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Hazra R, Chattopadhyay S, Mallick A, Gayen S, Roy S. Unravelling CD24-Siglec-10 pathway: Cancer immunotherapy from basic science to clinical studies. Immunology 2024; 173:442-469. [PMID: 39129256 DOI: 10.1111/imm.13847] [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: 03/22/2024] [Accepted: 07/27/2024] [Indexed: 08/13/2024] Open
Abstract
Cancer immunotherapy has revolutionized the treatment landscape by harnessing the power of the immune system to combat malignancies. Two of the most promising players in this field are cluster of differentiation 24 (CD24) and sialic acid-binding Ig-like lectin 10 (Siglec-10), and both of them play pivotal roles in modulating immune responses. CD24, a cell surface glycoprotein, emerges as a convincing fundamental signal transducer for therapeutic intervention, given its significant implication in the processes related to tumour progression and immunogenic evasion. Additionally, the immunomodulatory functions of Siglec-10, a prominent member within the Siglec family of immune receptors, have recently become a crucial point of interest, particularly in the context of the tumour microenvironment. Hence, the intricate interplay of both CD24 and Siglec-10 assumes a critical role in fostering tumour growth, facilitating metastasis and also orchestrating immune evasion. Recent studies have found multiple evidences supporting the therapeutic potential of targeting CD24 in cancer treatment. Siglec-10, on the other hand, exhibits immunosuppressive properties that contribute to immune tolerance within the tumour microenvironment. Therefore, we delve into the complex mechanisms through which Siglec-10 modulates immune responses and facilitates immune escape in cancer. Siglec-10 also acts as a viable target for cancer immunotherapy and presents novel avenues for the development of therapeutic interventions. Furthermore, we examine the synergy between CD24 and Siglec-10 in shaping the immunosuppressive tumour microenvironment and discuss the implications for combination therapies. Therefore, understanding the roles of CD24 and Siglec-10 in cancer immunotherapy opens exciting possibilities for the development of novel therapeutics.
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Affiliation(s)
- Rudradeep Hazra
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
| | - Soumyadeep Chattopadhyay
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
| | - Arijit Mallick
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
| | - Sakuntala Gayen
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
| | - Souvik Roy
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
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Zhao K, Wu C, Li X, Niu M, Wu D, Cui X, Zhao H. From mechanism to therapy: the journey of CD24 in cancer. Front Immunol 2024; 15:1401528. [PMID: 38881902 PMCID: PMC11176514 DOI: 10.3389/fimmu.2024.1401528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 04/25/2024] [Indexed: 06/18/2024] Open
Abstract
CD24 is a glycosylphosphatidylinositol-anchored protein that is expressed in a wide range of tissues and cell types. It is involved in a variety of physiological and pathological processes, including cell adhesion, migration, differentiation, and apoptosis. Additionally, CD24 has been studied extensively in the context of cancer, where it has been found to play a role in tumor growth, invasion, and metastasis. In recent years, there has been growing interest in CD24 as a potential therapeutic target for cancer treatment. This review summarizes the current knowledge of CD24, including its structure, function, and its role in cancer. Finally, we provide insights into potential clinical application of CD24 and discuss possible approaches for the development of targeted cancer therapies.
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Affiliation(s)
- Kai Zhao
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Caifeng Wu
- Department of Hand and Foot, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiangjun Li
- Department of Breast Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Mengchao Niu
- Department of Operation Room, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Dan Wu
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaofeng Cui
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hai Zhao
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
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Lee YJ, Kim WR, Park EG, Lee DH, Kim JM, Shin HJ, Jeong HS, Roh HY, Kim HS. Exploring the Key Signaling Pathways and ncRNAs in Colorectal Cancer. Int J Mol Sci 2024; 25:4548. [PMID: 38674135 PMCID: PMC11050203 DOI: 10.3390/ijms25084548] [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: 03/29/2024] [Revised: 04/19/2024] [Accepted: 04/19/2024] [Indexed: 04/28/2024] Open
Abstract
Colorectal cancer (CRC) is the third most prevalent cancer to be diagnosed, and it has a substantial mortality rate. Despite numerous studies being conducted on CRC, it remains a significant health concern. The disease-free survival rates notably decrease as CRC progresses, emphasizing the urgency for effective diagnostic and therapeutic approaches. CRC development is caused by environmental factors, which mostly lead to the disruption of signaling pathways. Among these pathways, the Wingless/Integrated (Wnt) signaling pathway, Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway, Mitogen-Activated Protein Kinase (MAPK) signaling pathway, Transforming Growth Factor-β (TGF-β) signaling pathway, and p53 signaling pathway are considered to be important. These signaling pathways are also regulated by non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). They have emerged as crucial regulators of gene expression in CRC by changing their expression levels. The altered expression patterns of these ncRNAs have been implicated in CRC progression and development, suggesting their potential as diagnostic and therapeutic targets. This review provides an overview of the five key signaling pathways and regulation of ncRNAs involved in CRC pathogenesis that are studied to identify promising avenues for diagnosis and treatment strategies.
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Affiliation(s)
- Yun Ju Lee
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (Y.J.L.); (W.R.K.); (E.G.P.); (D.H.L.); (J.-m.K.); (H.J.S.); (H.-s.J.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea;
| | - Woo Ryung Kim
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (Y.J.L.); (W.R.K.); (E.G.P.); (D.H.L.); (J.-m.K.); (H.J.S.); (H.-s.J.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea;
| | - Eun Gyung Park
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (Y.J.L.); (W.R.K.); (E.G.P.); (D.H.L.); (J.-m.K.); (H.J.S.); (H.-s.J.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea;
| | - Du Hyeong Lee
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (Y.J.L.); (W.R.K.); (E.G.P.); (D.H.L.); (J.-m.K.); (H.J.S.); (H.-s.J.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea;
| | - Jung-min Kim
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (Y.J.L.); (W.R.K.); (E.G.P.); (D.H.L.); (J.-m.K.); (H.J.S.); (H.-s.J.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea;
| | - Hae Jin Shin
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (Y.J.L.); (W.R.K.); (E.G.P.); (D.H.L.); (J.-m.K.); (H.J.S.); (H.-s.J.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea;
| | - Hyeon-su Jeong
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (Y.J.L.); (W.R.K.); (E.G.P.); (D.H.L.); (J.-m.K.); (H.J.S.); (H.-s.J.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea;
| | - Hyun-Young Roh
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea;
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea
| | - Heui-Soo Kim
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea;
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea
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4
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Wang H, Shi P, Shi X, Lv Y, Xie H, Zhao H. Surprising magic of CD24 beyond cancer. Front Immunol 2024; 14:1334922. [PMID: 38313430 PMCID: PMC10834733 DOI: 10.3389/fimmu.2023.1334922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 12/28/2023] [Indexed: 02/06/2024] Open
Abstract
CD24 has emerged as a molecule of significant interest beyond the oncological arena. Recent studies have unveiled its surprising and diverse roles in various biological processes and diseases. This review encapsulates the expanding spectrum of CD24 functions, delving into its involvement in immune regulation, cancer immune microenvironment, and its potential as a therapeutic target in autoimmune diseases and beyond. The 'magic' of CD24, once solely attributed to cancer, now inspires a new paradigm in understanding its multifunctionality in human health and disease, offering exciting prospects for medical advancements.
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Affiliation(s)
- He Wang
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Peng Shi
- Department of Emergency Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xinyu Shi
- Department of Radiology, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yaqing Lv
- Department of Outpatient, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hongwei Xie
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hai Zhao
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
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5
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Chen W, Hu Z, Guo Z. Targeting CD24 in Cancer Immunotherapy. Biomedicines 2023; 11:3159. [PMID: 38137380 PMCID: PMC10740697 DOI: 10.3390/biomedicines11123159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/19/2023] [Accepted: 11/22/2023] [Indexed: 12/24/2023] Open
Abstract
Immunotherapy is a hot area in cancer treatment, and one of the keys to this therapy is the identification of the right tumour-associated or tumour-specific antigen. Cluster of differentiation 24 (CD24) is an emerging tumour-associated antigen that is commonly and highly expressed in various tumours. In addition, CD24 is associated with several cancer-related signalling pathways and closely interacts with other molecules and immune cells to influence tumour progression. Monoclonal antibodies, antibody-drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, and CAR-NK cell therapy are currently available for the treatment of CD24. In this review, we summarise the existing therapeutic approaches and possible future directions targeting CD24.
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Affiliation(s)
| | - Zhigang Hu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210023, China;
| | - Zhigang Guo
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210023, China;
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6
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Yang Y, Zhu G, Yang L, Yang Y. Targeting CD24 as a novel immunotherapy for solid cancers. Cell Commun Signal 2023; 21:312. [PMID: 37919766 PMCID: PMC10623753 DOI: 10.1186/s12964-023-01315-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 09/13/2023] [Indexed: 11/04/2023] Open
Abstract
Cluster of differentiation 24 (CD24), a mucin-like highly glycosylated molecule has been extensively studied as a cancer stem cell marker in a variety of solid cancers. The functional role of CD24 is either fulfilled by combining with ligands or participating in signal transduction, which mediate the initiation and progression of neoplasms. Recently, CD24 was also described as an innate immune checkpoint with apparent significance in several types of solid cancers. Herein, we review the current understanding of the molecular fundamentals of CD24, the role of CD24 in tumorigenesis and cancer progression, the possibility as a promising therapeutic target and summarized different therapeutic agents or strategies targeting CD24 in solid cancers. Video Abstract.
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Affiliation(s)
- Yan Yang
- Xinxiang Engineering Technology Research Center of Tumor-Targeted Drug Development, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453000, Henan, China
| | - Guangming Zhu
- Clinical Laboratory, The First People's Hospital of Taian, Taian 271000, Shandong, China
| | - Li Yang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou Key Laboratory of Endometrial Disease Prevention and Treatment Zhengzhou China, Zhengzhou, 450052, Henan, China
| | - Yun Yang
- Xinxiang Engineering Technology Research Center of Tumor-Targeted Drug Development, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453000, Henan, China.
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Guo Q, Pan K, Qiu P, Liu Z, Chen J, Lin J. Identification of an exosome-related signature associated with prognosis and immune infiltration in breast cancer. Sci Rep 2023; 13:18198. [PMID: 37875600 PMCID: PMC10598067 DOI: 10.1038/s41598-023-45325-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 10/18/2023] [Indexed: 10/26/2023] Open
Abstract
Exosomes, nanosized vesicles, play a vital role in breast cancer (BC) occurrence, development, and drug resistance. Hence, we proceeded to study the potential prognostic value of exosome-related genes and their relationship to the immune microenvironment in BC. 121 exosome-related genes were provided by the ExoBCD database, and 7 final genes were selected to construct the prognostic signature. Besides, the expression levels of the 7 exosome-related genes were validated by the experiment in BC cell lines. Based on the signature, BC patients from the training and validation cohorts were separated into low- and high-risk groups. Subsequently, the R clusterProfiler package was applied to identify the distinct enrichment pathways between high-risk groups and low-risk groups. The relevance of the tumor immune microenvironment and exosome-related gene risk score were analyzed in BC. Eventually, the different expression levels of immune checkpoint-related genes were compared between the two risk groups. Based on the risk model, the low-risk groups were identified with a higher survival rate both in the training and validation cohorts. A better overall survival was revealed in patients with higher scores evaluated by the estimation of stromal and immune cells in malignant tumor tissues using expression (ESTIMATE) algorithm. Subsequently, BC patients with lower risk scores were indicated by higher expression levels of some immune checkpoint-related genes and immune cell infiltration. Exosomes are closely associated with the prognosis and immune cell infiltration of BC. These findings may contribute to improving immunotherapy and provide a new vision for BC treatment strategies.
