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Mielcarska S, Kot A, Kula A, Dawidowicz M, Sobków P, Kłaczka D, Waniczek D, Świętochowska E. B7H3 in Gastrointestinal Tumors: Role in Immune Modulation and Cancer Progression: A Review of the Literature. Cells 2025; 14:530. [PMID: 40214484 PMCID: PMC11988818 DOI: 10.3390/cells14070530] [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: 03/11/2025] [Revised: 03/29/2025] [Accepted: 03/31/2025] [Indexed: 04/14/2025] Open
Abstract
B7-H3 (CD276), a member of the B7 immune checkpoint family, plays a critical role in modulating immune responses and has emerged as a promising target in cancer therapy. It is highly expressed in various malignancies, where it promotes tumor evasion from T cell surveillance and contributes to cancer progression, metastasis, and therapeutic resistance, showing a correlation with the poor prognosis of patients. Although its receptors were not fully identified, B7-H3 signaling involves key intracellular pathways, including JAK/STAT, NF-κB, PI3K/Akt, and MAPK, driving processes crucial for supporting tumor growth such as cell proliferation, invasion, and apoptosis inhibition. Beyond immune modulation, B7-H3 influences cancer cell metabolism, angiogenesis, and epithelial-to-mesenchymal transition, further exacerbating tumor aggressiveness. The development of B7-H3-targeting therapies, including monoclonal antibodies, antibody-drug conjugates, and CAR-T cells, offers promising avenues for treatment. This review provides an up-to-date summary of the B7H3 mechanisms of action, putative receptors, and ongoing clinical trials evaluating therapies targeting B7H3, focusing on the molecule's role in gastrointestinal tumors.
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Affiliation(s)
- Sylwia Mielcarska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
| | - Anna Kot
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
| | - Agnieszka Kula
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-514 Katowice, Poland; (A.K.); (M.D.); (D.W.)
| | - Miriam Dawidowicz
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-514 Katowice, Poland; (A.K.); (M.D.); (D.W.)
| | - Piotr Sobków
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
| | - Daria Kłaczka
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
| | - Dariusz Waniczek
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-514 Katowice, Poland; (A.K.); (M.D.); (D.W.)
| | - Elżbieta Świętochowska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
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Chen X, Sun F, Wang X, Feng X, Aref AR, Tian Y, Ashrafizadeh M, Wu D. Inflammation, microbiota, and pancreatic cancer. Cancer Cell Int 2025; 25:62. [PMID: 39987122 PMCID: PMC11847367 DOI: 10.1186/s12935-025-03673-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 02/04/2025] [Indexed: 02/24/2025] Open
Abstract
Pancreatic cancer (PC) is a malignancy of gastrointestinal tract threatening the life of people around the world. In spite of the advances in the treatment of PC, the overall survival of this disease in advanced stage is less than 12%. Moreover, PC cells have aggressive behaviour in proliferation and metastasis as well as capable of developing therapy resistance. Therefore, highlighting the underlying molecular mechanisms in PC pathogenesis can provide new insights for its treatment. In the present review, inflammation and related pathways as well as role of gut microbiome in the regulation of PC pathogenesis are highlighted. The various kinds of interleukins and chemokines are able to regulate angiogenesis, metastasis, proliferation, inflammation and therapy resistance in PC cells. Furthermore, a number of molecular pathways including NF-κB, TLRs and TGF-β demonstrate dysregulation in PC aggravating inflammation and tumorigenesis. Therapeutic regulation of these pathways can reverse inflammation and progression of PC. Both chronic and acute pancreatitis have been shown to be risk factors in the development of PC, further highlighting the role of inflammation. Finally, the composition of gut microbiota can be a risk factor for PC development through affecting pathways such as NF-κB to mediate inflammation.
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Affiliation(s)
- XiaoLiang Chen
- Department of General Surgery and Integrated Traditional Chinese and Western Medicine Oncology, Tiantai People'S Hospital of Zhejiang Province(Tiantai Branch of Zhejiang Provincial People'S Hospital), Hangzhou Medical College, Taizhou, Zhejiang, China
| | - Feixia Sun
- Nursing Department, Shandong First Medical University Affiliated Occupational Disease Hospital (Shandong Provincial Occupational Disease Hospital), Jinan, China
| | - Xuqin Wang
- Department of Oncology, Chongqing General Hospital, Chongqing University, Chongqing, 401120, China
| | - Xiaoqiang Feng
- Center of Stem Cell and Regenerative Medicine, Gaozhou People's Hospital, Gaozhou, 525200, Guangdong, China
| | - Amir Reza Aref
- VitroVision Department, DeepkinetiX, Inc, Boston, MA, USA
| | - Yu Tian
- Research Center, the Huizhou Central People'S Hospital, Guangdong Medical University, Huizhou, Guangdong, China.
- School of Public Health, Benedictine University, No. 5700 College Road, Lisle, IL, 60532, USA.
| | - Milad Ashrafizadeh
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250000, Shandong, China.
| | - Dengfeng Wu
- Department of Emergency, The People'S Hospital of Gaozhou, No. 89 Xiguan Road, Gaozhou, 525200, Guangdong, China.
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Wu S, Hu C, Hui K, Jiang X. Non-immune functions of B7-H3: bridging tumor cells and the tumor vasculature. Front Oncol 2024; 14:1408051. [PMID: 38952550 PMCID: PMC11215132 DOI: 10.3389/fonc.2024.1408051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 06/04/2024] [Indexed: 07/03/2024] Open
Abstract
B7-H3 (CD276), an immune checkpoint molecule, is overexpressed in various types of cancer and their tumor vasculature, demonstrating significant associations with adverse clinical outcomes. In addition to its well-known immune functions, B7-H3 exhibits dual co-stimulatory/co-inhibitory roles in normal physiology and the tumor microenvironment. The non-immune functions of B7-H3 in tumor cells and the tumor vasculature, including promoting tumor cell anti-apoptosis, proliferation, invasion, migration, drug resistance, radioresistance, as well as affecting cellular metabolism and angiogenesis, have increasingly gained attention from researchers. Particularly, the co-expression of B7-H3 in both tumor cells and tumor endothelial cells highlights the higher potential and clinical utility of therapeutic strategies targeting B7-H3. This review aims to summarize the recent advances in understanding the non-immune functions of B7-H3 in tumors and provide insights into therapeutic approaches targeting B7-H3, focusing on its co-expression in tumor cells and endothelial cells. The aim is to establish a theoretical foundation and practical reference for the development and optimization of B7-H3-targeted therapies.
