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1
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Chien YC, Wu JY, Liu LC, Yu YL. Capsanthin inhibits migration and reduces N-linked glycosylation of PD-L1 via the EZH2-PD-L1 axis in triple-negative breast cancer brain metastasis. Cell Death Discov 2025; 11:85. [PMID: 40038276 DOI: 10.1038/s41420-025-02368-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 01/22/2025] [Accepted: 02/20/2025] [Indexed: 03/06/2025] Open
Abstract
Breast cancer metastasis to the brain, occurring in about 15-25% of cases, represents a major obstacle in the treatment of triple-negative breast cancer (TNBC). The molecular mechanisms driving this form of metastasis are still largely unknown. PD-L1, an immune checkpoint protein, is central to tumor immune evasion and has become a focus for immunotherapy development. While PD-L1 inhibitors have shown success in various cancer types, their effectiveness in TNBC brain metastases remains to be fully investigated. This highlights the urgent need to understand the complex interactions between metastatic brain tumors and the tumor microenvironment in TNBC patients. Gaining insights into these dynamics is crucial for developing new targeted therapies, including those that modulate the PD-L1 pathway, to better manage and treat TNBC brain metastases. We explore the impact of Capsanthin on the tumor microenvironment of brain metastases in triple-negative breast cancer (TNBC). Our results reveal that Capsanthin effectively inhibits the migration of brain metastasis TNBC cells. Furthermore, Capsanthin significantly reduces the expression of EZH2 and N-linked glycosylated PD-L1 proteins and mRNA in TNBC cells, encompassing both primary and metastatic sites, as well as in mesenchymal stem cells (3A6). Data from The Cancer Genome Atlas (TCGA) indicate that elevated expression levels of EZH2 correlate with poorer patient prognosis. Immunoprecipitation assays demonstrate a direct interaction between EZH2 and PD-L1 in brain metastases of TNBC, underscoring the pivotal role of the EZH2-PD-L1 axis. Additionally, Capsanthin was found to suppress the expression of epithelial-mesenchymal transition (EMT) markers in metastatic brain TNBC cells and mesenchymal stem cells. Our results suggest that Capsanthin can modulate the tumor microenvironment and inhibit key pathways involved in cancer progression, offering potential therapeutic benefits for patients with TNBC brain metastases.
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Affiliation(s)
- Yi-Chung Chien
- Institute of Translational Medicine and New Drug Development, China Medical University, Taichung, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jia-Yan Wu
- Institute of Translational Medicine and New Drug Development, China Medical University, Taichung, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Liang-Chih Liu
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.
- Department of Surgery, China Medical University Hospital, Taichung, Taiwan.
| | - Yung-Luen Yu
- Institute of Translational Medicine and New Drug Development, China Medical University, Taichung, Taiwan.
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan.
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2
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Hu Q, Feng J, Qi L, Jin Y. Stromal Reprogramming Optimizes KRAS-Specific Chemotherapy Inducing Antitumor Immunity in Pancreatic Cancer. ACS APPLIED MATERIALS & INTERFACES 2024; 16:61583-61598. [PMID: 39480275 DOI: 10.1021/acsami.4c10404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer and is often characterized with rich stroma and mutated KRAS, which determines the tumor microenvironment (TME) and therapy response. Turning immunologically "cold" PDAC into "hot" is an unmet need to improve the therapeutic outcome. Herein, we propose a programmable strategy by sequential delivery of pirfenidone (PFD) and nanoengineered KRAS specific inhibitor (AMG510) and gemcitabine (GEM) liposomes. PFD could achieve precise reduction of the extracellular matrix (ECM) by reprogramming pancreatic stellate cells (PSCs). Subsequently, targeting the KRAS-directed oncogenic signaling pathway effectively inhibited tumor proliferation and migration, which sensitized a chemotherapeutic drug and promoted immunogenic cell death (ICD). In preclinical mouse models of PDAC, PFD mediated stromal modulation enhanced the deep penetration of nanoparticles and improved their subsequent performance in tumor growth inhibition. The molecular mechanisms elucidated that the stroma intervention and KRAS signal pathway regulation reshaped the immunosuppression of PDAC and optimized cytotoxic T-cell-mediated antitumor immunity with sustained antitumor memory. Overall, our study provides a practical strategy with clinical translational promise for immunologically cold tumor PDAC treatment.