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Affiliation(s)
- Qiaonan Guo
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Kelun Pan
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Pengjun Qiu
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Zundong Liu
- Stem Cell Laboratory, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Jianpeng Chen
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Jianqing Lin
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.
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Wang Y, Yu H, Yu M, Liu H, Zhang B, Wang Y, Zhao S, Xia Q. CD24 blockade as a novel strategy for cancer treatment. Int Immunopharmacol 2023; 121:110557. [PMID: 37379708 DOI: 10.1016/j.intimp.2023.110557] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 05/22/2023] [Accepted: 06/21/2023] [Indexed: 06/30/2023]
Abstract
The CD24 protein is a heat-stable protein with a small core that undergoes extensive glycosylation. It is expressed on the surface of various normal cells, including lymphocytes, epithelial cells, and inflammatory cells. CD24 exerts its function by binding to different ligands. Numerous studies have demonstrated the close association of CD24 with tumor occurrence and progression. CD24 not only facilitates tumor cell proliferation, metastasis, and immune evasion but also plays a role in tumor initiation, thus, serving as a marker on the surface of cancer stem cells (CSCs). Additionally, CD24 induces drug resistance in various tumor cells following chemotherapy. To counteract the tumor-promoting effects of CD24, several treatment strategies targeting CD24 have been explored, such as the use of CD24 monoclonal antibodies (mAb) alone, the combination of CD24 and chemotoxic drugs, or the combination of these drugs with other targeted immunotherapeutic techniques. Regardless of the approach, targeting CD24 has demonstrated significant anti-tumor effects. Therefore, the present study focuses on anti-tumor therapy and provides a comprehensive review of the structure and fundamental physiological function of CD24 and its impact on tumor development, and suggests that targeting CD24 may represent an effective strategy for treating malignant tumors.
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Affiliation(s)
- Yawen Wang
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China; Henan Medical Key Laboratory of Tumor Pathology and Artificial Intelligence Diagnosis, Zhengzhou 450008, China; Zhengzhou Key Laboratory of Accurate Pathological Diagnosis of Intractable Tumors, Zhengzhou 450008, China; Henan Engineering Research Center of Pathological Diagnostic Antibody, Zhengzhou 450008, China
| | - Haoran Yu
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China; Henan Medical Key Laboratory of Tumor Pathology and Artificial Intelligence Diagnosis, Zhengzhou 450008, China; Zhengzhou Key Laboratory of Accurate Pathological Diagnosis of Intractable Tumors, Zhengzhou 450008, China; Henan Engineering Research Center of Pathological Diagnostic Antibody, Zhengzhou 450008, China
| | - Mengyuan Yu
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China; Henan Medical Key Laboratory of Tumor Pathology and Artificial Intelligence Diagnosis, Zhengzhou 450008, China; Zhengzhou Key Laboratory of Accurate Pathological Diagnosis of Intractable Tumors, Zhengzhou 450008, China; Henan Engineering Research Center of Pathological Diagnostic Antibody, Zhengzhou 450008, China
| | - Hui Liu
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China
| | - Bing Zhang
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China; Zhengzhou Key Laboratory of Accurate Pathological Diagnosis of Intractable Tumors, Zhengzhou 450008, China
| | - Yuanyuan Wang
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China; Henan Medical Key Laboratory of Tumor Pathology and Artificial Intelligence Diagnosis, Zhengzhou 450008, China; Zhengzhou Key Laboratory of Accurate Pathological Diagnosis of Intractable Tumors, Zhengzhou 450008, China
| | - Simin Zhao
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China; Henan Medical Key Laboratory of Tumor Pathology and Artificial Intelligence Diagnosis, Zhengzhou 450008, China; Zhengzhou Key Laboratory of Accurate Pathological Diagnosis of Intractable Tumors, Zhengzhou 450008, China.
| | - Qingxin Xia
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China; Henan Medical Key Laboratory of Tumor Pathology and Artificial Intelligence Diagnosis, Zhengzhou 450008, China; Zhengzhou Key Laboratory of Accurate Pathological Diagnosis of Intractable Tumors, Zhengzhou 450008, China; Henan Engineering Research Center of Pathological Diagnostic Antibody, Zhengzhou 450008, China.
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Emerging phagocytosis checkpoints in cancer immunotherapy. Signal Transduct Target Ther 2023; 8:104. [PMID: 36882399 PMCID: PMC9990587 DOI: 10.1038/s41392-023-01365-z] [Citation(s) in RCA: 118] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 01/31/2023] [Accepted: 02/14/2023] [Indexed: 03/09/2023] Open
Abstract
Cancer immunotherapy, mainly including immune checkpoints-targeted therapy and the adoptive transfer of engineered immune cells, has revolutionized the oncology landscape as it utilizes patients' own immune systems in combating the cancer cells. Cancer cells escape immune surveillance by hijacking the corresponding inhibitory pathways via overexpressing checkpoint genes. Phagocytosis checkpoints, such as CD47, CD24, MHC-I, PD-L1, STC-1 and GD2, have emerged as essential checkpoints for cancer immunotherapy by functioning as "don't eat me" signals or interacting with "eat me" signals to suppress immune responses. Phagocytosis checkpoints link innate immunity and adaptive immunity in cancer immunotherapy. Genetic ablation of these phagocytosis checkpoints, as well as blockade of their signaling pathways, robustly augments phagocytosis and reduces tumor size. Among all phagocytosis checkpoints, CD47 is the most thoroughly studied and has emerged as a rising star among targets for cancer treatment. CD47-targeting antibodies and inhibitors have been investigated in various preclinical and clinical trials. However, anemia and thrombocytopenia appear to be formidable challenges since CD47 is ubiquitously expressed on erythrocytes. Here, we review the reported phagocytosis checkpoints by discussing their mechanisms and functions in cancer immunotherapy, highlight clinical progress in targeting these checkpoints and discuss challenges and potential solutions to smooth the way for combination immunotherapeutic strategies that involve both innate and adaptive immune responses.
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Panagiotou E, Syrigos NK, Charpidou A, Kotteas E, Vathiotis IA. CD24: A Novel Target for Cancer Immunotherapy. J Pers Med 2022; 12:jpm12081235. [PMID: 36013184 PMCID: PMC9409925 DOI: 10.3390/jpm12081235] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 07/25/2022] [Accepted: 07/26/2022] [Indexed: 12/31/2022] Open
Abstract
Cluster of differentiation 24 (CD24) is a small, highly glycosylated cell adhesion protein that is normally expressed by immune as well as epithelial, neural, and muscle cells. Tumor CD24 expression has been linked with alterations in several oncogenic signaling pathways. In addition, the CD24/Siglec-10 interaction has been implicated in tumor immune evasion, inhibiting macrophage-mediated phagocytosis as well as natural killer (NK) cell cytotoxicity. CD24 blockade has shown promising results in preclinical studies. Although there are limited data on efficacy, monoclonal antibodies against CD24 have demonstrated clinical safety and tolerability in two clinical trials. Other treatment modalities evaluated in the preclinical setting include antibody–drug conjugates and chimeric antigen receptor (CAR) T cell therapy. In this review, we summarize current evidence and future perspectives on CD24 as a potential target for cancer immunotherapy.
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11
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Chen Y, Pan X, Tian B, Hu Y. Polysaccharide immunization and colorectal cancer: A systematic review and network meta-analysis. Front Nutr 2022; 9:961507. [PMID: 35938128 PMCID: PMC9354139 DOI: 10.3389/fnut.2022.961507] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 07/04/2022] [Indexed: 12/24/2022] Open
Abstract
Polysaccharides have a variety of biological activities, and in the anti-tumor field, they produce tumor suppressive effects by regulating the polarization of tumor-associated macrophages (TAMs). In immunotherapy, it has significant activities in modulating cytokines and antibody production. We reviewed them and selected CD24, an immune target, for meta-analysis with colorectal cancer (CRC) to investigate the correlation between CD24 expression and CRC. Correlation of CD24 positive expression with clinical-pathological features: age, sex, Duke’s stage, diameter, depth of invasion, degree of differentiation, and lymph node metastasis. It showed that: CD24 expression in CRC was significantly correlated with advanced nuclear grade of CRC, lymph node metastasis, Duke’s stage of CRC and age of CRC patients, while there was no significant correlation with gender, tumor diameter and invasion depth. The aim is to clarify the specific mechanism of polysaccharide immune anti-tumor, combined with targeted site-specific anti-solid tumor.
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Affiliation(s)
- Yuefeng Chen
- Department of Medical College of Shaoxing University, Shaoxing, China
| | - Xinnan Pan
- Department of Medical College of Wenzhou Medical University, Wenzhou, China
| | - Baoming Tian
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou, China
- Zhejiang Institute of Modern TCM and Natural Medicine Co., Ltd., Hangzhou, China
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- *Correspondence: Baoming Tian,
| | - Yajun Hu
- Department of Medical College of Shaoxing University, Shaoxing, China
- Yajun Hu,
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12
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Pashirzad M, Sathyapalan T, Sheikh A, Kesharwani P, Sahebkar A. Cancer stem cells: An overview of the pathophysiological and prognostic roles in colorectal cancer. Process Biochem 2022. [DOI: 10.1016/j.procbio.2022.02.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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13
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Ni YH, Zhao X, Wang W. CD24, A Review of its Role in Tumor Diagnosis, Progression and Therapy. Curr Gene Ther 2021; 20:109-126. [PMID: 32576128 DOI: 10.2174/1566523220666200623170738] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 05/28/2020] [Accepted: 06/02/2020] [Indexed: 02/08/2023]
Abstract
CD24, is a mucin-like GPI-anchored molecules. By immunohistochemistry, it is widely detected in many solid tumors, such as breast cancers, genital system cancers, digestive system cancers, neural system cancers and so on. The functional roles of CD24 are either fulfilled by combination with ligands or participate in signal transduction, which mediate the initiation and progression of neoplasms. However, the character of CD24 remains to be intriguing because there are still opposite voices about the impact of CD24 on tumors. In preclinical studies, CD24 target therapies, including monoclonal antibodies, target silencing by RNA interference and immunotherapy, have shown us brighten futures on the anti-tumor application. Nevertheless, evidences based on clinical studies are urgently needed. Here, with expectancy to spark new ideas, we summarize the relevant studies about CD24 from a tumor perspective.