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Affiliation(s)
- Shuo Wu
- Department of Oncology, Lianyungang Clinical College of Nanjing Medical University, Lianyungang, China
| | - Chenxi Hu
- Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, China
| | - Kaiyuan Hui
- Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, China
| | - Xiaodong Jiang
- Department of Oncology, Lianyungang Clinical College of Nanjing Medical University, Lianyungang, China
- Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, China
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Cai H, Zhao J, Zhang Q, Wu H, Sun Y, Guo F, Zhou Y, Qin G, Xia W, Zhao Y, Liang X, Yin S, Qin Y, Li D, Wu H, Ren D. Ubiquitin ligase TRIM15 promotes the progression of pancreatic cancer via the upregulation of the IGF2BP2-TLR4 axis. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167183. [PMID: 38657551 DOI: 10.1016/j.bbadis.2024.167183] [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: 11/30/2023] [Revised: 03/17/2024] [Accepted: 04/15/2024] [Indexed: 04/26/2024]
Abstract
BACKGROUND The tripartite motif family, predominantly characterized by its E3 ubiquitin ligase activities, is involved in various cellular processes including signal transduction, apoptosis and autophagy, protein quality control, immune regulation, and carcinogenesis. Tripartite Motif Containing 15 (TRIM15) plays an important role in melanoma progression through extracellular signal-regulated kinase activation; however, data on its role in pancreatic tumors remain lacking. We previously demonstrated that TRIM15 targeted lipid synthesis and metabolism in pancreatic cancer; however, other specific regulatory mechanisms remain elusive. METHODS We used transcriptomics and proteomics, conducted a series of phenotypic experiments, and used a mouse orthotopic transplantation model to study the specific mechanism of TRIM15 in pancreatic cancer in vitro and in vivo. RESULTS TRIM15 overexpression promoted the progression of pancreatic cancer by upregulating the toll-like receptor 4. The TRIM15 binding protein, IGF2BP2, could combine with TLR4 to inhibit its mRNA degradation. Furthermore, the ubiquitin level of IGF2BP2 was positively correlated with TRIM15. CONCLUSIONS TRIM15 could ubiquitinate IGF2BP2 to enhance the function of phase separation and the maintenance of mRNA stability of TLR4. TRIM15 is a potential therapeutic target against pancreatic cancer.
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Affiliation(s)
- Hongkun Cai
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jingyuan Zhao
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Qiyue Zhang
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Heyu Wu
- Department of Operating Room, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yan Sun
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Feng Guo
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yingke Zhou
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Gengdu Qin
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wentao Xia
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yuhan Zhao
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xueyi Liang
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shilin Yin
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yang Qin
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Dan Li
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Heshui Wu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Dianyun Ren
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Wang J, Wu X, Xu J, Liao Y, Deng M, Wang X, Li J. Differential expression and bioinformatics analysis of exosome circRNAs in pancreatic ductal adenocarcinoma. Transl Oncol 2023; 33:101686. [PMID: 37182508 DOI: 10.1016/j.tranon.2023.101686] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/20/2023] [Accepted: 05/03/2023] [Indexed: 05/16/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignant tumor with an unfavorable prognosis. Increasing evidence indicated circRNAs were associated with the pathogenesis and progression of tumors, but data on the expression of serum exosomal circRNAs in PDAC are scarce. This study attempted to explore the prognostic value and function of serum exosomes in PDAC patients. METHODS Microarray-based circRNA expression was determined in PDAC and paired with normal serum samples, and the intersection of differentially expressed circRNAs (DECs) in serum exosomal samples and GSE79634 tissue samples was conducted. A specific CircRNA database was applied to investigate DECs binding miRNAs. Target genes were predicted using the R package multiMiR. Cox regression analyses were applied for constructing a prognostic model. The immunological characteristics analysis was carried out through the TIMER, QUANTISEQ, XCELL, EPIC, and ssGSEA algorithms. RESULTS 15 DECs were finally identified, and a circRNA-miRNA-mRNA network was established. A prognostic risk model was developed to categorize patients according to the risk scores. Furthermore, the association between risk score and immune checkpoint genes including CD80, TNFSF9, CD276, CD274, LGALS9, and CD44 were significantly elevated in the high-risk group, while ICOSLG and ADORA2A were upregulated in the low-risk group. CONCLUSIONS Our results may provide new clues for the prognosis and treatment of PDAC.
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Affiliation(s)
- Jiayi Wang
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha 41000, China
| | - Xing Wu
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha 41000, China
| | - Jiahao Xu
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha 41000, China
| | - Yangjie Liao
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha 41000, China
| | - Minzi Deng
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha 41000, China
| | - Xiaoyan Wang
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha 41000, China
| | - Jingbo Li
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha 41000, China.
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Li L, Gao L, Zhou H, Shi C, Zhang X, Zhang D, Liu H. High Expression Level of BRD4 Is Associated with a Poor Prognosis and Immune Infiltration in Esophageal Squamous Cell Carcinoma. Dig Dis Sci 2023:10.1007/s10620-023-07907-3. [PMID: 36933111 DOI: 10.1007/s10620-023-07907-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 02/28/2023] [Indexed: 03/19/2023]
Abstract
BACKGROUND Bromodomain-containing protein 4 (BRD4) is a reader of histone acetylation and is associated with a variety of diseases. AIM To investigate the expression level of BRD4 in esophageal squamous cell carcinoma (ESCC), its prognostic value and its relationship with immune infiltration. METHODS The study included 94 ESCC patients from The Cancer Genome Atlas (TCGA) database and 179 ESCC patients from Affiliated Hospital 2 of Nantong University. The expression levels of proteins in tissue microarray were detected by immunohistochemistry. The prognostic factors were analyzed by Kaplan-Meier curve and univariate and multivariate cox regression. The ESTIMATE website was used to calculate the stromal, immune and ESTIMATE score. CIBERSORT was used to calculate the abundance of immune infiltrates. Spearman and Phi coefficient were used for correlation analysis. The TIDE algorithm was used to predict treatment response to immune checkpoint blockade. RESULTS BRD4 is up-regulated in ESCC, and high BRD4 expression level is associated with poor prognosis and adverse clinicopathological features. In addition, the monocyte count, systemic inflammatory-immunologic index, platelet-lymphocyte ratio, and monocyte-lymphocyte ratio in the BRD4 high expression level group were higher than in the low expression level group. Finally, we found that BRD4 expression level correlated with immune infiltration and that it was inversely correlated with infiltration of CD8 + T cells. Higher TIDE scores in the BRD4 high expression group than in the low expression group. CONCLUSION BRD4 is associated with poor prognosis and immune infiltration in ESCC, and may be a potential biomarker for prognosis and immunotherapy application.