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Affiliation(s)
- Qinglian Hu
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Jiayu Feng
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Lulu Qi
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Yuanxiang Jin
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
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3
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Sun Z, Ma X, Zhao C, Fan L, Yin S, Hu H. Delta-tocotrienol disrupts PD-L1 glycosylation and reverses PD-L1-mediated immune suppression. Biomed Pharmacother 2024; 170:116078. [PMID: 38159375 DOI: 10.1016/j.biopha.2023.116078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 12/11/2023] [Accepted: 12/21/2023] [Indexed: 01/03/2024] Open
Abstract
PD-L1-mediated immune escape plays an important role in cancer development and progression. Targeting PD-L1 is consider to be an attractive approach for cancer treatment. PD-L1 is a heavily N-linked glycosylated protein, and the glycosylation of PD-L1 is essential for its ability to interact with its receptor PD-1 to mediate immune suppression. In the present study, we demonstrated for the first time that delta-tocotrienol (δ-T3) not any of the other forms of vitamin E was able to disrupt PD-L1 glycosylation mechanistically associated with the suppression of TCF4-STT3a/STT3b axis. The inhibition of PD-L1 glycosylation by δ-T3 resulted in the decrease of PD-L1 expression and its exosomal secretion, leading to the reduction of PD-L1 and PD-1 interaction, and reversing PD-L1-mediated immune suppression, which in turn contributed to the inhibitory effect on tumor growth. The findings of the present study provide a novel mechanistic interpretation for the superior anticancer activity of δ-T3 among 8 isomers of the vitamin E.
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Affiliation(s)
- Zhenou Sun
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory for Food Non-thermal Processing, China Agricultural University, No.17 Qinghua East Road, Haidian District, Beijing 100083, China; College of Food Science and Nutritional Engineering, Tianjin University of Science and Technology, Tianjin, China
| | - Xuan Ma
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory for Food Non-thermal Processing, China Agricultural University, No.17 Qinghua East Road, Haidian District, Beijing 100083, China; College of Biochemical Engineering, Beijing Union University, Beijing, China
| | - Chong Zhao
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory for Food Non-thermal Processing, China Agricultural University, No.17 Qinghua East Road, Haidian District, Beijing 100083, China
| | - Lihong Fan
- College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Shutao Yin
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory for Food Non-thermal Processing, China Agricultural University, No.17 Qinghua East Road, Haidian District, Beijing 100083, China.
| | - Hongbo Hu
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory for Food Non-thermal Processing, China Agricultural University, No.17 Qinghua East Road, Haidian District, Beijing 100083, China.
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4
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Peri SS, Narayanaa Y K, Hubert TD, Rajaraman R, Arfuso F, Sundaram S, Archana B, Warrier S, Dharmarajan A, Perumalsamy LR. Navigating Tumour Microenvironment and Wnt Signalling Crosstalk: Implications for Advanced Cancer Therapeutics. Cancers (Basel) 2023; 15:5847. [PMID: 38136392 PMCID: PMC10741643 DOI: 10.3390/cancers15245847] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/06/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
Cancer therapeutics face significant challenges due to drug resistance and tumour recurrence. The tumour microenvironment (TME) is a crucial contributor and essential hallmark of cancer. It encompasses various components surrounding the tumour, including intercellular elements, immune system cells, the vascular system, stem cells, and extracellular matrices, all of which play critical roles in tumour progression, epithelial-mesenchymal transition, metastasis, drug resistance, and relapse. These components interact with multiple signalling pathways, positively or negatively influencing cell growth. Abnormal regulation of the Wnt signalling pathway has been observed in tumorigenesis and contributes to tumour growth. A comprehensive understanding and characterisation of how different cells within the TME communicate through signalling pathways is vital. This review aims to explore the intricate and dynamic interactions, expressions, and alterations of TME components and the Wnt signalling pathway, offering valuable insights into the development of therapeutic applications.
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Affiliation(s)
- Shraddha Shravani Peri
- Department of Biomedical Sciences, Faculty of Biomedical Sciences, Technology and Research, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, India; (S.S.P.); (K.N.Y.); (T.D.H.); (R.R.)
| | - Krithicaa Narayanaa Y
- Department of Biomedical Sciences, Faculty of Biomedical Sciences, Technology and Research, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, India; (S.S.P.); (K.N.Y.); (T.D.H.); (R.R.)
| | - Therese Deebiga Hubert
- Department of Biomedical Sciences, Faculty of Biomedical Sciences, Technology and Research, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, India; (S.S.P.); (K.N.Y.); (T.D.H.); (R.R.)
| | - Roshini Rajaraman
- Department of Biomedical Sciences, Faculty of Biomedical Sciences, Technology and Research, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, India; (S.S.P.); (K.N.Y.); (T.D.H.); (R.R.)
| | - Frank Arfuso
- School of Human Sciences, The University of Western Australia, Nedlands, WA 6009, Australia;
| | - Sandhya Sundaram
- Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, India; (S.S.); (B.A.)
| | - B. Archana
- Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, India; (S.S.); (B.A.)
| | - Sudha Warrier
- Department of Biotechnology, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, India;
| | - Arun Dharmarajan
- Department of Biomedical Sciences, Faculty of Biomedical Sciences, Technology and Research, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, India; (S.S.P.); (K.N.Y.); (T.D.H.); (R.R.)