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Affiliation(s)
- Yang-Hong Ni
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu 610041, Sichuan, China
| | - Xia Zhao
- Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, 610041, China
| | - Wei Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu 610041, Sichuan, China
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Wu H, Liu J, Wang Z, Yuan W, Chen L. Prospects of antibodies targeting CD47 or CD24 in the treatment of glioblastoma. CNS Neurosci Ther 2021; 27:1105-1117. [PMID: 34363319 PMCID: PMC8446212 DOI: 10.1111/cns.13714] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 07/25/2021] [Accepted: 07/26/2021] [Indexed: 02/06/2023] Open
Abstract
Glioma is a malignant tumor with the highest incidence among all brain tumors (about 46% of intracranial tumors) and is the most common primary intracranial tumor. Among them, glioblastoma (GBM) is highly malignant and is one of the three refractory tumors with the highest mortality rate in the world. The survival time from glioblastoma diagnosis to death is only 14–16 months for patients with standard treatment such as surgery plus radiotherapy and chemotherapy. Due to its high malignancy and poor prognosis, in‐depth studies have been conducted to explore effective therapeutic strategies for glioblastoma. In addition to the conventional surgery, radiotherapy, and chemotherapy, the glioblastoma treatments also include targeted therapy, immunotherapy, and electric field treatment. However, current treatment methods provide limited benefits because of the heterogeneity of glioblastoma and the complexity of the immune microenvironment within a tumor. Therefore, seeking an effective treatment plan is imperative. In particular, developing an active immunotherapy for glioblastoma has become an essential objective in the field. This article reviews the feasibility of CD47/CD24 antibody treatment, either individually or in combination, to target the tumor stem cells and the antitumor immunity in glioblastoma. The potential mechanisms underlying the antitumor effects of CD47/CD24 antibodies are also discussed.
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Affiliation(s)
- Hao Wu
- The Third Xiangya Hospital of Central South University, Changsha, China.,Chinese PLA General Hospital and PLA Medical College, Chinese PLA Institute of Neurosurgery, Beijing, China
| | - Jialin Liu
- Chinese PLA General Hospital and PLA Medical College, Chinese PLA Institute of Neurosurgery, Beijing, China
| | - Zhifei Wang
- The Third Xiangya Hospital of Central South University, Changsha, China
| | - Wen Yuan
- Zhuzhou Central Hospital, Zhuzhou, China
| | - Ling Chen
- Chinese PLA General Hospital and PLA Medical College, Chinese PLA Institute of Neurosurgery, Beijing, China
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15
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Nitzan K, Toledano R, Shapira S, Arber N, Doron R. Behavioral Characterizing of CD24 Knockout Mouse-Cognitive and Emotional Alternations. J Pers Med 2021; 11:105. [PMID: 33562144 PMCID: PMC7915412 DOI: 10.3390/jpm11020105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 01/31/2021] [Accepted: 02/02/2021] [Indexed: 11/17/2022] Open
Abstract
CD24 is a small, glycophosphatidylinositol-anchored cell surface protein, mostly investigated with respect to cancer, inflammation, and autoimmune diseases. CD24 knockdown or inhibition has been used to test various biochemical mechanisms and neurological conditions; however, the association between CD24 and behavioral phenotypes has not yet been examined. This study aims to characterize cognitive and emotional functions of CD24 knockout mice (CD24-/-) compared with CD24 wild-type mice at three time-points: adolescence, young adulthood, and adulthood. Our results show that CD24-/- mice exhibited better cognitive performance and less anxiety-like behavior compared with WT mice, with no effect on depression-like behavior. This phenotype was constant from childhood (2 months old) to adulthood (6 months old). The results from our study suggest that CD24 may influence important behavioral aspects at the whole-organism level, which should be taken into consideration when using CD24 knockout models.
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Affiliation(s)
- Keren Nitzan
- Department of Education and Psychology, The Open University Israel, Rannana 4353701, Israel; (K.N.); (R.T.)
| | - Roni Toledano
- Department of Education and Psychology, The Open University Israel, Rannana 4353701, Israel; (K.N.); (R.T.)
| | - Shiran Shapira
- The Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel; (S.S.); (N.A.)
- Department of Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Nadir Arber
- The Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel; (S.S.); (N.A.)
- Department of Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Ravid Doron
- Department of Education and Psychology, The Open University Israel, Rannana 4353701, Israel; (K.N.); (R.T.)
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16
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Yin SS, Gao FH. Molecular Mechanism of Tumor Cell Immune Escape Mediated by CD24/Siglec-10. Front Immunol 2020; 11:1324. [PMID: 32765491 PMCID: PMC7379889 DOI: 10.3389/fimmu.2020.01324] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 05/26/2020] [Indexed: 12/11/2022] Open
Abstract
Tumor immune escape is an important part of tumorigenesis and development. Tumor cells can develop a variety of immunosuppressive mechanisms to combat tumor immunity. Exploring tumor cells that escape immune surveillance through the molecular mechanism of related immunosuppression in-depth is helpful to develop the treatment strategies of targeted tumor immune escape. The latest studies show that CD24 on the surface of tumor cells interacts with Siglec-10 on the surface of immune cells to promote the immune escape of tumor cells. It is necessary to comment on the molecular mechanism of inhibiting the activation of immune cells through the interaction between CD24 on tumor cells and Siglec-10 on immune cells, and a treatment strategy of tumors through targeting CD24 on the surface of tumor cells or Siglec-10 on immune cells.
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Affiliation(s)
- Shan-Shan Yin
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Feng-Hou Gao
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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17
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Cha BS, Park KS, Park JS. Signature mRNA markers in extracellular vesicles for the accurate diagnosis of colorectal cancer. J Biol Eng 2020; 14:4. [PMID: 32042310 PMCID: PMC7001337 DOI: 10.1186/s13036-020-0225-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 01/21/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND With the increasing incidence of colorectal cancer (CRC), its accurate diagnosis is critical and in high demand. However, conventional methods are not ideal due to invasiveness and low accuracy. Herein, we aimed to identify efficient CRC mRNA markers in a non-invasive manner using CRC-derived extracellular vesicles (EVs). The expression levels of EV mRNAs from cancer cell lines were compared with those of a normal cell line using quantitative polymerase chain reaction. Eight markers were evaluated in plasma EVs from CRC patients and healthy controls. The diagnostic value of each marker, individually or in combination, was then determined using recessive operating characteristics analyses and the Mann-Whitney U test. RESULTS Eight mRNA markers (MYC, VEGF, CDX2, CD133, CEA, CK19, EpCAM, and CD24) were found to be more abundant in EVs derived from cancer cell lines compared to control cell lines. A combination of VEGF and CD133 showed the highest sensitivity (100%), specificity (80%), and accuracy (93%) and an area under the curve of 0.96; hence, these markers were deemed to be the CRC signature. Moreover, this signature was found to be highly expressed in CRC-derived EVs compared to healthy controls. CONCLUSIONS VEGF and CD133 mRNAs comprise a unique CRC signature in EVs that has the potential to act as a novel, non-invasive, and accurate biomarker that would improve the current diagnostic platform for CRC, while also serving to strengthen the value of EV mRNA as diagnostic markers for myriad of diseases.
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Affiliation(s)
- Byung Seok Cha
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, Republic of Korea
| | - Ki Soo Park
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, Republic of Korea
| | - Jun Seok Park
- School of Medicine, Kyungpook National University, Daegu, Republic of Korea
- Colorectal Cancer Center, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea
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18
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Yang SH, Hu MH, Wu CC, Chen CW, Sun YH, Yang KC. CD24 expression indicates healthier phenotype and less tendency of cellular senescence in human nucleus pulposus cells. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:3021-3028. [PMID: 31334674 DOI: 10.1080/21691401.2019.1642205] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Identification of specific cell markers is crucial for recognizing functionally healthy nucleus pulposus (NP) cells. The objective of this study was to investigate the role of CD24 expression in adult human NP cells. Cells were retrieved from NP tissues of 20 patients (aged 17-44) operated on for lumbar disc herniation. Based on CD24 expression, NP cells were separated by sorting and then used to examine phenotypic behavior, the effects of culture conditions and cellular senescence pathway related proteins. CD24 expression was positive in 35.5 ± 3.7% (range 9.1-65.2%) of NP cells. Consistently, normoxic expansion and serial passages in monolayers decreased percentage positivity for CD24 in NP cells. CD24- NP cells showed a markedly decreased GSK-3β activity and increased mitogen-activated protein kinase phosphorylation accompanying by an increased β-catenin expression. Higher levels of matrix metalloproteinases, as well as lower levels of ACAN and COL2 in CD24- cells, indicated the breakdown and reduced the formation of key extracellular matrix components. CD24+ NP cells presented a more favorable phenotype while CD24- cells showed a more prominent cellular senescence fate. CD24 in NP cells may be a surrogate marker of healthy cells, in the cell-based therapeutic treatment of degenerative disc disorders.
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Affiliation(s)
- Shu-Hua Yang
- a Department of Orthopedics, National Taiwan University College of Medicine and National Taiwan University Hospital , Taipei , Taiwan
| | - Ming-Hsiao Hu
- a Department of Orthopedics, National Taiwan University College of Medicine and National Taiwan University Hospital , Taipei , Taiwan
| | - Chang-Chin Wu
- a Department of Orthopedics, National Taiwan University College of Medicine and National Taiwan University Hospital , Taipei , Taiwan
| | - Chih-Wei Chen
- a Department of Orthopedics, National Taiwan University College of Medicine and National Taiwan University Hospital , Taipei , Taiwan
| | - Yuan-Hui Sun
- a Department of Orthopedics, National Taiwan University College of Medicine and National Taiwan University Hospital , Taipei , Taiwan
| | - Kai-Chiang Yang
- b Department of Dental Technology, College of Oral Medicine, Taipei Medical University , Taipei , Taiwan
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19
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Zhuo J, Wang X. Combination of targeting CD24 and inhibiting autophagy suppresses the proliferation and enhances the apoptosis of colorectal cancer cells. Mol Med Rep 2019; 20:539-548. [PMID: 31180548 PMCID: PMC6579989 DOI: 10.3892/mmr.2019.10288] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 04/17/2019] [Indexed: 12/20/2022] Open
Abstract
CD24 can regulate angiogenesis, drug sensitivity and the progression of colorectal cancer (CRC). However, whether CD24 regulates autophagy and apoptosis in CRC cells remains to be fully elucidated. The present study investigated the functional role of the altered expression of CD24 in the autophagy and apoptosis of HCT116 and HT29 human CRC cells. The results revealed lower expression levels of CD24 in HCT116 cells but higher levels in HT29 cells. Inducing the overexpression or the knockdown of CD24 did not affect the viability or spontaneous apoptosis of HCT116 and HT29 cells, respectively. Induction of the overexpression of CD24 significantly decreased the relative expression levels of Beclin‑1, autophagy‑related (Atg)3 and Atg5, and the numbers of microtubule‑associated protein‑1 light chain‑3 (LC3)‑positive puncta, but increased the expression of p62 in HCT116 cells. By contrast, CD24 silencing increased the expression of Beclin‑1, Atg3 and Atg5, and the numbers of LC3‑positive puncta, but decreased the expression of p62 in HT29 cells. Treatment with 3‑methyladenine, or the knockdown of Atg5 by specific small interfering RNA to attenuate autophagy significantly enhanced the viability of CD24‑overexpressing HCT116 cells, but reduced the viability of CD24‑silenced HT29 cells, relative to their controls. As a result, the attenuation of autophagy significantly decreased the frequency of apoptotic CD24‑overexpressing HCT116 cells, but increased the percentages of apoptotic CD24‑silenced HT29 cells. The overexpression of CD24 promoted the activation of nuclear factor (NF)‑κBp65, whereas CD24 silencing attenuated its activation in CRC cells. Inhibition of the activation of NF‑κB enhanced the CD24 overexpression‑induced decrease in autophagy, but attenuated the CD24 silencing‑induced increase in autophagy in CRC cells. Therefore, CD24 inhibited the autophagy of CRC cells, and the combination of targeting CD24 and inhibiting autophagy promoted the apoptosis of CRC cells. Conceivably, these findings may aid in the design of novel therapies for the intervention of CRC.