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Affiliation(s)
- Li Li
- Department of Pathology, Affiliated Hospital 2 of Nantong University and First People's Hospital of Nantong City, Shengli Road No. 666, Nantong, 226001, Jiangsu, People's Republic of China
| | - Lin Gao
- Medical Research Center, Affiliated Hospital 2 of Nantong University and First People's Hospital of Nantong City, Nantong, 226001, People's Republic of China
| | - Hong Zhou
- Department of Pathology, Affiliated Hospital 2 of Nantong University and First People's Hospital of Nantong City, Shengli Road No. 666, Nantong, 226001, Jiangsu, People's Republic of China
| | - Chao Shi
- Department of Pathology, Affiliated Hospital 2 of Nantong University and First People's Hospital of Nantong City, Shengli Road No. 666, Nantong, 226001, Jiangsu, People's Republic of China
| | - Xiaojuan Zhang
- Department of Pathology, Affiliated Hospital 2 of Nantong University and First People's Hospital of Nantong City, Shengli Road No. 666, Nantong, 226001, Jiangsu, People's Republic of China
| | - Dongmei Zhang
- Medical Research Center, Affiliated Hospital 2 of Nantong University and First People's Hospital of Nantong City, Nantong, 226001, People's Republic of China
| | - Hongbin Liu
- Department of Pathology, Affiliated Hospital 2 of Nantong University and First People's Hospital of Nantong City, Shengli Road No. 666, Nantong, 226001, Jiangsu, People's Republic of China.
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Getu AA, Tigabu A, Zhou M, Lu J, Fodstad Ø, Tan M. New frontiers in immune checkpoint B7-H3 (CD276) research and drug development. Mol Cancer 2023; 22:43. [PMID: 36859240 PMCID: PMC9979440 DOI: 10.1186/s12943-023-01751-9] [Citation(s) in RCA: 95] [Impact Index Per Article: 47.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 02/22/2023] [Indexed: 03/03/2023] Open
Abstract
B7-H3 (CD276), a member of the B7 family of proteins, is a key player in cancer progression. This immune checkpoint molecule is selectively expressed in both tumor cells and immune cells within the tumor microenvironment. In addition to its immune checkpoint function, B7-H3 has been linked to tumor cell proliferation, metastasis, and therapeutic resistance. Furthermore, its drastic difference in protein expression levels between normal and tumor tissues suggests that targeting B7-H3 with drugs would lead to cancer-specific toxicity, minimizing harm to healthy cells. These properties make B7-H3 a promising target for cancer therapy.Recently, important advances in B7-H3 research and drug development have been reported, and these new findings, including its involvement in cellular metabolic reprograming, cancer stem cell enrichment, senescence and obesity, have expanded our knowledge and understanding of this molecule, which is important in guiding future strategies for targeting B7-H3. In this review, we briefly discuss the biology and function of B7-H3 in cancer development. We emphasize more on the latest findings and their underlying mechanisms to reflect the new advances in B7-H3 research. In addition, we discuss the new improvements of B-H3 inhibitors in cancer drug development.
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Affiliation(s)
- Ayechew Adera Getu
- Institute of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
- Department of Physiology, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Abiye Tigabu
- Institute of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
| | - Ming Zhou
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, China
| | - Jianrong Lu
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, USA
| | - Øystein Fodstad
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
| | - Ming Tan
- Institute of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan.
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Chen X, Li J, Chen Y, Que Z, Du J, Zhang J. B7 Family Members in Pancreatic Ductal Adenocarcinoma: Attractive Targets for Cancer Immunotherapy. Int J Mol Sci 2022; 23:ijms232315005. [PMID: 36499340 PMCID: PMC9740860 DOI: 10.3390/ijms232315005] [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: 11/02/2022] [Revised: 11/25/2022] [Accepted: 11/27/2022] [Indexed: 12/05/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a five-year survival rate of approximately 5-10%. The immune checkpoint blockade represented by PD-1/PD-L1 inhibitors has been effective in a variety of solid tumors but has had little clinical response in pancreatic cancer patients. The unique suppressive immune microenvironment is the primary reason for this outcome, and it is essential to identify key targets to remodel the immune microenvironment. Some B7 family immune checkpoints, particularly PD-L1, PD-L2, B7-H3, B7-H4, VISTA and HHLA2, have been identified as playing a significant role in the control of tumor immune responses. This paper provides a comprehensive overview of the recent research progress of some members of the B7 family in pancreatic cancer, which revealed that they can be involved in tumor progression through immune-dependent and non-immune-dependent pathways, highlighting the mechanisms of their involvement in tumor immune escape and assessing the prospects of their clinical application. Targeting B7 family immune checkpoints is expected to result in novel immunotherapeutic treatments for patients with pancreatic cancer.
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Affiliation(s)
- Xin Chen
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing 210009, China
- Jiangsu Key Laboratory of Molecular Imaging and Function Imaging, Medical School, Southeast University, Nanjing 210009, China
| | - Jie Li
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing 210009, China
| | - Yue Chen
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing 210009, China
| | - Ziting Que
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing 210009, China
| | - Jiawei Du
- Jiangsu Key Laboratory of Molecular Imaging and Function Imaging, Medical School, Southeast University, Nanjing 210009, China
| | - Jianqiong Zhang
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing 210009, China
- Jiangsu Key Laboratory of Molecular Imaging and Function Imaging, Medical School, Southeast University, Nanjing 210009, China
- Correspondence: ; Tel.: +86-25-83272314
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Crame EE, Nourmohammadi S, Wardill HR, Coller JK, Bowen JM. Contribution of TLR4 to colorectal tumor microenvironment, etiology and prognosis. J Cancer Res Clin Oncol 2022:10.1007/s00432-022-04199-4. [PMID: 35841426 DOI: 10.1007/s00432-022-04199-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/07/2022] [Indexed: 11/29/2022]
Abstract
PURPOSE Toll-like receptor 4 (TLR4) is increasingly recognized for its ability to govern the etiology and prognostic outcomes of colorectal cancer (CRC) due to its profound immunomodulatory capacity. Despite widespread interest in TLR4 and CRC, no clear analysis of current literature and data exists. Therefore, translational advances have failed to move beyond conceptual ideas and suggestions. METHODS We aimed to determine the relationship between TLR4 and CRC through a systematic review and analysis of published literature and datasets. Data were extracted from nine studies that reported survival, CRC staging and tumor progression data in relation to TLR4 expression. Primary and metastatic tumor samples with associated clinical data were identified through the Cancer Genome Atlas (TCGA) database. RESULTS Systematic review identified heterogeneous relationships between TLR4 and CRC traits, with no clear theme evident across studies. A total of 448 datasets were identified through the TCGA database. Analysis of TCGA datasets revealed TLR4 mRNA expression is decreased in advanced CRC stages (P < 0.05 for normal vs Stage II, Stage III and Stage IV). Stage-dependent impact of TLR4 expression on survival outcomes were also found, with high TLR4 expression associated with poorer prognosis (stage I vs III (HR = 4.2, P = 0.008) and stage I vs IV (HR = 11.3, P < 0.001)). CONCLUSION While TLR4 mRNA expression aligned with CRC staging, it appeared to heterogeneously regulate survival outcomes depending on the stage of disease. This underscores the complex relationship between TLR4 and CRC, with unique impacts dependent on disease stage.
