum Tower Hospital Affiliated to Nanjing University Nanjing China
| | - Lingyun Sun
- Department of Rheumatology and ImmunologyDrum Tower Hospital Affiliated to Nanjing University Nanjing China
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Mii S, Enomoto A, Shiraki Y, Taki T, Murakumo Y, Takahashi M. CD109: a multifunctional GPI‐anchored protein with key roles in tumor progression and physiological homeostasis. Pathol Int 2019; 69:249-259. [DOI: 10.1111/pin.12798] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 03/13/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Shinji Mii
- Department of PathologyNagoya University Graduate School of Medicine Nagoya Japan
| | - Atsushi Enomoto
- Department of PathologyNagoya University Graduate School of Medicine Nagoya Japan
| | - Yukihiro Shiraki
- Department of PathologyNagoya University Graduate School of Medicine Nagoya Japan
- Division of Molecular Pathology, Center for Neurological Disease and CancerNagoya University Graduate School of Medicine Nagoya Japan
| | - Tetsuro Taki
- Department of PathologyNagoya University Graduate School of Medicine Nagoya Japan
| | - Yoshiki Murakumo
- Department of PathologyKitasato University School of Medicine Sagamihara Japan
| | - Masahide Takahashi
- Department of PathologyNagoya University Graduate School of Medicine Nagoya Japan
- Division of Molecular Pathology, Center for Neurological Disease and CancerNagoya University Graduate School of Medicine Nagoya Japan
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Kim SY, Choi KU, Hwang C, Lee HJ, Lee JH, Shin DH, Kim JY, Sol MY, Kim JH, Kim KH, Suh DS, Kwon BS. Prognostic Significance of CD109 Expression in Patients with Ovarian Epithelial Cancer. J Pathol Transl Med 2019; 53:244-252. [PMID: 31316041 PMCID: PMC6639710 DOI: 10.4132/jptm.2019.04.16] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Accepted: 04/16/2019] [Indexed: 01/25/2023] Open
Abstract
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.
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Affiliation(s)
- So Young Kim
- Department of Pathology, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Kyung Un Choi
- Department of Pathology, Pusan National University Hospital, Busan, Korea
| | - Chungsu Hwang
- Department of Pathology, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Hyung Jung Lee
- Department of Pathology, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Jung Hee Lee
- Department of Pathology, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Dong Hoon Shin
- Department of Pathology, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Jee Yeon Kim
- Department of Pathology, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Mee Young Sol
- Department of Pathology, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Jae Ho Kim
- Department of Physiology, Pusan National University School of Medicine, Busan, Korea
| | - Ki Hyung Kim
- Department of Obstetrics and Gynecology, Pusan National University Hospital, Busan, Korea
| | - Dong Soo Suh
- Department of Obstetrics and Gynecology, Pusan National University Hospital, Busan, Korea
| | - Byung Su Kwon
- Department of Obstetrics and Gynecology, Pusan National University Hospital, Busan, Korea
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Yu H, Hackenbroch L, Meyer FRL, Reiser J, Razzazi-Fazeli E, Nöbauer K, Besenfelder U, Vogl C, Brem G, Mayrhofer C. Identification of Rabbit Oviductal Fluid Proteins Involved in Pre-Fertilization Processes by Quantitative Proteomics. Proteomics 2019; 19:e1800319. [PMID: 30637940 DOI: 10.1002/pmic.201800319] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Revised: 12/28/2018] [Indexed: 01/28/2023]
Abstract
Oviductal fluid (ODF) proteins modulate and support reproductive processes in the oviduct. In the present study, proteins involved in the biological events that precede fertilization have been identified in the rabbit ODF proteome, isolated from the ampulla and isthmus of the oviduct at different time points within 8 h after intrauterine insemination. A workflow is used that integrates lectin affinity capture with stable-isotope dimethyl labeling prior to nanoLC-MS/MS analysis. In total, over 400 ODF proteins, including 214 lectin enriched glycoproteins, are identified and quantified. Selected data are validated by Western blot analysis. Spatiotemporal alterations in the abundance of ODF proteins in response to insemination are detected by global analysis. A subset of 63 potentially biologically relevant ODF proteins is identified, including extracellular matrix components, chaperones, oxidoreductases, and immunity proteins. Functional enrichment analysis reveals an altered peptidase regulator activity upon insemination. In addition to protein identification and abundance changes, N-glycopeptide analysis further identifies 281 glycosites on 199 proteins. Taken together, these results show, for the first time, the evolving oviductal milieu early upon insemination. The identified proteins are likely those that modulate in vitro processes, including spermatozoa function.