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Affiliation(s)
- Jingwei Zhuo
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Xinying Wang
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
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20
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Hüser L, Sachindra S, Granados K, Federico A, Larribère L, Novak D, Umansky V, Altevogt P, Utikal J. SOX2-mediated upregulation of CD24 promotes adaptive resistance toward targeted therapy in melanoma. Int J Cancer 2018; 143:3131-3142. [PMID: 29905375 DOI: 10.1002/ijc.31609] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 04/06/2018] [Accepted: 05/03/2018] [Indexed: 12/19/2022]
Abstract
Melanoma is often characterized by a constitutively active RAS-RAF-MEK-ERK pathway. For targeted therapy, BRAF inhibitors are available that are powerful in the beginning but resistance occurs rather fast. A better understanding of the mechanisms of resistance is urgently needed to increase the success of the treatment. Here, we observed that SOX2 and CD24 are upregulated upon BRAF inhibitor treatment. A similar upregulation was seen in targeted therapy-resistant, melanoma-derived induced pluripotent cancer cells (iPCCs). SOX2 and CD24 are known to promote an undifferentiated and cancer stem cell-like phenotype associated with resistance. We, therefore, elucidated the role of SOX2 and CD24 in targeted therapy resistance in more detail. We found that the upregulation of SOX2 and CD24 required activation of STAT3 and that SOX2 induced the expression of CD24 by binding to its promoter. We find that the overexpression of SOX2 or CD24 significantly increases the resistance toward BRAF inhibitors, while SOX2 knock-down rendered cells more sensitivity toward treatment. The overexpression of CD24 or SOX2 induced Src and STAT3 activity. Importantly, by either CD24 knock-down or Src/STAT3 inhibition in resistant SOX2-overexpressing cells, the sensitivity toward BRAF inhibitors was re-established. Hence, we suggest a novel mechanism of adaptive resistance whereby BRAF inhibition is circumvented via the activation of STAT3, SOX2 and CD24. Thus, to prevent adaptive resistance, it might be beneficial to combine Src/STAT3 inhibitors together with MAPK pathway inhibitors.
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Affiliation(s)
- Laura Hüser
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, D-68135, Germany
| | - Sachindra Sachindra
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, D-68135, Germany
| | - Karol Granados
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, D-68135, Germany
| | - Aniello Federico
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, D-68135, Germany
| | - Lionel Larribère
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, D-68135, Germany
| | - Daniel Novak
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, D-68135, Germany
| | - Viktor Umansky
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, D-68135, Germany
| | - Peter Altevogt
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, D-68135, Germany
| | - Jochen Utikal
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, D-68135, Germany
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21
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Tarhriz V, Bandehpour M, Dastmalchi S, Ouladsahebmadarek E, Zarredar H, Eyvazi S. Overview of CD24 as a new molecular marker in ovarian cancer. J Cell Physiol 2018; 234:2134-2142. [PMID: 30317611 DOI: 10.1002/jcp.27581] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 09/18/2018] [Indexed: 02/06/2023]
Abstract
Ovarian cancer (OC) is the fifth leading cause of cancer-related death among women. The high mortality rate is due to lack of early symptoms, late diagnosis, limited treatment options, and also emerging of drug resistance. Todays, molecular markers have become promising in tumor-targeted therapy. Several molecular markers have been known in OC immunotherapy. Identification of the specific molecular markers with prognostic significance is interested. CD24 is a small sialoglycoprotein which is localized in lipid rafts through its glycosylphosphatidylinositol (GPI) anchor. It has been reported that CD24 is overexpressed in many cancers including OC. Also, CD24 is identified as a cancer stem cell marker in OC. The CD24 expression is associated with the development, invasion, and metastasis of cancer cells. The exact role of CD24 in cancer cells is not clearly understood. Recently, CD24 has been identified as an independent prognostic marker of survival in patients with OC. In this study, we reviewed the molecular targets in OC immune-targeted therapy and also presented an overview of the new molecular marker CD24 and its association with the OC by reviewing the recent literature.
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Affiliation(s)
- Vahideh Tarhriz
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mojgan Bandehpour
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Siavoush Dastmalchi
- Biotechnology Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.,Faculty of Pharmacy, Near East University, Nicosia, North Cyprus, Turkey
| | - Elaheh Ouladsahebmadarek
- Women's Reproductive Health Research Center, Clinical Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Habib Zarredar
- Tuberculosis and Lung Disease Research Center, Clinical Institute, Tabriz University of Medical Science, Tabriz, Iran
| | - Shirin Eyvazi
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Biotechnology Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
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22
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Eyvazi S, Kazemi B, Bandehpour M, Dastmalchi S. Identification of a novel single chain fragment variable antibody targeting CD24-expressing cancer cells. Immunol Lett 2017; 190:240-246. [DOI: 10.1016/j.imlet.2017.08.028] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Revised: 05/29/2017] [Accepted: 08/28/2017] [Indexed: 02/06/2023]
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23
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Soni P, Qayoom S, Husain N, Kumar P, Chandra A, Ojha BK, Gupta RK. CD24 and Nanog expression in Stem Cells in Glioblastoma: Correlation with Response to Chemoradiation and Overall Survival. Asian Pac J Cancer Prev 2017; 18:2215-2219. [PMID: 28843258 PMCID: PMC5697483 DOI: 10.22034/apjcp.2017.18.8.2215] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Background and aim: Glioblastoma (GBM) is one of the most common and aggressive brain tumors with a median survival of 12-14 months. The aim of present study was to evaluate the gene expression profile of stem cell markers Nanog and CD24 in GBM and to determine its relationship to outcome in terms of treatment response and overall survival. Material and methods: This was a retrospective as well as retrospective study which included 51 histologically confirmed cases of GBM. Expression of CD24, and Nanog was evaluated by RT-PCR. Control tissue included debrided brain tissue from open head injury cases. All cases of GBM underwent total surgical resection and subsequently chemotherapy. Immediate treatment response was evaluated at 3 months using Response Evaluation Criteria In Solid Tumors (RECIST) guidelines and overall survival was measured at 36 months. Result: As compared to control gene, expression of CD24 and Nanog was seen to be unregulated to 24.5% and 31.7% respectively. However, the difference in mean expression of cases and controls was not statistically significant. Correlation between expressions of these two markers was also not statistically significant. On univariate cox regression analysis, cases with >2 fold expression of CD24 and Nanog had significantly poor survival as compared to those with <2 fold expression. On multivariate analysis > 2 fold CD24 expression had a statistically significant correlation with poor survival. Conclusion: An overexpression of CD24 by more than two fold was associated with poor overall survival in GBM. Poor survival may be related to increased “stemness” of tumour cells. Targeted therapy inclusive of drugs targeting stem cells directly or indirectly may be a promising therapeutic option.
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Affiliation(s)
- Priyanka Soni
- Department of Pathology, Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
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24
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Highly tumorigenic hepatocellular carcinoma cell line with cancer stem cell-like properties. PLoS One 2017; 12:e0171215. [PMID: 28152020 PMCID: PMC5289561 DOI: 10.1371/journal.pone.0171215] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 01/18/2017] [Indexed: 12/21/2022] Open
Abstract
There are limited numbers of models to study hepatocellular carcinoma (HCC) in vivo in immunocompetent hosts. In an effort to develop a cell line with improved tumorigenicity, we derived a new cell line from Hepa1-6 cells through an in vivo passage in C57BL/6 mice. The resulting Dt81Hepa1-6 cell line showed enhanced tumorigenicity compared to Hepa1-6 with more frequent (28±12 vs. 0±0 lesions at 21 days) and more rapid tumor development (21 (100%) vs. 70 days (10%)) in C57BL/6 mice. The minimal Dt81Hepa1-6 cell number required to obtain visible tumors was 100,000 cells. The Dt81Hepa1-6 cell line showed high hepatotropism with subcutaneous injection leading to liver tumors without development of tumors in lungs or spleen. In vitro, Dt81Hepa1-6 cells showed increased anchorage-independent growth (34.7±6.8 vs. 12.3±3.3 colonies; P<0.05) and increased EpCAM (8.7±1.1 folds; P<0.01) and β-catenin (5.4±1.0 folds; P<0.01) expression. A significant proportion of Dt81Hepa1-6 cells expressed EpCAM compared to Hepa1-6 (34.8±1.1% vs 0.9±0.13%; P<0.001). Enriched EpCAM+ Dt81Hepa1-6 cells led to higher tumor load than EpCAM- Dt81Hepa1-6 cells (1093±74 vs 473±100 tumors; P<0.01). The in vivo selected Dt81Hepa1-6 cell line shows high liver specificity and increased tumorigenicity compared to Hepa1-6 cells. These properties are associated with increased expression of EpCAM and β-catenin confirming that EpCAM+ HCC cells comprise a subset with characteristics of tumor-initiating cells with stem/progenitor cell features. The Dt81Hepa1-6 cell line with its cancer stem cell-like properties will be a useful tool for the study of hepatocellular carcinoma in vivo.