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Affiliation(s)
- Elise E Crame
- Discipline of Physiology, School of Biomedicine, The University of Adelaide, Level 2 Helen Mayo South, North Terrace, Adelaide, SA, 5000, Australia.
| | - Saeed Nourmohammadi
- Discipline of Physiology, School of Biomedicine, The University of Adelaide, Level 2 Helen Mayo South, North Terrace, Adelaide, SA, 5000, Australia
| | - Hannah R Wardill
- Discipline of Physiology, School of Biomedicine, The University of Adelaide, Level 2 Helen Mayo South, North Terrace, Adelaide, SA, 5000, Australia.,Precision Medicine (Cancer), The South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Janet K Coller
- Discipline of Pharmacology, School of Biomedicine, The University of Adelaide, Adelaide, SA, Australia
| | - Joanne M Bowen
- Discipline of Physiology, School of Biomedicine, The University of Adelaide, Level 2 Helen Mayo South, North Terrace, Adelaide, SA, 5000, Australia
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10
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Zhao S, Wang Y, Yang N, Mu M, Wu Z, Li H, Tang X, Zhong K, Zhang Z, Huang C, Cao T, Zheng M, Wang G, Nie C, Yang H, Guo G, Zhou L, Zheng X, Tong A. Genome-scale CRISPR-Cas9 screen reveals novel regulators of B7-H3 in tumor cells. J Immunother Cancer 2022; 10:jitc-2022-004875. [PMID: 35768165 PMCID: PMC9244714 DOI: 10.1136/jitc-2022-004875] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/02/2022] [Indexed: 02/05/2023] Open
Abstract
Background Despite advances in B7 homolog 3 protein (B7-H3) based immunotherapy, the development of drug resistance remains a major clinical concern. The heterogeneity and emerging loss of B7-H3 expression are the main causes of drug resistance and treatment failure in targeted therapies, which reveals an urgent need to elucidate the mechanism underlying the regulation of B7-H3 expression. In this study, we identified and explored the crucial role of the transcription factor SPT20 homolog (SP20H) in B7-H3 expression and tumor progression. Methods Here, we performed CRISPR/Cas9-based genome scale loss-of-function screening to identify regulators of B7-H3 in human ovarian cancer cells. Signaling pathways altered by SP20H knockout were revealed by RNA sequencing. The regulatory role and mechanism of SP20H in B7-H3 expression were validated using loss-of-function and gain-of-function assays in vitro. The effects of inhibiting SP20H on tumor growth and efficacy of anti-B7-H3 treatment were evaluated in tumor-bearing mice. Results We identified SUPT20H (SP20H) as negative and eIF4E as positive regulators of B7-H3 expression in various cancer cells. Furthermore, we provided evidence that either SP20H loss or TNF-α stimulation in tumor cells constitutively activates p38 MAPK-eIF4E signaling, thereby upregulating B7-H3 expression. Loss of SP20H upregulated B7-H3 expression both in vitro and in vivo. Additionally, deletion of SP20H significantly suppressed tumor growth and increased immune cells infiltration in tumor microenvironment. More importantly, antibody–drug conjugates targeting B7-H3 exhibited superior antitumor performance against SP20H-deficient tumors relative to control groups. Conclusions Activation of p38 MAPK-eIF4E signaling serves as a key event in the transcription initiation and B7-H3 protein expression in tumor cells. Genetically targeting SP20H upregulates target antigen expression and sensitizes tumors to anti-B7-H3 treatment. Collectively, our findings provide new insight into the mechanisms underlying B7-H3 expression and introduce a potential synergistic target for existing antibody-based targeted therapy against B7-H3.
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Affiliation(s)
- Shasha Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - Yuelong Wang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Nian Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - Min Mu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - Zhiguo Wu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - Hexian Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - Xin Tang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Kunhong Zhong
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - Zongliang Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - Cheng Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - Ting Cao
- Lab of Infectious Diseases and Vaccine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Meijun Zheng
- Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Guoqing Wang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chunlai Nie
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - Hui Yang
- Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Gang Guo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - Liangxue Zhou
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xi Zheng
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Aiping Tong
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan, China
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11
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Mori JO, Shafran JS, Stojanova M, Katz MH, Gignac GA, Wisco JJ, Heaphy CM, Denis GV. Novel forms of prostate cancer chemoresistance to successful androgen deprivation therapy demand new approaches: Rationale for targeting BET proteins. Prostate 2022; 82:1005-1015. [PMID: 35403746 PMCID: PMC11134172 DOI: 10.1002/pros.24351] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/23/2022] [Accepted: 03/28/2022] [Indexed: 12/13/2022]
Abstract
In patients with prostate cancer, the duration of remission after treatment with androgen deprivation therapies (ADTs) varies dramatically. Clinical experience has demonstrated difficulties in predicting individual risk for progression due to chemoresistance. Drug combinations that inhibit androgen biosynthesis (e.g., abiraterone acetate) and androgen signaling (e.g., enzalutamide or apalutamide) have proven so effective that new forms of ADT resistance are emerging. In particular, prostate cancers with a neuroendocrine transcriptional signature, which demonstrate greater plasticity, and potentially, increased predisposition to metastasize, are becoming more prevalent. Notably, these subtypes had in fact been relatively rare before the widespread success of novel ADT regimens. Therefore, better understanding of these resistance mechanisms and potential alternative treatments are necessary to improve progression-free survival for patients treated with ADT. Targeting the bromodomain and extra-terminal (BET) protein family, specifically BRD4, with newer investigational agents may represent one such option. Several families of chromatin modifiers appear to be involved in ADT resistance and targeting these pathways could also offer novel approaches. However, the limited transcriptional and genomic information on ADT resistance mechanisms, and a serious lack of patient diversity in clinical trials, demand profiling of a much broader clinical and demographic range of patients, before robust conclusions can be drawn and a clear direction established.
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Affiliation(s)
- Joakin O. Mori
- Section of Hematology and Medical Oncology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
| | - Jordan S. Shafran
- Section of Hematology and Medical Oncology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
| | - Marija Stojanova
- Section of Hematology and Medical Oncology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
| | - Mark H. Katz
- Department of Urology, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Gretchen A. Gignac
- Section of Hematology and Medical Oncology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
| | - Jonathan J. Wisco
- Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Christopher M. Heaphy
- Section of Hematology and Medical Oncology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
- Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Gerald V. Denis
- Section of Hematology and Medical Oncology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
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12
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Sun HY, Du ST, Li YY, Deng GT, Zeng FR. Bromodomain and extra-terminal inhibitors emerge as potential therapeutic avenues for gastrointestinal cancers. World J Gastrointest Oncol 2022; 14:75-89. [PMID: 35116104 PMCID: PMC8790409 DOI: 10.4251/wjgo.v14.i1.75] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 08/11/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancers, including colorectal cancer, pancreatic cancer, liver cancer and gastric cancer, are severe social burdens due to high incidence and mortality rates. Bromodomain and extra-terminal (BET) proteins are epigenetic readers consisting of four conserved members (BRD2, BRD3, BRD4 and BRDT). BET family perform pivotal roles in tumorigenesis through transcriptional regulation, thereby emerging as potential therapeutic targets. BET inhibitors, disrupting the interaction between BET proteins and acetylated lysines, have been reported to suppress tumor initiation and progression in most of GI cancers. In this review, we will demonstrate how BET proteins participate in the GI cancers progression and highlight the therapeutic potential of targeting BET proteins for GI cancers treatment.