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Affiliation(s)
- Hans Yu
- Institute of Biotechnology in Animal Production, Interuniversity Department for Agrobiotechnology (IFA Tulln), University of Natural Resources and Applied Life Sciences Vienna, 3430, Tulln, Austria.,Institute of Animal Breeding and Genetics, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, 1210, Vienna, Austria
| | - Lena Hackenbroch
- Institute of Biotechnology in Animal Production, Interuniversity Department for Agrobiotechnology (IFA Tulln), University of Natural Resources and Applied Life Sciences Vienna, 3430, Tulln, Austria.,Institute of Animal Breeding and Genetics, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, 1210, Vienna, Austria
| | - Florian R L Meyer
- Institute of Biotechnology in Animal Production, Interuniversity Department for Agrobiotechnology (IFA Tulln), University of Natural Resources and Applied Life Sciences Vienna, 3430, Tulln, Austria.,Institute of Animal Breeding and Genetics, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, 1210, Vienna, Austria
| | - Judith Reiser
- Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilian University, 85764, Munich, Germany
| | - Ebrahim Razzazi-Fazeli
- VetCore Facility for Research, University of Veterinary Medicine Vienna, 1210, Vienna, Austria
| | - Katharina Nöbauer
- VetCore Facility for Research, University of Veterinary Medicine Vienna, 1210, Vienna, Austria
| | - Urban Besenfelder
- Reproduction Centre Wieselburg, University of Veterinary Medicine Vienna, 3250, Vienna, Austria
| | - Claus Vogl
- Institute of Animal Breeding and Genetics, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, 1210, Vienna, Austria
| | - Gottfried Brem
- Institute of Biotechnology in Animal Production, Interuniversity Department for Agrobiotechnology (IFA Tulln), University of Natural Resources and Applied Life Sciences Vienna, 3430, Tulln, Austria.,Institute of Animal Breeding and Genetics, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, 1210, Vienna, Austria
| | - Corina Mayrhofer
- Institute of Biotechnology in Animal Production, Interuniversity Department for Agrobiotechnology (IFA Tulln), University of Natural Resources and Applied Life Sciences Vienna, 3430, Tulln, Austria.,Institute of Animal Breeding and Genetics, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, 1210, Vienna, Austria
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40
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Bojic S, Hallam D, Alcada N, Ghareeb A, Queen R, Pervinder S, Buck H, Amitai Lange A, Figueiredo G, Rooney P, Stojkovic M, Shortt A, Figueiredo FC, Lako M. CD200 Expression Marks a Population of Quiescent Limbal Epithelial Stem Cells with Holoclone Forming Ability. Stem Cells 2018; 36:1723-1735. [PMID: 30157305 DOI: 10.1002/stem.2903] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 08/02/2018] [Accepted: 08/09/2018] [Indexed: 12/12/2022]
Abstract
One of the main challenges in limbal stem cell (LSC) biology and transplantation is the lack of definitive cell surface markers which can be used to identify and enrich viable LSCs. In this study, expression of 361 cell surface proteins was assessed in ex vivo expanded limbal epithelial cells. One marker, CD200 was selected for further characterization based on expression in a small subset of limbal epithelial cells (2.25% ± 0.69%) and reduced expression through consecutive passaging and calcium induced differentiation. CD200 was localized to a small population of cells at the basal layer of the human and mouse limbal epithelium. CD200+ cells were slow cycling and contained the majority of side population (SP) and all the holoclone forming progenitors. CD200+ cells displayed higher expression of LSCs markers including PAX6, WNT7A, CDH3, CK14, CK15, and ABCB5 and lower expression of Ki67 when compared to CD200- . Downregulation of CD200 abrogated the ability of limbal epithelial cells to form holoclones, suggesting an important function for CD200 in the maintenance and/or self-renewal of LSCs. A second marker, CD109, which was expressed in 56.29% ± 13.96% of limbal epithelial cells, was also found to co-localize with ΔNp63 in both human and mouse cornea, albeit more abundantly than CD200. CD109 expression decreased slowly through calcium induced cell differentiation and CD109+ cells were characterized by higher expression of Ki67, when compared to CD109- subpopulation. Together our data suggest that CD200 expression marks a quiescent population of LSCs with holoclone forming potential, while CD109 expression is associated with a proliferative progenitor phenotype. Stem Cells 2018;36:1723-1735.