- School of Human Sciences, The University of Western Australia, Nedlands, WA 6009, Australia;
- Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
| | - Lakshmi R. Perumalsamy
- Department of Biomedical Sciences, Faculty of Biomedical Sciences, Technology and Research, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, India; (S.S.P.); (K.N.Y.); (T.D.H.); (R.R.)
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5
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Cao J, Zhang Z, Zhou L, Luo M, Li L, Li B, Nice EC, He W, Zheng S, Huang C. Oncofetal reprogramming in tumor development and progression: novel insights into cancer therapy. MedComm (Beijing) 2023; 4:e427. [PMID: 38045829 PMCID: PMC10693315 DOI: 10.1002/mco2.427] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 10/20/2023] [Accepted: 10/23/2023] [Indexed: 12/05/2023] Open
Abstract
Emerging evidence indicates that cancer cells can mimic characteristics of embryonic development, promoting their development and progression. Cancer cells share features with embryonic development, characterized by robust proliferation and differentiation regulated by signaling pathways such as Wnt, Notch, hedgehog, and Hippo signaling. In certain phase, these cells also mimic embryonic diapause and fertilized egg implantation to evade treatments or immune elimination and promote metastasis. Additionally, the upregulation of ATP-binding cassette (ABC) transporters, including multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), and breast cancer-resistant protein (BCRP), in drug-resistant cancer cells, analogous to their role in placental development, may facilitate chemotherapy efflux, further resulting in treatment resistance. In this review, we concentrate on the underlying mechanisms that contribute to tumor development and progression from the perspective of embryonic development, encompassing the dysregulation of developmental signaling pathways, the emergence of dormant cancer cells, immune microenvironment remodeling, and the hyperactivation of ABC transporters. Furthermore, we synthesize and emphasize the connections between cancer hallmarks and embryonic development, offering novel insights for the development of innovative cancer treatment strategies.
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Affiliation(s)
- Jiangjun Cao
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Zhe Zhang
- Zhejiang Provincial Key Laboratory of Pancreatic Diseasethe First Affiliated HospitalSchool of MedicineZhejiang UniversityZhejiangChina
| | - Li Zhou
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education)Department of Infectious Diseasesthe Second Affiliated HospitalInstitute for Viral Hepatitis, Chongqing Medical UniversityChongqingChina
| | - Maochao Luo
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Lei Li
- Department of anorectal surgeryHospital of Chengdu University of Traditional Chinese Medicine and Chengdu University of Traditional Chinese MedicineChengduChina
| | - Bowen Li
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Edouard C. Nice
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVICAustralia
| | - Weifeng He
- State Key Laboratory of TraumaBurn and Combined InjuryInstitute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University)ChongqingChina
| | - Shaojiang Zheng
- Hainan Cancer Medical Center of The First Affiliated Hospital, the Hainan Branch of National Clinical Research Center for Cancer, Hainan Engineering Research Center for Biological Sample Resources of Major DiseasesHainan Medical UniversityHaikouChina
- Key Laboratory of Tropical Cardiovascular Diseases Research of Hainan Province, Hainan Women and Children's Medical Center, Key Laboratory of Emergency and Trauma of Ministry of EducationHainan Medical UniversityHaikouChina
| | - Canhua Huang
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
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6
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Liu Z, Xu X, Liu H, Zhao X, Yang C, Fu R. Immune checkpoint inhibitors for multiple myeloma immunotherapy. Exp Hematol Oncol 2023; 12:99. [PMID: 38017516 PMCID: PMC10685608 DOI: 10.1186/s40164-023-00456-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 11/02/2023] [Indexed: 11/30/2023] Open
Abstract
Multiple myeloma (MM) is related to immune disorders, recent studys have revealed that immunotherapy can greatly benefit MM patients. Immune checkpoints can negatively modulate the immune system and are closely associated with immune escape. Immune checkpoint-related therapy has attracted much attention and research in MM. However, the efficacy of those therapies need further improvements. There need more thoughts about the immune checkpoint to translate their use in clinical work. In our review, we aggregated the currently known immune checkpoints and their corresponding ligands, further more we propose various ways of potential translation applying treatment based on immune checkpoints for MM patients.