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Affiliation(s)
- Hui-Yan Sun
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Song-Tao Du
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Colorectal Surgical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Ya-Yun Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Guang-Tong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Fu-Rong Zeng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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13
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Feng R, Chen Y, Liu Y, Zhou Q, Zhang W. The role of B7-H3 in tumors and its potential in clinical application. Int Immunopharmacol 2021; 101:108153. [PMID: 34678689 DOI: 10.1016/j.intimp.2021.108153] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 09/08/2021] [Accepted: 09/08/2021] [Indexed: 02/07/2023]
Abstract
B7-H3 (CD276 molecule) is an immune checkpoint from the B7 family of molecules that acts more as a co-inhibitory molecule to promote tumor progression. It is abnormally expressed on tumor cells and can be induced to express on antigen-presenting cells (APCs) including dendritic cells (DCs) and macrophages. In the tumor microenvironment (TME), B7-H3 promotes tumor progression by impairing T cell response, promoting the polarization of tumor-associated macrophages (TAMs) to M2, inhibiting the function of DCs, and promoting the migration and invasion of cancer-associated fibroblasts (CAFs). In addition, through non-immunological functions, B7-H3 promotes tumor cell proliferation, invasion, metastasis, resistance, angiogenesis, and metabolism, or in the form of exosomes to promote tumor progression. In this process, microRNAs can regulate the expression of B7-H3. B7-H3 may serve as a potential biomarker for tumor diagnosis and a marker of poor prognosis. Immunotherapy targeting B7-H3 and the combination of B7-H3 and other immune checkpoints have shown certain efficacy. In this review, we summarized the basic characteristics of B7-H3 and its mechanism to promote tumor progression by inducing immunosuppression and non-immunological functions, as well as the potential clinical applications of B7-H3 and immunotherapy based on B7-H3.
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Affiliation(s)
- Ranran Feng
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Department of Andrology, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China
| | - Yong Chen
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Ying Liu
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Qing Zhou
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Wenling Zhang
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
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14
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Lara-Ureña N, García-Domínguez M. Relevance of BET Family Proteins in SARS-CoV-2 Infection. Biomolecules 2021; 11:1126. [PMID: 34439792 PMCID: PMC8391731 DOI: 10.3390/biom11081126] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/22/2021] [Accepted: 07/27/2021] [Indexed: 12/14/2022] Open
Abstract
The recent pandemic we are experiencing caused by the coronavirus disease 2019 (COVID-19) has put the world's population on the rack, with more than 191 million cases and more than 4.1 million deaths confirmed to date. This disease is caused by a new type of coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A massive proteomic analysis has revealed that one of the structural proteins of the virus, the E protein, interacts with BRD2 and BRD4 proteins of the Bromodomain and Extra Terminal domain (BET) family of proteins. BETs are essential to cell cycle progression, inflammation and immune response and have also been strongly associated with infection by different types of viruses. The fundamental role BET proteins play in transcription makes them appropriate targets for the propagation strategies of some viruses. Recognition of histone acetylation by BET bromodomains is essential for transcription control. The development of drugs mimicking acetyl groups, and thereby able to displace BET proteins from chromatin, has boosted interest on BETs as attractive targets for therapeutic intervention. The success of these drugs against a variety of diseases in cellular and animal models has been recently enlarged with promising results from SARS-CoV-2 infection studies.
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Affiliation(s)
| | - Mario García-Domínguez
- Andalusian Centre for Molecular Biology and Regenerative Medicine (CABIMER), CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Av. Américo Vespucio 24, 41092 Seville, Spain;
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15
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Geerdes EE, Sideras K, Aziz MH, van Eijck CH, Bruno MJ, Sprengers D, Boor PPC, Kwekkeboom J. Cancer Cell B7-H3 Expression Is More Prevalent in the Pancreato-Biliary Subtype of Ampullary Cancer Than in Pancreatic Cancer. Front Oncol 2021; 11:615691. [PMID: 33996541 PMCID: PMC8117087 DOI: 10.3389/fonc.2021.615691] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 03/30/2021] [Indexed: 11/29/2022] Open
Abstract
B7-H3 is an immunomodulatory member of the B7-superfamily with limited expression in normal tissues, but overexpression in several types of cancer. Therefore it is currently being explored as a potential target for cancer immunotherapy. The biological relevance of B7-H3 expression in pancreatic cancer is unclear, while there are no data on B7-H3 expression in ampullary cancer. We aimed to compare intra-tumoral B7-H3 expression between these two closely related cancer types and analyze its association with post-surgical disease course. B7-H3 expression levels were determined by immunohistochemistry in tissue microarrays of resected tumors of 137 pancreatic cancer patients and 83 patients with ampullary cancer of the pancreato-biliary subtype. B7-H3 was more frequently expressed in cancer cells of ampullary cancer patients compared to pancreatic cancer patients (51% versus 21%; p< 0.001). In ampullary cancer patients, but not in pancreatic cancer patients, B7-H3 cancer cell expression was associated with longer disease-free survival and patient survival. However, the prognostic value of B7-H3 was lost upon adjustment for CA19-9 levels. The frequencies of B7-H3 expression in tumor stroma did not differ between the two types of cancer (66% versus 63%). In both cancer types, stromal B7-H3 expression was not associated with post-surgical disease course. Compared to pancreatic cancer, B7-H3 is more frequently expressed in cancer cells of patients with the pancreato-biliary subtype of ampullary cancer. These data suggest that B7-H3 may represent an interesting potential target for immunotherapy in ampullary cancer rather than in pancreatic cancer.