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Affiliation(s)
- Sanja Bojic
- Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
| | - Dean Hallam
- Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
| | - Nuno Alcada
- Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
| | - Ali Ghareeb
- Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
| | - Rachel Queen
- Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
| | - Sagoo Pervinder
- UCL Institute of Immunology and Transplantation, London, United Kingdom
| | - Harley Buck
- UCL Institute of Immunology and Transplantation, London, United Kingdom
| | - Aya Amitai Lange
- Department of Genetics and Developmental Biology, The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Gustavo Figueiredo
- Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
| | - Paul Rooney
- Tissue Services, NHS Blood and Transplant, Liverpool, United Kingdom
| | - Miodrag Stojkovic
- Faculty of Medical Sciences, Department of Genetics, University of Kragujevac, Serbia.,SPEBO Medical, Leskovac, Kragujevac, Serbia
| | - Alex Shortt
- UCL Institute of Immunology and Transplantation, London, United Kingdom
| | - Francisco C Figueiredo
- Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.,Department of Ophthalmology, Royal Victoria Infirmary, Newcastle University, Newcastle, United Kingdom
| | - Majlinda Lako
- Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
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41
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Mii S, Hoshino A, Enomoto A, Murakumo Y, Ito M, Yamaguchi A, Takahashi M. CD109 deficiency induces osteopenia with an osteoporosis-like phenotype in vivo. Genes Cells 2018; 23:590-598. [PMID: 29767469 DOI: 10.1111/gtc.12593] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 04/13/2018] [Indexed: 12/16/2022]
Abstract
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.
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Affiliation(s)
- Shinji Mii
- Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akiyoshi Hoshino
- Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Tokyo Metropolitan Police Hospital, Tokyo, Japan
| | - Atsushi Enomoto
- Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshiki Murakumo
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Masako Ito
- Center for Diversity and Inclusion, Nagasaki University, Nagasaki, Japan
| | - Akira Yamaguchi
- Oral Health Science Center, Tokyo Dental College, Tokyo, Japan
| | - Masahide Takahashi
- Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Qi R, Dong F, Liu Q, Murakumo Y, Liu J. CD109 and squamous cell carcinoma. J Transl Med 2018; 16:88. [PMID: 29625613 PMCID: PMC5889571 DOI: 10.1186/s12967-018-1461-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Accepted: 03/27/2018] [Indexed: 12/16/2022] Open
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.
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Affiliation(s)
- Ruixia Qi
- Taishan Medical College, Tai'an, Shandong, China.,Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan, 250014, Shandong, China
| | - Fengyun Dong
- Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan, 250014, Shandong, China
| | - Qiang Liu
- Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan, 250014, Shandong, China
| | - Yoshiki Murakumo
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Ju Liu
- Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan, 250014, Shandong, China.
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43
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Suppression of skin tumorigenesis in CD109-deficient mice. Oncotarget 2018; 7:82836-82850. [PMID: 27756876 PMCID: PMC5347736 DOI: 10.18632/oncotarget.12653] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 10/02/2016] [Indexed: 12/17/2022] Open
Abstract
CD109 is a glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed in several types of human cancers, particularly squamous cell carcinomas. We previously reported that CD109-deficient mice exhibit epidermal hyperplasia and chronic skin inflammation. Although we found that CD109 regulates differentiation of keratinocytes in vivo, the function of CD109 in tumorigenesis remains unknown. In this study, we investigated the role of CD109 in skin tumorigenesis using a two-stage carcinogenesis model in CD109-deficient mice with chronic skin inflammation. Immunohistochemical analysis revealed a higher level of TGF-β protein expression in the dermis of CD109-deficient mice than in that of wild-type mice. Additionally, immunofluorescence analysis showed that Smad2 phosphorylation and Nrf2 expression were enhanced in primary keratinocytes from CD109-deficient mice compared with in those from wild-type mice. Although no significant difference was found in conversion rates from papilloma to carcinoma between wild-type and CD109-deficient mice in the carcinogenesis model, we observed fewer and smaller papillomas in CD109-deficient mice than in wild-type mice. Apoptosis and DNA damage marker levels were significantly reduced in CD109-deficient skin compared with in wild-type skin at 24 h after 7, 12-dimethylbenz (α) anthracene treatment. Furthermore, mutation-specific PCR revealed that the mutation frequency of the H-ras gene was less in CD109-deficient skin than in wild-type skin in this model. These results suggest that CD109 deficiency suppresses skin tumorigenesis by enhancing TGF-β/Smad/Nrf2 pathway activity and decreasing the mutation frequency of the H-ras gene.