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25
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Abbas M, Saeed F, Anjum FM, Afzaal M, Tufail T, Bashir MS, Ishtiaq A, Hussain S, Suleria HAR. Natural polyphenols: An overview. INTERNATIONAL JOURNAL OF FOOD PROPERTIES 2016. [DOI: 10.1080/10942912.2016.1220393] [Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Munawar Abbas
- Institute of Home and Food Sciences, Government College University, Faisalabad, Pakistan
| | - Farhan Saeed
- Institute of Home and Food Sciences, Government College University, Faisalabad, Pakistan
| | - Faqir Muhammad Anjum
- Institute of Home and Food Sciences, Government College University, Faisalabad, Pakistan
| | - Muhammad Afzaal
- Institute of Home and Food Sciences, Government College University, Faisalabad, Pakistan
| | - Tabussam Tufail
- Institute of Home and Food Sciences, Government College University, Faisalabad, Pakistan
| | - Muhammad Shakeel Bashir
- Institute of Agricultural Sciences, Department of Food Science and Nutrition, University of the Punjab, Lahore-Pakistan, King Saud University, Riyadh, SA
| | - Adnan Ishtiaq
- Institute of Agricultural Sciences, Department of Food Science and Nutrition, University of the Punjab, Lahore-Pakistan, King Saud University, Riyadh, SA
| | - Shahzad Hussain
- UQ School of Medicine, The University of Queensland, Australia
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26
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The CD24 surface antigen in neural development and disease. Neurobiol Dis 2016; 99:133-144. [PMID: 27993646 DOI: 10.1016/j.nbd.2016.12.011] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 12/12/2016] [Accepted: 12/15/2016] [Indexed: 12/11/2022] Open
Abstract
A cell's surface molecular signature enables its reciprocal interactions with the associated microenvironments in development, tissue homeostasis and pathological processes. The CD24 surface antigen (heat-stable antigen, nectadrin; small cell lung cancer antigen cluster-4) represents a prime example of a neural surface molecule that has long been known, but whose diverse molecular functions in intercellular communication we have only begun to unravel. Here, we briefly summarize the molecular fundamentals of CD24 structure and provide a comprehensive review of CD24 expression and functional studies in mammalian neural developmental systems and disease models (rodent, human). Striving for an integrated view of the intracellular signaling processes involved, we discuss the most pertinent routes of CD24-mediated signaling pathways and functional networks in neurobiology (neural migration, neurite extension, neurogenesis) and pathology (tumorigenesis, multiple sclerosis).
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27
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Shapira S, Ben-Amotz O, Sher O, Kazanov D, Mashiah J, Kraus S, Gur E, Arber N. Delayed Wound Healing in Heat Stable Antigen (HSA/CD24)-Deficient Mice. PLoS One 2015; 10:e0139787. [PMID: 26440795 PMCID: PMC4594912 DOI: 10.1371/journal.pone.0139787] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 09/17/2015] [Indexed: 12/19/2022] Open
Abstract
Background Healthy individuals rarely have problems with wound healing. Most skin lesions heal rapidly and efficiently within one to two weeks. However, many medical and surgical complications can be attributed to deficiencies in wound repair. Open wounds have lost the barrier that protects tissues from bacterial invasion and allows the escape of vital fluids. Without expeditious healing, infections become more frequent. The CD24 gene encodes a heavily-glycosylated cell surface protein anchored to the membrane by phosphatidylinositol. CD24 plays an important role in the adaptive immune response and controls an important genetic checkpoint for homeostasis and autoimmune diseases in both mice and humans. We have previously shown that overexpression of CD24 results in increased proliferation and migration rates. Aim To examine the role of CD24 in the wound healing process. Methods An excisional model of wound healing was used and delayed wound healing was studied in genetically modified heat stable antigen (HSA/CD24)-deficient mice (HSA-/-) compared to wild-type (WT) mice. Results Large full-thickness skin wounds, excised on the back of mice, exhibited a significant delay in the formation of granulation tissue, and in wound closure when compared to their WTHSA+/+ littermates. Wounds were histologically analyzed and scored, based on the degree of cellular invasion, granulation tissue formation, vascularity, and re-epithelialization. Additionally, in stitched wounds, the HSA-/- mice failed to maintain their stitches; they did not hold and fell already 24 hours, revealing erythematous wound fields. Re-expression of HSA, delivered by lentivirus, restored the normal healing phenotype, within 24 hours post-injury, and even improved the healing in WT, and in BalbC mice. Conclusions Delayed wound-healing in the absence of HSA/CD24 suggests that CD24 plays an important role in this process. Increased expression of CD24, even in the normal state, may be used to enhance wound repair.
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Affiliation(s)
- Shiran Shapira
- The Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Oded Ben-Amotz
- The Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Department of Plastic and Reconstructive Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Osnat Sher
- Unit of Bone and Soft Tissue Oncology, The Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Dina Kazanov
- The Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Jacob Mashiah
- Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Sarah Kraus
- The Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Eyal Gur
- Department of Plastic and Reconstructive Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Nadir Arber
- The Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- * E-mail:
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Tanaka T, Terai Y, Kogata Y, Ashihara K, Maeda K, Fujiwara S, Yoo S, Tanaka Y, Tsunetoh S, Sasaki H, Kanemura M, Tanabe A, Ohmichi M. CD24 expression as a marker for predicting clinical outcome and invasive activity in uterine cervical cancer. Oncol Rep 2015; 34:2282-8. [PMID: 26351781 PMCID: PMC4583540 DOI: 10.3892/or.2015.4257] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Accepted: 07/08/2015] [Indexed: 01/06/2023] Open
Abstract
CD24, a small heavily glycosylated mucin-like glycosylphosphatidylinositol-anchored cell surface protein, plays an important role in the carcinogenesis of various human malignancies. However, its function in cervical cancer remains unclear. The aim of the present study was to evaluate the expression of CD24 clinicopathologically and to analyze its functional behavior biologically in cervical cancer. A total of 117 uterine cervical cancer tumors were immunohistochemically analyzed using a CD24 monoclonal antibody on paraffin blocks. We also examined whether CD24 enhanced the invasive activity or the Akt, ERK, NF-κB and MMP activity in a uterine cervical cancer cell line (CaSki) by a western blot analysis. The patients with enhanced CD24 expression had a higher rate of advanced clinical stage (50 vs. 16.5%, p<0.01), lymph node metastasis (34.6 vs. 14.3%) and lymphovascular involvement (65.4 vs. 20.4%, p=0.01), and a poor overall and disease-free survival (5-year survival rate: 62 vs. 86%, p=0.03). CD24 overexpression in CaSki cells resulted in activation of Cell Signaling proteins, including Akt, ERK, NF-κB and MMP-9. An invasion assay showed that CD24 overexpression in CaSki cells led to increased invasion ability. The CD24 overexpression also increased mRNA expression of Slug but not Snail. Moreover, the CD24 overexpression also decreased expression of E-cadherin and increased N-cadherin protein levels. Increased expression of CD24 may be associated with tumor progression and prognosis in patients with uterine cervical cancer. CD24 expression may therefore be used not only as a prognostic marker in uterine cervical cancer, but also as a target for the development of new therapeutic approaches.
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Affiliation(s)
- Tomohito Tanaka
- Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Yoshito Terai
- Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Yuhei Kogata
- Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Keisuke Ashihara
- Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Kazuya Maeda
- Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Satoe Fujiwara
- Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Saha Yoo
- Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Yoshimichi Tanaka
- Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Satoshi Tsunetoh
- Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Hiroshi Sasaki
- Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Masanori Kanemura
- Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Akiko Tanabe
- Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Masahide Ohmichi
- Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
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Wang YC, Wang JL, Kong X, Sun TT, Chen HY, Hong J, Fang JY. CD24 mediates gastric carcinogenesis and promotes gastric cancer progression via STAT3 activation. Apoptosis 2015; 19:643-56. [PMID: 24327257 DOI: 10.1007/s10495-013-0949-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The development of gastric cancer (GC) is a complex multistep process, including numerous genetic and epigenetic changes. CD24 is associated with enhanced invasiveness of GC and a poor prognosis. However, the mechanism by which CD24 induces GC progression remains poorly characterized. Here, we found that the expression of CD24 gradually increased in samples of normal gastric mucosa, non-atrophic chronic gastritis, chronic atrophic gastritis (CAG), CAG with intestinal metaplasia, dysplasia and GC. Moreover, the knockdown of CD24 induced significant levels of apoptosis in GC cells via the mitochondrial apoptotic pathway. CD24 may also promote cellular invasion and regulate the expression of E-cadherin, fibronectin and vitamin D receptor in GC cells. The activation of signal transducer and activator of transcription 3 (STAT3) may mediate CD24-induced GC survival and invasion in vitro. Furthermore, CD24-induced GC progression and STAT3 activation could also be detected in vivo and in clinical GC tissues samples. Taken together, our results indicate that CD24 mediates gastric carcinogenesis and may promote GC progression by suppressing apoptosis and promoting invasion, with the activation of STAT3 playing a critical role.
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Affiliation(s)
- Ying-Chao Wang
- GI Division, Ren Ji Hospital, School of Medicine, Shanghai Jiao-Tong University, Shanghai Institution of Digestive Disease, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao-Tong University), State Key Laboratory of Oncogene and Related Genes, 145 Middle Shandong Rd., Shanghai, 200001, China
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Shen Y, Lu B, Zhang S, Ma ZJ. Diterpenoid C of Radix Curcumae: an inhibitor of proliferation and inducer of apoptosis in human colon adenocarcinoma cells acting via inhibiting MAPK signaling pathway. PHARMACEUTICAL BIOLOGY 2014; 52:1158-1165. [PMID: 24646305 DOI: 10.3109/13880209.2013.879907] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
CONTEXT Radix Curcumae is a traditional Chinese medicine that possesses antitumor properties, from which a new compound, diterpenoid C, was previously isolated and characterized. OBJECTIVE In this study, using human colon adenocarcinoma SW620 cells, we further investigated the antitumor effects of diterpenoid C and the underlying mechanisms. MATERIALS AND METHODS Cell proliferation was assessed with the MTT assay. Cell apoptosis and cell-cycle progression were analyzed with flow cytometry. The expression of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK), and their phosphorylated forms, as well as caspase-3 protein levels were examined with Western blots. RESULTS Diterpenoid C could inhibit the proliferation of SW620 cells in a dose- and time-dependent manner. The median inhibitory concentration (IC50) at 24, 48, and 72 h were 28.31, 15.58, and 6.14 μg/ml, respectively. The inhibition of proliferation was found to be statistically significant as compared with the well-established drugs 5-fluorouracil (5-Fu) and oxaliplatin (L-OHP) (p < 0.01). Diterpenoid C also induced apoptosis and arrested cell cycle. It showed the highest apoptosis rate (98.20 ± 0.91%) at 70 μg/ml, at 72 h. Meanwhile, diterpenoid C suppressed the phosphorylation of ERK, JNK, and p38 MAPK proteins, and markedly induced the cleavage of caspase 3. DISCUSSION AND CONCLUSION Diterpenoid C inhibits proliferation and induces apoptosis of cancer cells by suppressing the MAPK signaling pathway and inducing apoptotic factor caspase-3. Our results suggest that this novel compound might become a potent chemotherapeutic agent for the treatment of colon cancer and further studies are warranted.