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Affiliation(s)
- Emma E Geerdes
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Kostandinos Sideras
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands.,Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - M Hosein Aziz
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Casper H van Eijck
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Marco J Bruno
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Dave Sprengers
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Patrick P C Boor
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Jaap Kwekkeboom
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands
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16
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Guo F, Zhou Y, Guo H, Ren D, Jin X, Wu H. NR5A2 transcriptional activation by BRD4 promotes pancreatic cancer progression by upregulating GDF15. Cell Death Discov 2021; 7:78. [PMID: 33850096 PMCID: PMC8044179 DOI: 10.1038/s41420-021-00462-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/08/2021] [Accepted: 03/21/2021] [Indexed: 12/24/2022] Open
Abstract
NR5A2 is a transcription factor regulating the expression of various oncogenes. However, the role of NR5A2 and the specific regulatory mechanism of NR5A2 in pancreatic ductal adenocarcinoma (PDAC) are not thoroughly studied. In our study, Western blotting, real-time PCR, and immunohistochemistry were conducted to assess the expression levels of different molecules. Wound-healing, MTS, colony formation, and transwell assays were employed to evaluate the malignant potential of pancreatic cancer cells. We demonstrated that NR5A2 acted as a negative prognostic biomarker in PDAC. NR5A2 silencing inhibited the proliferation and migration abilities of pancreatic cancer cells in vitro and in vivo. While NR5A2 overexpression markedly promoted both events in vitro. We further identified that NR5A2 was transcriptionally upregulated by BRD4 in pancreatic cancer cells and this was confirmed by Chromatin immunoprecipitation (ChIP) and ChIP-qPCR. Besides, transcriptome RNA sequencing (RNA-Seq) was performed to explore the cancer-promoting effects of NR5A2, we found that GDF15 is a component of multiple down-regulated tumor-promoting gene sets after NR5A2 was silenced. Next, we showed that NR5A2 enhanced the malignancy of pancreatic cancer cells by inducing the transcription of GDF15. Collectively, our findings suggest that NR5A2 expression is induced by BRD4. In turn, NR5A2 activates the transcription of GDF15, promoting pancreatic cancer progression. Therefore, NR5A2 and GDF15 could be promising therapeutic targets in pancreatic cancer.
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Affiliation(s)
- Feng Guo
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yingke Zhou
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hui Guo
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dianyun Ren
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Xin Jin
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
| | - Heshui Wu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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17
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Hu X, Xu M, Hu Y, Li N, Zhou L. B7-H3, Negatively Regulated by miR-128, Promotes Colorectal Cancer Cell Proliferation and Migration. Cell Biochem Biophys 2021; 79:397-405. [PMID: 33743142 DOI: 10.1007/s12013-021-00975-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 03/05/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND B7 homolog 3 (B7-H3), a member of the immunoregulatory ligand B7 family, is pivotal in T-cell-mediated immune response. It is widely expressed in diverse human tumors and its high expression indicates the poor prognosis of the patients. Nonetheless, B7-H3's role in colorectal cancer (CRC) needs to be further explored. METHODS Western blot and immunohistochemistry were employed for detecting B7-H3 protein expression in CRC tissues and cell lines, respectively. Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized for detecting B7-H3 mRNA and miR-128 expression levels. CRC cell lines SW620 and HT29 were used to construct B7-H3 overexpression or knockdown cell models, respectively. Cell counting kit-8 (CCK-8), 5-bromo-2'-deoxyuridine (BrdU), and scratch wound healing assays were employed for evaluating the effects of B7-H3 on CRC cell multiplication and migration. Besides, the regulatory relationship between miR-128 and B7-H3 was validated through dual-luciferase reporter gene assay, qRT-PCR, and western blotting. RESULTS B7-H3 expression level was remarkably elevated in CRC tissues and cell lines, and its high expression level was associated with increased tumor size, positive lymph node metastasis, and increased T stage. In CRC cells, B7-H3 overexpression significantly facilitated the cell multiplication and migration, while B7-H3 knockdown worked oppositely. Moreover, B7-H3 was identified as a target of miR-128, and miR-128 negatively regulated B7-H3 expression in CRC cells. CONCLUSION B7-H3 expression is upregulated in CRC tissues and cell lines, and B7-H3 participates in promoting the proliferation and migration of CRC cells. Besides, B7-H3 expression is negatively regulated by miR-128 in CRC.
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Affiliation(s)
- Xiaomao Hu
- Department of Oncology, Affiliated Hospital of Xiangnan University, Chenzhou, 423000, Hunan, China.
- Department of Oncology, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, Guangdong, China.
| | - Minxian Xu
- Department of Oncology, Affiliated Hospital of Xiangnan University, Chenzhou, 423000, Hunan, China
| | - Yangzhi Hu
- Department of Gastroenterology Surgery, Affiliated Hospital of Xiangnan University, Chenzhou, 423000, Hunan, China
| | - Na Li
- Department of Oncology, Affiliated Hospital of Xiangnan University, Chenzhou, 423000, Hunan, China
| | - Lei Zhou
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
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18
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Wang N, Wu R, Comish PB, Kang R, Tang D. Pharmacological Modulation of BET Family in Sepsis. Front Pharmacol 2021; 12:642294. [PMID: 33776776 PMCID: PMC7990776 DOI: 10.3389/fphar.2021.642294] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 01/25/2021] [Indexed: 12/29/2022] Open
Abstract
The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis 3.0) recommended defining sepsis as a life-threatening organ dysfunction caused by the host's uncontrolled response to infection. The bromodomain and extra-terminal (BET) protein family (such as BRD2, BRD3, and BRD4), an epigenetic regulator of gene transcription, has recently been recognized as a significant septic regulator of inflammation and immune response, including cytokine and chemokine production. Mechanistically, the two N-terminal conserved tandem bromodomains (namely the first bromodomain [BD1] and the second bromodomain [BD2]) favor the binding of BETs to acetylated histones or transcription factors, thereby initiating gene transcription machinery after CycT1 and CDK9 (also known as P-TEFb) are recruited to gene promoters to phosphorylate RNA pol II. Notably, BD1 and BD2 are not functionally redundant because they have different target genes in innate immune cells. Small-molecule BET inhibitors (BETis) for different BDs, such as I-BET, JQ1, I-BET151, apabetalone, RVX-297, and dBET1 have shown promising therapeutic effects in experimental sepsis models. This mini-review summarizes the emerging roles of BETs and the applications of BETis in sepsis, discusses the existing shortcomings of BETis, and introduces possible future research directions in this area.
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Affiliation(s)
- Nian Wang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, United States
| | - Runliu Wu
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, United States
| | - Paul B Comish
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, United States
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, United States
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, United States
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Zhang C, Chen Y, Li F, Yang M, Meng F, Zhang Y, Chen W, Wang W. B7-H3 is spliced by SRSF3 in colorectal cancer. Cancer Immunol Immunother 2021; 70:311-321. [PMID: 32719950 PMCID: PMC10991627 DOI: 10.1007/s00262-020-02683-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 07/22/2020] [Indexed: 02/07/2023]
Abstract
B7-H3, an important co-inhibitor, is abnormally highly expressed in a variety of malignancies. The antibodies targeting B7-H3 have exhibited beneficial therapeutic effects in clinical trials. Therefore, discovery of the regulatory factors in B7-H3 expression may provide new strategies for tumor therapy. Here, we investigated the splicing factors involved in the splicing of B7-H3. By individual knockdown of the splicing factors in colorectal cancer (CRC) cells, we found that B7-H3 expression was markedly inhibited by SRSF3 and SRSF8, especially SRSF3. Then we found that both SRSF3 and B7-H3 were highly expressed in CRC tissues. Moreover, high-expression of either SRSF3 or B7-H3 was significantly correlated with poor prognosis of patients. The expression of B7-H3 mRNA and protein were evidently reduced by SRSF3 silence, but were enhanced by overexpression of SRSF3 in both HCT-116 and HCT-8 cells. The results from the RNA immunoprecipitation (RIP) assays demonstrated that SRSF3 protein directly binds to B7-H3 mRNA. In addition, we constructed a minigene recombinant plasmid for expressing B7-H3 exons 3-6. We found that SRSF3 contributed to the retention of B7-H3 exon 4. These findings demonstrate that SRSF3 involves in the splicing of B7-H3 by directly binding to its exon 4 and/or 6. It may provide novel insights into the regulatory mechanisms of B7-H3 expression and potential strategies for the treatment of CRC.