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Shiraki Y, Mii S, Enomoto A, Momota H, Han YP, Kato T, Ushida K, Kato A, Asai N, Murakumo Y, Aoki K, Suzuki H, Ohka F, Wakabayashi T, Todo T, Ogawa S, Natsume A, Takahashi M. Significance of perivascular tumour cells defined by CD109 expression in progression of glioma. J Pathol 2017; 243:468-480. [DOI: 10.1002/path.4981] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 07/29/2017] [Accepted: 09/05/2017] [Indexed: 12/11/2022]
Affiliation(s)
- Yukihiro Shiraki
- Department of Pathology; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Shinji Mii
- Department of Pathology; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Atsushi Enomoto
- Department of Pathology; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Hiroyuki Momota
- Division of Innovative Cancer Therapy, The Institute of Medical Science; The University of Tokyo; Tokyo Japan
| | - Yi-Peng Han
- Department of Pathology; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Takuya Kato
- Department of Pathology; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Kaori Ushida
- Department of Pathology; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Akira Kato
- Department of Neurosurgery; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Naoya Asai
- Department of Pathology; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Yoshiki Murakumo
- Department of Pathology; Kitasato University School of Medicine; Sagamihara Japan
| | - Kosuke Aoki
- Department of Neurosurgery; Nagoya University Graduate School of Medicine; Nagoya Japan
- Department of Pathology and Tumor Biology, Graduate School of Medicine; Kyoto University; Kyoto Japan
| | - Hiromichi Suzuki
- Department of Neurosurgery; Nagoya University Graduate School of Medicine; Nagoya Japan
- Department of Pathology and Tumor Biology, Graduate School of Medicine; Kyoto University; Kyoto Japan
| | - Fumiharu Ohka
- Department of Neurosurgery; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Toshihiko Wakabayashi
- Department of Neurosurgery; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Tomoki Todo
- Division of Innovative Cancer Therapy, The Institute of Medical Science; The University of Tokyo; Tokyo Japan
| | - Seishi Ogawa
- Department of Pathology and Tumor Biology, Graduate School of Medicine; Kyoto University; Kyoto Japan
| | - Atsushi Natsume
- Department of Neurosurgery; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Masahide Takahashi
- Department of Pathology; Nagoya University Graduate School of Medicine; Nagoya Japan
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45
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De Vita A, Recine F, Mercatali L, Miserocchi G, Liverani C, Spadazzi C, Casadei R, Bongiovanni A, Pieri F, Riva N, Amadori D, Ibrahim T. Myxofibrosarcoma primary cultures: molecular and pharmacological profile. Ther Adv Med Oncol 2017; 9:755-767. [PMID: 29449896 PMCID: PMC5808841 DOI: 10.1177/1758834017737472] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 09/22/2017] [Indexed: 12/29/2022] Open
Abstract
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.
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Affiliation(s)
- Alessandro De Vita
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Federica Recine
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Laura Mercatali
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Piero Maroncelli 40, 47014 Meldola (FC), Italy
| | - Giacomo Miserocchi
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Chiara Liverani
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Chiara Spadazzi
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Roberto Casadei
- Department of Orthopedics, Istituto Ortopedico Rizzoli, University of Bologna, Bologna, Italy
| | - Alberto Bongiovanni
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Federica Pieri
- Pathology Unit, Morgagni-Pierantoni Hospital, Forlì, Italy
| | - Nada Riva
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Dino Amadori
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Toni Ibrahim
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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46
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Dong F, Wang J, Xu Y, Cheng Z, Chen X, Wang Y, Liu J. CD109 expression is upregulated in penile squamous cell carcinoma. Oncol Lett 2017; 14:6012-6016. [PMID: 29113239 PMCID: PMC5661394 DOI: 10.3892/ol.2017.6975] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 07/28/2017] [Indexed: 01/07/2023] Open
Abstract
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.