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Affiliation(s)
- Yan Shen
- Department of Gastroenterology, the First Affiliated Hospital of Zhejiang Chinese Medical University , Hangzhou, Zhejiang Province , China
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CD24 regulates stemness and the epithelial to mesenchymal transition through modulation of Notch1 mRNA stability by p38MAPK. Arch Biochem Biophys 2014; 558:120-6. [PMID: 24977325 DOI: 10.1016/j.abb.2014.06.022] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Revised: 06/19/2014] [Accepted: 06/20/2014] [Indexed: 01/07/2023]
Abstract
We report here that CD24 knockdown resulted in decreased expression of Notch1 in MCF-7 cells. CD24-downstream p38MAPK was shown to regulate Notch1 at the level of mRNA stability. We also found that CD24-mediated cell migration, invasion, mammosphere formation, and drug resistance was regulated by its downstream target Notch1. Together, our results indicate that CD24 may regulate the epithelial to mesenchymal transition and stemness through Notch1 signaling in breast cancer cells.
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Li R, Zhang L, Jia L, Duan Y, Li Y, Bao L, Sha N. Long non-coding RNA BANCR promotes proliferation in malignant melanoma by regulating MAPK pathway activation. PLoS One 2014; 9:e100893. [PMID: 24967732 PMCID: PMC4072697 DOI: 10.1371/journal.pone.0100893] [Citation(s) in RCA: 125] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Accepted: 06/02/2014] [Indexed: 01/11/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) have been shown to be implicated in the complex network of cancer including malignant melanoma and play important roles in tumorigenesis and progression. However, their functions and downstream mechanisms are largely unknown. This study aimed to investigate whether BRAF-activated non-coding RNA (BANCR), a novel and potential regulator of melanoma cell, participates in the proliferation of malignant melanoma and elucidate the underlying mechanism in this process. We found that BANCR was abnormally overexpressed in human malignant melanoma cell lines and tissues, and increased with tumor stages by quantitative PCR. BANCR knockdown induced by shRNA transfection significantly inhibited proliferation of tumor cells and inactivated MAPK pathway, especially by silencing the ERK1/2 and JNK component. Moreover, combination treatment of BANCR knockdown and suppression ERK1/2 or JNK (induced by specific inhibitors U0126 or SP600125 respectively) produced synergistic inhibitory effects in vitro. And the inhibitory effects induced by ERK1/2 or JNK could be rescued by BANCR overexpression. By tumorigenicity assay in BALB/c nude mice, we further found that BANCR knockdown inhibited tumor growth in vivo. In addition, patients with high expression of BANCR had a lower survival rate. Taken together, we confirmed the abnormal upregulation of a novel lncRNA, BANCR, in human malignant melanoma. BANCR was involved in melanoma cell proliferation both in vitro and in vivo. The linkage between BANCR and MAPK pathway may provide a novel interpretation for the mechanism of proliferation regulation in malignant melanoma.
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Affiliation(s)
- Ruiya Li
- Department of Dermatology, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia Autonomous Region, China
| | - Lingli Zhang
- Department of Pathology, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia Autonomous Region, China
| | - Lizhou Jia
- Department of Pathology, The Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Yan Duan
- Department of Dermatology, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia Autonomous Region, China
| | - Yan Li
- Department of Dermatology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Lidao Bao
- Department of Pharmacy, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Na Sha
- Department of Dermatology, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia Autonomous Region, China
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Hosonaga M, Arima Y, Sugihara E, Kohno N, Saya H. Expression of CD24 is associated with HER2 expression and supports HER2-Akt signaling in HER2-positive breast cancer cells. Cancer Sci 2014; 105:779-87. [PMID: 24754246 PMCID: PMC4317915 DOI: 10.1111/cas.12427] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 04/04/2014] [Accepted: 04/12/2014] [Indexed: 12/24/2022] Open
Abstract
Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is treated with HER2-targeted agents, such as trastuzumab and lapatinib, that suppress signaling by phosphatidylinositol 3-kinase (PI3K)-Akt and MAPK pathways. However, resistance to HER2-targeted therapy remains a major clinical problem. Overexpression of CD24 has been detected in many cancers and is associated with a poor prognosis in women with breast cancer. HER2-positive breast tumors are predominantly positive for CD24, suggesting that the expression of the two molecules is related. To investigate the relation between HER2 and CD24, we overexpressed HER2 in breast cancer cells that were triple-negative for the estrogen receptor, progesterone receptor and HER2. We found that expression of CD24 was increased by stable overexpression of HER2. Flow cytometry thus revealed that the percentage of CD24-positive cells was markedly higher in the HER2-positive fraction than in the HER2-negative fraction. Knockdown of CD24 in breast cancer cells positive for endogenous HER2 downregulated HER2 expression, whereas knockdown of HER2 did not affect the expression of CD24. Knockdown of CD24 also suppressed the phosphorylation of Akt, which functions downstream of HER2 and PI3K to promote cell survival. Moreover, knockdown of CD24 increased the sensitivity of HER2-positive breast cancer cells to lapatinib treatment. Our results thus indicate that CD24 supports both the expression of HER2 and the consequent activation of PI3K-Akt signaling. Furthermore, CD24 may contribute to resistance to HER2-targeted therapy and, therefore, is itself a potential therapeutic target in HER2-positive breast cancer.
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Affiliation(s)
- Mari Hosonaga
- Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan; Department of Breast Oncology, Tokyo Medical University, Tokyo, Japan
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Naumov I, Zilberberg A, Shapira S, Avivi D, Kazanov D, Rosin-Arbesfeld R, Arber N, Kraus S. CD24 knockout prevents colorectal cancer in chemically induced colon carcinogenesis and in APC(Min)/CD24 double knockout transgenic mice. Int J Cancer 2014; 135:1048-59. [PMID: 24500912 DOI: 10.1002/ijc.28762] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023]
Abstract
Increased expression of CD24 is seen in a large variety of solid tumors, including up to 90% of gastrointestinal (GI) tumors. Stable derivatives of SW480 colorectal cancer (CRC) cells that overexpress CD24 proliferate faster, and increase cell motility, saturation density, plating efficiency, and growth in soft agar. They also produce larger tumors in nude mice as compared to the parental SW480 cells. Most significantly, even depletion of one copy of the CD24 allele in the APC(Min/+) mice of a transgenic mouse model led to a dramatic reduction in tumor burden in all sections of the small intestine. Homozygous deletion of both CD24 alleles resulted in complete abolishment of tumor formation. Moreover, CD24 knockout mice exhibited resistance to chemically induced inflammation-associated CRC. Finally, a new signal transduction pathway is suggested: namely, CD24 expression downstream to COX2 and PGE2 synthesis, which is directly regulated by β-catenin. CD24 is shown in vitro and in vivo as being an important oncogene in the gut, and one that plays a critical role in the initiation and progression of carcinogenesis.
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Affiliation(s)
- Inna Naumov
- The Integrated Cancer Prevention Center Tel Aviv Sourasky Medical Center Tel Aviv Israel Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Khuda-Bukhsh AR, Das S, Saha SK. Molecular Approaches Toward Targeted Cancer Prevention with Some Food Plants and Their Products: Inflammatory and Other Signal Pathways. Nutr Cancer 2013; 66:194-205. [DOI: 10.1080/01635581.2014.864420] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Leelawat K, Keeratichamroen S, Leelawat S, Tohtong R. CD24 induces the invasion of cholangiocarcinoma cells by upregulating CXCR4 and increasing the phosphorylation of ERK1/2. Oncol Lett 2013; 6:1439-1446. [PMID: 24179538 PMCID: PMC3813815 DOI: 10.3892/ol.2013.1587] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Accepted: 08/09/2013] [Indexed: 12/21/2022] Open
Abstract
Cholangiocarcinoma is a malignant biliary tract tumor with an extremely poor prognosis. CD24 expression has been linked to the aggressiveness of cholangiocarcinoma cells and the adverse prognosis of cholangiocarcinoma patients. In the present study, the underlying mechanism of aggressive CD24+ cholangiocarcinoma cell behavior was elucidated. The magnetic-activated cell sorting system was used to isolate CD24+ and CD24- cell populations from RMCCA1 cholangiocarcinoma cells. Using a human tumor metastasis PCR array, it was observed that numerous tumor-associated genes were upregulated in the CD24+ cells, including CXC chemokine receptor type 4 (CXCR4). In addition, an intracellular signaling array demonstrated the activation of extracellular signal-regulated kinase (ERK)1/2, which is downstream of the CXCR4 signaling cascade, in the CD24+ cells. Inhibition of CXCR4 or ERK1/2 significantly inhibited the motility and invasiveness of the CD24+ cells. The present study indicates that CXCR4 and ERK1/2 are induced by CD24 and that these proteins are associated with cholangiocarcinoma cell invasion.
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Affiliation(s)
- Kawin Leelawat
- Department of Surgery, Rajavithi Hospital, Rajathevi, Bangkok 10400, Thailand ; College of Medicine, Rangsit University, Bangkok 10400, Thailand
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Liu YW, Fang JY. Advances in understanding the relationship between CD24 and colorectal cancer. Shijie Huaren Xiaohua Zazhi 2013; 21:2557-2562. [DOI: 10.11569/wcjd.v21.i25.2557] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third cause of cancer-related morbidity and mortality in America. In China and other Asian countries, an increasingly westernized diet has led to a high incidence of CRC. There is currently an urgent demand for the discovery of novel biomarkers for CRC prognostic evaluation and molecular targeted therapies. CD24 is a mucin-like glycoprotein that is highly expressed on the surface of CRC cells. It may play a significant role in the multistep process of CRC carcinogenesis, invasion and metastasis and is correlated with therapeutic resistance and poor prognosis of CRC. As one of surface markers for potential cancer stem cells (CSCs), CD24 may be used as an ideal target for curative CRC therapy. In this review, we summarize the role of CD24 in CRC initiation, progression and metastasis. Moreover, we discuss the vital part of CD24 in CSC identification, isolation and complete CRC eradication.
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Huang X, Lv B, Zhang S, Dai Q, Chen BB, Meng LN. Effects of radix curcumae-derived diterpenoid C on Helicobacter pylori-induced inflammation and nuclear factor kappa B signal pathways. World J Gastroenterol 2013; 19:5085-5093. [PMID: 23964142 PMCID: PMC3746380 DOI: 10.3748/wjg.v19.i31.5085] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2013] [Revised: 06/05/2013] [Accepted: 07/19/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To study effect of diterpenoid C extracted from radix curcumae on Helicobacter pylori (H. pylori)-infected inflammation, intestinal metaplasia, and nuclear factor kappa B (NF-κB) signaling pathway in vitro.
METHODS: We used I-type H. pylori to infect human gastric epithelial gastric epithelium cell line (GES-1) cell lines, and then H. pylori-infected GES-1 cells were treated with radix curcumae (RC)-derived diterpenoid C of different concentrations (5, 10, 20 μg/mL) and amoxicillin. The expression of p65, IκB kinase (IKK) α and IKKγ proteins was detected with Western blotting, and the expression of interleukin (IL)-8, IL-6 and IL-4 was determined with enzyme-linked immunosorbent assay method. Data were analyzed using SPSS software ver18.0. For comparisons between groups of more than two unpaired values, one-way analysis of variance (ANOVA) was used. If an ANOVA F value was significant, post hoc comparisons were performed between groups. If results were not normally distributed, the Mann-Whitney U test was used to compare two groups of unpaired values, whereas for comparisons between groups of more than two unpaired values, the Kruskal-Wallis H test was used. Statistical significance was established at P < 0.05.