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Affiliation(s)
- Chunxia Zhang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, 215006, China
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Yinshuang Chen
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
| | - Fuchao Li
- Department of Gerontology, The Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, 210008, China
| | - Man Yang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
| | - Fanyi Meng
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
| | - Yawen Zhang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
| | - Weichang Chen
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, 215006, China.
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Shizhi Street 188, Suzhou, 215006, China.
| | - Weipeng Wang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China.
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, 215006, China.
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
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20
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Wang N, Wu R, Tang D, Kang R. The BET family in immunity and disease. Signal Transduct Target Ther 2021; 6:23. [PMID: 33462181 PMCID: PMC7813845 DOI: 10.1038/s41392-020-00384-4] [Citation(s) in RCA: 175] [Impact Index Per Article: 43.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 09/27/2020] [Accepted: 10/20/2020] [Indexed: 12/19/2022] Open
Abstract
Innate immunity serves as the rapid and first-line defense against invading pathogens, and this process can be regulated at various levels, including epigenetic mechanisms. The bromodomain and extraterminal domain (BET) family of proteins consists of four conserved mammalian members (BRD2, BRD3, BRD4, and BRDT) that regulate the expression of many immunity-associated genes and pathways. In particular, in response to infection and sterile inflammation, abnormally expressed or dysfunctional BETs are involved in the activation of pattern recognition receptor (e.g., TLR, NLR, and CGAS) pathways, thereby linking chromatin machinery to innate immunity under disease or pathological conditions. Mechanistically, the BET family controls the transcription of a wide range of proinflammatory and immunoregulatory genes by recognizing acetylated histones (mainly H3 and H4) and recruiting transcription factors (e.g., RELA) and transcription elongation complex (e.g., P-TEFb) to the chromatin, thereby promoting the phosphorylation of RNA polymerase II and subsequent transcription initiation and elongation. This review covers the accumulating data about the roles of the BET family in innate immunity, and discusses the attractive prospect of manipulating the BET family as a new treatment for disease.
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Affiliation(s)
- Nian Wang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Runliu Wu
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
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21
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Flem-Karlsen K, Fodstad Ø, Nunes-Xavier CE. B7-H3 Immune Checkpoint Protein in Human Cancer. Curr Med Chem 2020; 27:4062-4086. [PMID: 31099317 DOI: 10.2174/0929867326666190517115515] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 04/29/2019] [Accepted: 05/04/2019] [Indexed: 02/07/2023]
Abstract
B7-H3 belongs to the B7 family of immune checkpoint proteins, which are important regulators of the adaptive immune response and emerging key players in human cancer. B7-H3 is a transmembrane protein expressed on the surface of tumor cells, antigen presenting cells, natural killer cells, tumor endothelial cells, but can also be present in intra- and extracellular vesicles. Additionally, B7-H3 may be present as a circulating soluble isoform in serum and other body fluids. B7-H3 is overexpressed in a variety of tumor types, in correlation with poor prognosis. B7-H3 is a promising new immunotherapy target for anti-cancer immune response, as well as a potential biomarker. Besides its immunoregulatory role, B7-H3 has intrinsic pro-tumorigenic activities related to enhanced cell proliferation, migration, invasion, angiogenesis, metastatic capacity and anti-cancer drug resistance. B7-H3 has also been found to regulate key metabolic enzymes, promoting the high glycolytic capacity of cancer cells. B7-H3 receptors are still not identified, and little is known about the molecular mechanisms underlying B7-H3 functions. Here, we review the current knowledge on the involvement of B7-H3 in human cancer.
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Affiliation(s)
- Karine Flem-Karlsen
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.,Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Øystein Fodstad
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.,Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Caroline E Nunes-Xavier
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
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22
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Wang R, Ma Y, Zhan S, Zhang G, Cao L, Zhang X, Shi T, Chen W. B7-H3 promotes colorectal cancer angiogenesis through activating the NF-κB pathway to induce VEGFA expression. Cell Death Dis 2020; 11:55. [PMID: 31974361 PMCID: PMC6978425 DOI: 10.1038/s41419-020-2252-3] [Citation(s) in RCA: 145] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 01/09/2020] [Accepted: 01/10/2020] [Indexed: 02/07/2023]
Abstract
Tumor angiogenesis is a hallmark of cancer and is involved in the tumorigenesis of solid tumors. B7-H3, an immune checkpoint molecule, plays critical roles in proliferation, metastasis and tumorigenesis in diverse tumors; however, little is known about the biological functions and molecular mechanism underlying B7-H3 in regulating colorectal cancer (CRC) angiogenesis. In this study, we first demonstrated that the expression of B7-H3 was significantly upregulated and was positively associated with platelet endothelial cell adhesion molecule-1 (CD31) level in tissue samples from patients with CRC. In addition, a series of in vitro and in vivo experiments showed that conditioned medium from B7-H3 knockdown CRC cells significantly inhibited the migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs), whereas overexpression of B7-H3 had the opposite effect. Furthermore, B7-H3 promoted tumor angiogenesis by upregulating VEGFA expression. Recombinant VEGFA abolished the inhibitory effects of conditioned medium from shB7-H3 CRC cells on HUVEC angiogenesis, while VEGFA siRNA or a VEGFA-neutralizing antibody reversed the effects of conditioned medium from B7-H3-overexpressing CRC cells on HUVEC angiogenesis. Moreover, we verified that B7-H3 upregulated VEGFA expression and angiogenesis by activating the NF-κB pathway. Collectively, our findings identify the B7-H3/NF-κB/VEGFA axis in promoting CRC angiogenesis, which serves as a promising approach for CRC treatment.
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Affiliation(s)
- Ruoqin Wang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 708 Renmin Road, Suzhou, China
| | - Yanchao Ma
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, China
| | - Shenghua Zhan
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China
| | - Guangbo Zhang
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 708 Renmin Road, Suzhou, China.,Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China
| | - Lei Cao
- Jiangsu Key Laboratory of Gastrointestinal tumor Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China
| | - Xueguang Zhang
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 708 Renmin Road, Suzhou, China.,Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China.,Jiangsu Key Laboratory of Gastrointestinal tumor Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China
| | - Tongguo Shi
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 708 Renmin Road, Suzhou, China. .,Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China.
| | - Weichang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, China.