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Affiliation(s)
- Fengyun Dong
- Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Jin Wang
- School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China.,Department of Urology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Yinghua Xu
- Taishan Medical College, Tai'an, Shandong 271021, P.R. China
| | - Zuowang Cheng
- Taishan Medical College, Tai'an, Shandong 271021, P.R. China
| | - Xiaocui Chen
- Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Yifan Wang
- Weifang Medical College, Weifang, Shandong 261053, P.R. China
| | - Ju Liu
- Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
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47
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Zhou Y, Sun W, Chen N, Xu C, Wang X, Dong K, Zhang B, Zhang J, Hao N, Sun A, Wei H, He F, Jiang Y. Discovery of NKCC1 as a potential therapeutic target to inhibit hepatocellular carcinoma cell growth and metastasis. Oncotarget 2017; 8:66328-66342. [PMID: 29029515 PMCID: PMC5630415 DOI: 10.18632/oncotarget.20240] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 07/11/2017] [Indexed: 01/20/2023] Open
Abstract
Metastasis is the essential cause for the high mortality of hepatocellular carcinoma (HCC). In order to investigate the mechanism of metastasis, and to discover therapeutic targets for HCC, the quantitative proteomic technique was applied to characterize the plasma membrane proteins of two HCC cell lines with low (MHCC97L) or high (MHCC97H) metastatic potentials. One of the plasma membrane proteins, sodium-potassium-chloride cotransporter 1 (NKCC1), was upregulated in MHCC97H cell line. Immunohistochemistry result in HCC patients showed that NKCC1 expression was associated with poor differentiation and microvascular invasion. Knockdown of NKCC1 via RNA interference reduced HCC cell proliferation and invasion abilities in vitro and in vivo, whereas over-expression of NKCC1 significantly increased HCC cell proliferation and invasion abilities in vitro and in vivo. Additionally, blocking NKCC1 activity with bumetanide attenuated the proliferation and invasion abilities of HCC cells in vitro and limited the HCC growth in vivo. Further results suggested that NKCC1 promotes the invasion ability via MMP-2 activity, and that the WNK1/OSR1/NKCC1 signal pathway might play roles in HCC metastasis. For the first time, our study demonstrated that NKCC1 plays a role in HCC metastasis, and could be served as a potential target to inhibit HCC cell growth and metastasis.
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Affiliation(s)
- Yaya Zhou
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, P. R. China
| | - Wei Sun
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, P. R. China
| | - Ning Chen
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, P. R. China
| | - Chen Xu
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, P. R. China
| | - Xinxin Wang
- Department of Pathology, Beijing Youan Hospital of Capital Medical University, Beijing 100069, P. R. China
| | - Kun Dong
- Department of Pathology, Beijing Youan Hospital of Capital Medical University, Beijing 100069, P. R. China
| | - Binxue Zhang
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, P. R. China
| | - Jian Zhang
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, P. R. China
| | - Ning Hao
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, P. R. China
| | - Aihua Sun
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, P. R. China
| | - Handong Wei
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, P. R. China
| | - Fuchu He
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, P. R. China.,Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P. R. China
| | - Ying Jiang
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, P. R. China
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48
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Chuang CH, Greenside PG, Rogers ZN, Brady JJ, Yang D, Ma RK, Caswell DR, Chiou SH, Winters AF, Grüner BM, Ramaswami G, Spencley AL, Kopecky KE, Sayles LC, Sweet-Cordero EA, Li JB, Kundaje A, Winslow MM. Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis. Nat Med 2017; 23:291-300. [PMID: 28191885 DOI: 10.1038/nm.4285] [Citation(s) in RCA: 124] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 01/18/2017] [Indexed: 12/14/2022]
Abstract
Lung cancer is the leading cause of cancer deaths worldwide, with the majority of mortality resulting from metastatic spread. However, the molecular mechanism by which cancer cells acquire the ability to disseminate from primary tumors, seed distant organs, and grow into tissue-destructive metastases remains incompletely understood. We combined tumor barcoding in a mouse model of human lung adenocarcinoma with unbiased genomic approaches to identify a transcriptional program that confers metastatic ability and predicts patient survival. Small-scale in vivo screening identified several genes, including Cd109, that encode novel pro-metastatic factors. We uncovered signaling mediated by Janus kinases (Jaks) and the transcription factor Stat3 as a critical, pharmacologically targetable effector of CD109-driven lung cancer metastasis. In summary, by coupling the systematic genomic analysis of purified cancer cells in distinct malignant states from mouse models with extensive human validation, we uncovered several key regulators of metastatic ability, including an actionable pro-metastatic CD109-Jak-Stat3 axis.