RESULTS: The MTT assay results revealed the inhibited rate of GES-1, and indicated that the IC5 of RC-derived diterpenoid C and amoxicillin all were 5 μg/mL for gastric GES-1 cells. The expression of IL-8 was significantly increased, especially at 12 h time point; and the expression of IL-4 was decreased in H. pylori-infected GES-1 cells. After H. pylori-infected GES-1 cells were treated with RC-derived diterpenoid C of different concentrations and amoxicillin, the expression of IL-8 was decreased at 12, 24, 48, 72 h points (P < 0.01), especially in high-concentration diterpenoid C (20 μg/mL) group; and the expression of IL-4 was increased, especially in moderate and high-concentration diterpenoid C (10 and 20 μg/mL) groups. RC-derived diterpenoid C had the inhibitory effects on H. pylori-induced p65 translocation from cytoplasm into cell nucleus, H. pylori-stimulant IkBα degradation, the phosphorylation of p65 and IkBα, and the expression of IKKα and IKKβ proteins.
CONCLUSION: RC-derived diterpenoid C can block NF-κB signal pathway, effectively reducing the secretion of H. pylori-induced proinflammatory cytokine and increasing the secretion of anti-inflammatory cytokine.
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Salnikov AV, Bretz NP, Perne C, Hazin J, Keller S, Fogel M, Herr I, Schlange T, Moldenhauer G, Altevogt P. Antibody targeting of CD24 efficiently retards growth and influences cytokine milieu in experimental carcinomas. Br J Cancer 2013; 108:1449-59. [PMID: 23511563 PMCID: PMC3629417 DOI: 10.1038/bjc.2013.102] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background: The targeting of cancer stem cells by monoclonal antibodies offers new options for therapy. CD24 is a glycosylphosphatidylinositol-anchored membrane protein with a small protein core and a high level of glycosylation. It is overexpressed in many human carcinomas and is correlated with poor prognosis. CD24 is a marker for pancreatic and ovarian cancer stem cells, whereas breast cancer stem cells are negative for CD24. In cancer cell lines, changes of CD24 expression can alter cellular properties in vitro and tumour growth in vivo. We have shown before that monotherapy with monoclonal antibody (mAb) SWA11 to CD24 effectively retarded tumour growth in xenotransplanted mice. Methods: Here, we have investigated in more detail the molecular mechanisms of mAb SWA11 therapeutic effects in A549 lung and SKOV3ip ovarian carcinoma models in scid/beige and CD1 mice, respectively. We focused on anti-proliferative, pro-apoptotic, anti-angiogenic and microenvironmental effects of SWA11 mAb treatment. Results: We find that CD24 targeting is associated with changes in tumour cell proliferation and angiogenesis. The treatment lead to increased infiltration of tumour tissues with immune cells suggesting involvement of ADCC. We found that SWA11 mAb treatment strongly altered the intratumoural cytokine microenvironment. The addition of SWA11 mAb to gemcitabine treatment strongly potentiated its anti-cancer efficacy in A549 lung cancer model. Conclusion: Our data demonstrate that targeting of CD24 could be beneficial for the anti-cancer treatment combined with standard chemotherapy regimes.
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Affiliation(s)
- A V Salnikov
- Department of Translational Immunology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany
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Bretz NP, Salnikov AV, Perne C, Keller S, Wang X, Mierke CT, Fogel M, Erbe-Hofmann N, Schlange T, Moldenhauer G, Altevogt P. CD24 controls Src/STAT3 activity in human tumors. Cell Mol Life Sci 2012; 69:3863-79. [PMID: 22760497 PMCID: PMC11114558 DOI: 10.1007/s00018-012-1055-9] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2011] [Revised: 06/01/2012] [Accepted: 06/11/2012] [Indexed: 12/13/2022]
Abstract
CD24 is a glycosyl-phosphatidylinositol-anchored membrane protein that is frequently over-expressed in a variety of human carcinomas and is correlated with poor prognosis. In cancer cell lines, changes of CD24 expression can alter several cellular properties in vitro and tumor growth in vivo. However, little is known about how CD24 mediates these effects. Here we have analyzed the functional consequences of CD24 knock-down or over-expression in human cancer cell lines. Depletion of CD24 reduced cell proliferation and adhesion, enhanced apoptosis, and regulated the expression of various genes some of which were identified as STAT3 target genes. Loss of CD24 reduced STAT3 and FAK phosphorylation. Diminished STAT3 activity was confirmed by specific reporter assays. We found that reduced STAT3 activity after CD24 knock-down was accompanied by altered Src phosphorylation. Silencing of Src, similar to CD24, targeted the expression of prototype STAT3-regulated genes. Likewise, the over-expression of CD24 augmented Src-Y416 phosphorylation, the recruitment of Src into lipid rafts and the expression of STAT3-dependent target genes. An antibody to CD24 was effective in reducing tumor growth of A549 lung cancer and BxPC3 pancreatic cancer xenografts in mice. Antibody treatment affected the level of Src-phosphorylation in the tumor and altered the expression of STAT3 target genes. Our results provide evidence that CD24 regulates STAT3 and FAK activity and suggest an important role of Src in this process. Finally, the targeting of CD24 by antibodies could represent a novel route for tumor therapy.
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Affiliation(s)
- Niko P. Bretz
- Tumor Immunology Programme, D015, DKFZ, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Alexei V. Salnikov
- Tumor Immunology Programme, D015, DKFZ, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Claudia Perne
- Tumor Immunology Programme, D015, DKFZ, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Sascha Keller
- Tumor Immunology Programme, D015, DKFZ, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Xiaoli Wang
- Tumor Immunology Programme, D015, DKFZ, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Claudia T. Mierke
- Institute of Experimental Physics I, University of Leipzig, Leipzig, Germany
| | - Mina Fogel
- Department of Pathology, Kaplan Hospital, Rehovot, Israel
| | - Natalie Erbe-Hofmann
- Tumor Immunology Programme, D015, DKFZ, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | | | - Gerhard Moldenhauer
- Tumor Immunology Programme, D015, DKFZ, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Peter Altevogt
- Tumor Immunology Programme, D015, DKFZ, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Thomas S, Harding MA, Smith SC, Overdevest JB, Nitz MD, Frierson HF, Tomlins SA, Kristiansen G, Theodorescu D. CD24 is an effector of HIF-1-driven primary tumor growth and metastasis. Cancer Res 2012; 72:5600-12. [PMID: 22926560 DOI: 10.1158/0008-5472.can-11-3666] [Citation(s) in RCA: 108] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hypoxia drives malignant progression in part by promoting accumulation of the oncogenic transcription factor hypoxia inducible factor-1α (HIF-1α) in tumor cells. Tumor aggressiveness also relates to elevation of the cancer stem cell-associated membrane protein CD24, which has been causally implicated in tumor formation and metastasis in experimental models. Here, we link these two elements by showing that hypoxia induces CD24 expression through a functional hypoxia responsive element in the CD24 promoter. HIF-1α overexpression induced CD24 mRNA and protein under normoxic conditions, with this effect traced to a recruitment of endogenous HIF-1α to the CD24 promoter. Short hairpin RNA-mediated attenuation of HIF-1α or CD24 expression reduced cancer cell survival in vitro and in vivo at the levels of primary and metastatic tumor growth. CD24 overexpression in HIF-1α-depleted cancer cells rescued this decrease, whereas HIF-1α overexpression in CD24-depleted cells did not. Analysis of clinical tumor specimens revealed a correlation between HIF-1α and CD24 levels and an association of their coexpression to decreased patient survival. Our results establish a mechanistic linkage between 2 critically important molecules in cancer, identifying CD24 as a critical HIF-1α transcriptional target and biologic effector, strengthening the rationale to target CD24 for cancer therapy.
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Affiliation(s)
- Shibu Thomas
- Departments of Urology, University of Virginia, Charlottesville, Virginia, USA
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King JB, von Furstenberg RJ, Smith BJ, McNaughton KK, Galanko JA, Henning SJ. CD24 can be used to isolate Lgr5+ putative colonic epithelial stem cells in mice. Am J Physiol Gastrointest Liver Physiol 2012; 303:G443-52. [PMID: 22723265 PMCID: PMC3423139 DOI: 10.1152/ajpgi.00087.2012] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
A growing body of evidence has implicated CD24, a cell-surface protein, as a marker of colorectal cancer stem cells and target for antitumor therapy, although its presence in normal colonic epithelium has not been fully characterized. Previously, our group showed that CD24-based cell sorting can be used to isolate a fraction of murine small intestinal epithelial cells enriched in actively cycling stem cells. Similarly, we hypothesized that CD24-based isolation of colonic epithelial cells would generate a fraction enriched in actively cycling colonic epithelial stem cells (CESCs). Immunohistochemistry performed on mouse colonic tissue showed CD24 expression in the bottom half of proximal colon crypts and the crypt base in the distal colon. This pattern of distribution was similar to enhanced green fluorescent protein (EGFP) expression in Lgr5-EGFP mice. Areas expressing CD24 contained actively proliferating cells as determined by ethynyl deoxyuridine (EdU) incorporation, with a distinct difference between the proximal colon, where EdU-labeled cells were most frequent in the midcrypt, and the distal colon, where they were primarily at the crypt base. Flow cytometric analyses of single epithelial cells, identified by epithelial cell adhesion molecule (EpCAM) positivity, from mouse colon revealed an actively cycling CD24(+) fraction that contained the majority of Lgr5-EGFP(+) putative CESCs. Transcript analysis by quantitative RT-PCR confirmed enrichment of active CESC markers [leucine-rich-repeat-containing G protein-coupled receptor 5 (Lgr5), ephrin type B receptor 2 (EphB2), and CD166] in the CD24(+)EpCAM(+) fraction but also showed enrichment of quiescent CESC markers [leucine-rich repeats and immunoglobin domains (Lrig), doublecortin and calmodulin kinase-like 1 (DCAMKL-1), and murine telomerase reverse transcriptase (mTert)]. We conclude that CD24-based sorting in wild-type mice isolates a colonic epithelial fraction highly enriched in actively cycling and quiescent putative CESCs. Furthermore, the presence of CD24 expression in normal colonic epithelium may have important implications for the use of anti-CD24-based colorectal cancer therapies.