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23
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Zhou L, Zhao Y. B7-H3 Induces Ovarian Cancer Drugs Resistance Through An PI3K/AKT/BCL-2 Signaling Pathway. Cancer Manag Res 2019; 11:10205-10214. [PMID: 31819652 PMCID: PMC6899073 DOI: 10.2147/cmar.s222224] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Accepted: 10/22/2019] [Indexed: 12/13/2022] Open
Abstract
Purpose This study was aimed to investigate the underlying mechanism of B7-H3 induced ovarian cancer proliferation and drugs resistance. Materials and methods We compared the expression of B7-H3 in ovarian tumor tissues from high-malignant or low-malignant patients by immunohistochemistry. We established B7-H3 overexpression and knockout ovarian cells by CRISPR-Cas9 technology and examined the expression of the PI3K/AKT/BCL-2 signals in tumor cells by Western blot or immunofluorescence. We detected the B7-H3 overexpression ovarian cancer cells drugs resistance by CCK8 cell proliferation analysis and Annexin V/PI staining. Tumor-bearing mice were used to investigate the anticancer effects of PI3K/AKT inhibitors in combination with B7-H3 neutralizing antibodies. Results Enhanced expression of B7-H3 was observed in ovarian tumor tissues from high-malignant patients compared to those from low-malignant patients. Notably, B7-H3 overexpression caused enhanced cells proliferation and chemo-resistance in vitro and in vivo through the activation of PI3K/AKT signaling pathways and up-regulation of BCL-2 protein. Combination of chemotherapeutic agents and B7-H3 neutralizing antibodies efficiently reverses the drugs resistance induced by B7-H3, resulting in improved anticancer effects in ovarian cancer. Conclusion B7-H3 expression induces the activation the PI3K/AKT signaling pathway and up-regulates BCL-2 in protein level, resulting in the sustained growth and chemo-resistance in ovarian cancer. Blockade of B7-H3 signals efficiently reverses the chemo-resistance, which provides an innovative target in ovarian cancer treatment.
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Affiliation(s)
- Li Zhou
- Department of Gynecology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Yangchun Zhao
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People's Republic of China
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24
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Brunetti O, Badalamenti G, De Summa S, Calabrese A, Argentiero A, Fucci L, Longo V, Galetta D, Perrotti PMS, Pinto R, Petriella D, Danza K, Tommasi S, Leonetti F, Silvestris N. Molecular Characterization of a Long-Term Survivor Double Metastatic Non-Small Cell Lung Cancer and Pancreatic Ductal Adenocarcinoma Treated with Gefitinib in Combination with Gemcitabine Plus Nab-Paclitaxel and mFOLFOX6 as First and Second Line Therapy. Cancers (Basel) 2019; 11:cancers11060749. [PMID: 31146476 PMCID: PMC6627355 DOI: 10.3390/cancers11060749] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Revised: 05/21/2019] [Accepted: 05/28/2019] [Indexed: 02/06/2023] Open
Abstract
The management of multiple primary cancers, an event not so infrequent in oncology practice, is a critical issue due to the lack of literature. In this study, we reported the case of a patient with non-small cell metastatic lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) who received gefitinib in combination with gemcitabine plus nab-paclitaxel and with mFOLFOX6 in first and second line, respectively. It achieved a progression-free survival and a28-months overall survival (OS) for NSCLC and PFS-1 and OS of 20 and 13 months, respectively for PDAC. Moreover, the combination of gefitinib and chemotherapy treatmentsshowed a good safety profile. Given the insignificant frequency of this case, we performed a molecular characterization of both neoplasms with the aim to investigate the existence of particular activated pathways and/or similar immunological mutations. It is interesting to note that two neoplasms shared a common mutation ofthe B7-H3 gene, with the consecutive impairment of its expressed protein. In both PDAC and NSCLC, the expression of this protein was associated with a worse survival rate. Since B7-H3 is an anti-apoptotic protein, the reduction of its expression or function should justify a pro-apoptotic activity with a leading justification of the long survival of the patient considered in this report.
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Affiliation(s)
- Oronzo Brunetti
- Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco, 65, 70124 Bari, Italy.
| | - Giuseppe Badalamenti
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy.
| | - Simona De Summa
- Pharmacogenetics and Molecular Diagnostic Unit, IRCCS IstitutoTumori "Giovanni Paolo II", Viale Orazio Flacco, 65, 70124 Bari, Italy.
| | - Angela Calabrese
- Department of Radiology, IRCCS IstitutoTumori "Giovanni Paolo II", VialeOrazio Flacco, 65, 70124 Bari, Italy.
| | - Antonella Argentiero
- Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco, 65, 70124 Bari, Italy.
| | - Livia Fucci
- Histopathological Unit, IRCCS IstitutoTumori "Giovanni Paolo II", VialeOrazio Flacco, 65, 70124 Bari, Italy.
| | - Vito Longo
- Medical ThoracicOncology Unit, IRCCS IstitutoTumori "Giovanni Paolo II", VialeOrazio Flacco, 65, 70124 Bari, Italy.
| | - Domenico Galetta
- Medical ThoracicOncology Unit, IRCCS IstitutoTumori "Giovanni Paolo II", VialeOrazio Flacco, 65, 70124 Bari, Italy.
| | - Pia Maria Soccorsa Perrotti
- Department of Radiology, IRCCS IstitutoTumori "Giovanni Paolo II", VialeOrazio Flacco, 65, 70124 Bari, Italy.
| | - Rosamaria Pinto
- Pharmacogenetics and Molecular Diagnostic Unit, IRCCS IstitutoTumori "Giovanni Paolo II", Viale Orazio Flacco, 65, 70124 Bari, Italy.
| | - Daniela Petriella
- Pharmacogenetics and Molecular Diagnostic Unit, IRCCS IstitutoTumori "Giovanni Paolo II", Viale Orazio Flacco, 65, 70124 Bari, Italy.
| | - Katia Danza
- Pharmacogenetics and Molecular Diagnostic Unit, IRCCS IstitutoTumori "Giovanni Paolo II", Viale Orazio Flacco, 65, 70124 Bari, Italy.
| | - Stefania Tommasi
- Pharmacogenetics and Molecular Diagnostic Unit, IRCCS IstitutoTumori "Giovanni Paolo II", Viale Orazio Flacco, 65, 70124 Bari, Italy.
| | - Francesco Leonetti
- Dipartimento di Farmacia-Scienze del Farmaco, Universityof Bari, 70125 Bari, Italy.
| | - Nicola Silvestris
- ScientificDirectorate, IRCCS IstitutoTumori "Giovanni Paolo II", Viale OrazioFlacco, 65, 70124 Bari, Italy.
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