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Affiliation(s)
- Chen-Hua Chuang
- Department of Genetics, Stanford University School of Medicine, Stanford, California, USA
| | - Peyton G Greenside
- Biomedical Informatics Training Program, Stanford University School of Medicine, Stanford, California, USA
| | - Zoë N Rogers
- Department of Genetics, Stanford University School of Medicine, Stanford, California, USA
| | - Jennifer J Brady
- Department of Genetics, Stanford University School of Medicine, Stanford, California, USA
| | - Dian Yang
- Cancer Biology Program, Stanford University School of Medicine, Stanford, California, USA
| | - Rosanna K Ma
- Department of Genetics, Stanford University School of Medicine, Stanford, California, USA
| | - Deborah R Caswell
- Cancer Biology Program, Stanford University School of Medicine, Stanford, California, USA
| | - Shin-Heng Chiou
- Department of Genetics, Stanford University School of Medicine, Stanford, California, USA
| | - Aidan F Winters
- Department of Genetics, Stanford University School of Medicine, Stanford, California, USA
| | - Barbara M Grüner
- Department of Genetics, Stanford University School of Medicine, Stanford, California, USA
| | - Gokul Ramaswami
- Department of Genetics, Stanford University School of Medicine, Stanford, California, USA
| | - Andrew L Spencley
- Cancer Biology Program, Stanford University School of Medicine, Stanford, California, USA
| | - Kimberly E Kopecky
- Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Leanne C Sayles
- Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA
| | - E Alejandro Sweet-Cordero
- Cancer Biology Program, Stanford University School of Medicine, Stanford, California, USA.,Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA
| | - Jin Billy Li
- Department of Genetics, Stanford University School of Medicine, Stanford, California, USA
| | - Anshul Kundaje
- Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.,Department of Computer Science, Stanford University, Stanford, California, USA
| | - Monte M Winslow
- Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.,Cancer Biology Program, Stanford University School of Medicine, Stanford, California, USA.,Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
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49
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Yokoyama M, Ichinoe M, Okina S, Sakurai Y, Nakada N, Yanagisawa N, Jiang SX, Numata Y, Umezawa A, Miyazaki K, Higashihara M, Murakumo Y. CD109, a negative regulator of TGF-β signaling, is a putative risk marker in diffuse large B-cell lymphoma. Int J Hematol 2016; 105:614-622. [PMID: 28032275 DOI: 10.1007/s12185-016-2173-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Revised: 12/20/2016] [Accepted: 12/21/2016] [Indexed: 12/16/2022]
Abstract
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.
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Affiliation(s)
- Maki Yokoyama
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.,Department of Hematology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Masaaki Ichinoe
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Sosei Okina
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.,Department of Hematology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yasutaka Sakurai
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Norihiro Nakada
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Nobuyuki Yanagisawa
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Shi-Xu Jiang
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Yoshiko Numata
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Atsuko Umezawa
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Koji Miyazaki
- Department of Transfusion and Cell Transplantation, Kitasato University School of Medicine, Sagamihara, Japan
| | - Masaaki Higashihara
- Department of Hematology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yoshiki Murakumo
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.
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50
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CD109 Mediates Cell Survival in Hepatocellular Carcinoma Cells. Dig Dis Sci 2016; 61:2303-2314. [PMID: 27074923 DOI: 10.1007/s10620-016-4149-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Accepted: 03/28/2016] [Indexed: 01/16/2023]
Abstract
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.
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