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Affiliation(s)
- Jeffrey B. King
- 1Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and
| | - Richard J. von Furstenberg
- 1Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and ,2Department of Cellular and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Brian J. Smith
- 1Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and
| | - Kirk K. McNaughton
- 2Department of Cellular and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Joseph A. Galanko
- 1Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and
| | - Susan J. Henning
- 1Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and ,2Department of Cellular and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Lee KM, Ju JH, Jang K, Yang W, Yi JY, Noh DY, Shin I. CD24 regulates cell proliferation and transforming growth factor β-induced epithelial to mesenchymal transition through modulation of integrin β1 stability. Cell Signal 2012; 24:2132-42. [PMID: 22800863 DOI: 10.1016/j.cellsig.2012.07.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2012] [Revised: 06/25/2012] [Accepted: 07/09/2012] [Indexed: 12/22/2022]
Abstract
To determine the role of CD24 in breast cancer cells, we knocked down CD24 in MCF-7 human breast cancer cells by retroviral delivery of shRNA. MCF-7 cells with knocked down CD24 (MCF-7 hCD24 shRNA) exhibited decreased cell proliferation and cell adhesion as compared to control MCF-7 mCD24 shRNA cells. Decreased proliferation of MCF-7 hCD24 shRNA cells resulted from the inhibition of cell cycle progression from G1 to S phase. The specific inhibition of MEK/ERK signaling by CD24 ablation might be responsible for the inhibition of cell proliferation. Phosphorylation of Src/FAK and TGF-β1-mediated epithelial to mesenchymal transition was also down-regulated in MCF-7 hCD24 shRNA cells. Reduced Src/FAK activity was caused by a decrease in integrin β1 bound with CD24 and subsequent destabilization of integrin β1. Our results suggest that down-regulation of Raf/MEK/ERK signaling via Src/FAK may be dependent on integrin β1 function and that this mechanism is largely responsible for the CD24 ablation-induced decreases in cell proliferation and epithelial to mesenchymal transition.
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Affiliation(s)
- Kyung-min Lee
- Department of Life Science, Hanyang University, Seoul, Korea
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Lyn is involved in CD24-induced ERK1/2 activation in colorectal cancer. Mol Cancer 2012; 11:43. [PMID: 22731636 PMCID: PMC3464950 DOI: 10.1186/1476-4598-11-43] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Accepted: 06/26/2012] [Indexed: 12/24/2022] Open
Abstract
Background and aim CD24 expression is associated with human colorectal cancer (CRC). Our previous data indicated that CD24 promoted the proliferation and invasion of colorectal cancer cells through the activation of ERK1/2. Since Src family kinases are frequently deregulated in CRC and closely related to the MAPK signaling pathway, we investigated the impact of Lyn, an important member of SFKs, on CD24-induced ERK1/2 activation in CRC. Methods and Results The interaction of CD24 and Lyn was identified by co-immunoprecipitation (Co-IP) and ectopic expression of CD24-induced Lyn activation. Inhibition of Lyn activation by phosphatase PP2 in SW480CD24cells abrogated CD24-induced invasion. The results of the Co-IP and immunofluorescence assay revealed that overexpression of CD24 enhanced the interaction of Lyn and ERK1/2 and induced the nuclear translocation of Lyn. However, inhibition of Lyn activity attenuated CD24-induced ERK1/2 activation, and depletion of CD24 disrupted Lyn-ERK1/2 interaction. Immunohistochemistry analysis for 202 cases of CRC showed that the expression of both CD24 and Lyn was positively correlated with tumor grade, stage, lymph node and distant metastasis. Patients with lower expression of CD24 or Lyn had a higher survival rate. The Cox multivariate analysis showed that CD24 expression, but not Lyn expression, was an independent prognostic factor of CRC. Conclusions Our results suggest that Lyn is involved in CD24-induced ERK1/2 activation in CRC. The expression of CD24 is associated with activation of Lyn and ERK1/2, which might be a novel mechanism related to CD24-mediated regulation of CRC development.
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CD24 expression as a marker for predicting clinical outcome in human gliomas. J Biomed Biotechnol 2012; 2012:517172. [PMID: 22500096 PMCID: PMC3303885 DOI: 10.1155/2012/517172] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2011] [Accepted: 12/05/2011] [Indexed: 11/23/2022] Open
Abstract
CD24 is overexpressed in glioma cells in vitro and in vivo. However, the correlation of its expression with clinicopathological parameters of gliomas and its prognostic significance in this tumor remain largely unknown. To address this problem, 151 glioma specimens and 10 nonneoplastic brain tissues were collected. Quantitative real-time PCR, immunochemistry assay, and Western blot analysis were carried out to investigate the expression of CD24. As per the results, CD24 was overexpressed in gliomas. Its expression levels in glioma tissues with higher grade (P < 0.001) and lower KPS (P < 0.001) were significantly higher than those with lower grade and higher KPS, respectively. Cox multifactor analysis showed that CD24 (P = 0.02) was an independent prognosis factor for human glioma. Our data provides convincing evidence for the first time that the overexpression of CD24 at gene and protein levels is correlated with advanced clinicopathological parameters and poor prognosis in patients with glioma.
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CD24 promotes tumor cell invasion by suppressing tissue factor pathway inhibitor-2 (TFPI-2) in a c-Src-dependent fashion. Clin Exp Metastasis 2011; 29:27-38. [DOI: 10.1007/s10585-011-9426-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2011] [Accepted: 09/05/2011] [Indexed: 11/25/2022]
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Shapira S, Kazanov D, Weisblatt S, Starr A, Arber N, Kraus S. The CD24 protein inducible expression system is an ideal tool to explore the potential of CD24 as an oncogene and a target for immunotherapy in vitro and in vivo. J Biol Chem 2011; 286:40548-55. [PMID: 21976680 DOI: 10.1074/jbc.m111.286534] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
CD24 is a cell surface, heavily glycosylated glycosylphosphatidylinositol-anchored mucin-like protein that is overexpressed in various human malignancies. To accurately analyze CD24 function and dissect its biological role in a defined genetic background, it is critical to tightly regulate its expression and be able to turn it on/off in a restricted environment and at a specific time. The tetracycline-induced expression system is most promising as it exhibits such regulation, lack of pleiotropic effects, and high and rapid induction levels. To evaluate the oncogenic and immunotherapeutic potential of CD24 by applying the Tet-On system, the human CD24 gene was cloned downstream to two tetracycline operator sequences, resulting in pCDNA4/TO-CD24, which was then transfected into tetracycline (Tet) repressor-expressing cells (293T-REx), allowing tight on/off regulation, thereby resulting in a very low background or leaky CD24 expression. Selected clones were chosen for further studies and characterized in vitro and in vivo, and several treatment modalities were examined. In addition, the role of CD24 in promoting cell proliferation and tumor growth was studied. The tetracycline-dependent system was successfully implemented. Tetracycline treatment induced CD24 expression in a dose- and time-dependent fashion, which was abrogated following treatment with anti-CD24 monoclonal antibodies (mAbs). CD24-induced expression led to an increased proliferation rate that was inhibited by mAb treatment. In vivo, significantly larger tumors were developed in tetracycline-fed mice. The CD24 Tet-On system is a good model to unravel the role and underlying CD24 pathogenesis in vivo. This valuable tool allows the successful study of novel treatment options, whose effectiveness depends on the CD24 expression level. This set of experiments supports CD24 oncogenic properties.
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Affiliation(s)
- Shiran Shapira
- Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel
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Shapira S, Shapira A, Starr A, Kazanov D, Kraus S, Benhar I, Arber N. An immunoconjugate of anti-CD24 and Pseudomonas exotoxin selectively kills human colorectal tumors in mice. Gastroenterology 2011; 140:935-46. [PMID: 21147107 DOI: 10.1053/j.gastro.2010.12.004] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2010] [Revised: 11/25/2010] [Accepted: 12/02/2010] [Indexed: 01/17/2023]
Abstract
BACKGROUND & AIMS Effective and selective treatment options are needed for patients with colorectal cancer (CRC). The CD24 mucin-like glycoprotein is overexpressed in CRCs; monoclonal antibodies (mAbs) against CD24 inhibit tumor cell growth in vitro and in vivo. Based on the tumor-specific expression of CD24, we investigated the potential of anti-CD24 SWA11 mAb, to deliver a cytotoxic agent into CRC cells. METHODS We conjugated SWA11 to a Pseudomonas exotoxin derivative (PE38) via an Fc-binding ZZ domain from Staphylococcal protein A (which binds the Fc domain of mouse IgG2a immunoglobulins) to generate the immunotoxin SWA11-ZZ-PE38; IgG-ZZ-PE38 was used as control. Human HT-29 and COLO320 (CD24-positive) and HCT116 (CD24-negative) CRC cell lines were assayed for immunotoxin binding, cytotoxicity, viability, and apoptosis. Toxicity and antitumor efficacy were tested in mice. RESULTS The immunotoxin preserved the affinity and specificity of SWA11, bound and selectively killed CD24-expressing CRC cells via apoptosis. IC(50) values ranged from 20 to 50 ng/mL-several orders of magnitude lower than that of the mAb alone. The immunotoxins were not toxic to mice at the maximum dose of 0.75 mg/kg. Growth of HT-29 xenograft tumors was significantly reduced in mice given SWA11-ZZ-PE38 (by 78%) compared to untreated mice. CONCLUSIONS Anti-CD24 SWA11 mAb can deliver a PE exotoxin derivative to CRC cells and cause them to undergo apoptosis, without toxicity to normal tissues. This immunotoxin might be developed as a therapeutic treatment for patients with CRC.
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Affiliation(s)
- Shiran Shapira
- The Integrated Cancer Prevention Center, Tel Aviv, Israel
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Polyphenols and human health: prevention of disease and mechanisms of action. Nutrients 2010; 2:1106-31. [PMID: 22254000 PMCID: PMC3257622 DOI: 10.3390/nu2111106] [Citation(s) in RCA: 479] [Impact Index Per Article: 31.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2010] [Revised: 10/25/2010] [Accepted: 11/01/2010] [Indexed: 12/11/2022] Open
Abstract
Polyphenols are found ubiquitously in plants and their regular consumption has been associated with a reduced risk of a number of chronic diseases, including cancer, cardiovascular disease (CVD) and neurodegenerative disorders. Rather than exerting direct antioxidant effects, the mechanisms by which polyphenols express these beneficial properties appear to involve their interaction with cellular signaling pathways and related machinery that mediate cell function under both normal and pathological conditions. We illustrate that their interactions with two such pathways, the MAP kinase (ERK, JNK, p38) and PI3 kinase/Akt signaling cascades, allow them to impact upon normal and abnormal cell function, thus influencing the cellular processes involved in the initiation and progression of cancer, CVD and neurodegeneration. For example, their ability to activate ERK in neurons leads to a promotion of neuronal survival and cognitive enhancements, both of which influence the progression of Alzheimer’s disease, whilst ERK activation by polyphenols in vascular endothelial cells influences nitric oxide production, blood pressure and ultimately CVD risk. The main focus of this review is to provide an overview of the role that polyphenols play in the prevention of cancer, cardiovascular disease and neurodegeneration. We present epidemiological data, human intervention study findings, as well as animal and in vitro studies in support of these actions and in each case we consider how their actions at the cellular level may underpin their physiological effects.
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