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Affiliation(s)
- Zhaoyun Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Xintong Xu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Hui Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Xianghong Zhao
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Chun Yang
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Rong Fu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052, China.
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7
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Feng C, Zhang L, Chang X, Qin D, Zhang T. Regulation of post-translational modification of PD-L1 and advances in tumor immunotherapy. Front Immunol 2023; 14:1230135. [PMID: 37554324 PMCID: PMC10405826 DOI: 10.3389/fimmu.2023.1230135] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Accepted: 07/10/2023] [Indexed: 08/10/2023] Open
Abstract
The immune checkpoint molecules programmed cell death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1) are one of the most promising targets for tumor immunotherapy. PD-L1 is overexpressed on the surface of tumor cells and inhibits T cell activation upon binding to PD⁃1 on the surface of T cells, resulting in tumor immune escape. The therapeutic strategy of targeting PD-1/PD-L1 involves blocking this binding and restoring the tumor-killing effect of immune cells. However, in clinical settings, a relatively low proportion of cancer patients have responded well to PD-1/PD-L1 blockade, and clinical outcomes have reached a bottleneck and no substantial progress has been made. In recent years, PD-L1 post-translation modifications (PTMs) have gradually become a hot topic in the field of PD-L1 research, which will provide new insights to improve the efficacy of current anti-PD-1/PD-L1 therapies. Here, we summarized and discussed multiple PTMs of PD-L1, including glycosylation, ubiquitination, phosphorylation, acetylation and palmitoylation, with a major emphasis on mechanism-based therapeutic strategies (including relevant enzymes and targets that are already in clinical use and that may become drugs in the future). We also summarized the latest research progress of PTMs of PD-L1/PD-1 in regulating immunotherapy. The review provided novel strategies and directions for tumor immunotherapy research based on the PTMs of PD-L1/PD-1.
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Affiliation(s)
- Chong Feng
- Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Lening Zhang
- Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Xin Chang
- Ophthalmology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Dongliang Qin
- Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Tao Zhang
- Gastrointestinal and Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
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Yang H, Xu F, Chen Y, Tian Z. Structural N-glycoproteomics characterization of cell-surface N-glycosylation of MCF-7/ADR cancer stem cells. J Chromatogr B Analyt Technol Biomed Life Sci 2023; 1219:123647. [PMID: 36870092 DOI: 10.1016/j.jchromb.2023.123647] [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: 01/02/2023] [Revised: 02/14/2023] [Accepted: 02/20/2023] [Indexed: 02/24/2023]
Abstract
Breast cancer is responsible for the highest mortality all over the world. Cancer stem cells (CSCs) along with epithelial mesenchymal transition (EMT) are identified as a driver of cancer which are responsible for cancer metastasis and drug resistance. Several signaling pathways are associated with drug resistance. Additionally, glycosyltransferases regulate different types of glycosylation which are involved in drug resistance. To the end, it is urgent to figure out the knowledge on cell-surface altered N-glycosylation and putative markers. Here, differential cell-surface intact N-glycopeptides in adriamycin (ADR)-resistant michigan breast cancer foundation-7 stem cells (MCF-7/ADR CSCs) relative to ADR-sensitive MCF-7 CSCs were analyzed with site- and structure-specific quantitative N-glycoproteomics. The intact N-glycopeptides and differentially expressed intact N-glycopeptides (DEGPs) were determined and quantified via intact N-glycopeptide search engine GPSeeker. Totally, 4777 intact N-glycopeptides were identified and N-glycan sequence structures among 2764 IDs were distinguished from their isomers by structure-diagnostic fragment ions. Among 1717 quantified intact N-glycopeptides, 104 DEGPs were determined (fold change ≥ 1.5 and p value < 0.05). Annotation of protein-protein interaction and biological processes among others of DEGPs were finally carried out; down-regulated intact N-glycopeptide with bisecting GlcNAc from p38-interacting protein and up-regulated intact N-glycopeptide with β1,6-branching N-glycan from integrin beta-5 were found.
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Affiliation(s)
- Hailun Yang
- School of Chemical Science & Engineering, Shanghai Key Laboratory of Chemical Assessment and Sustainability, Tongji University, Shanghai 200092, China
| | - Feifei Xu
- School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
| | - Yun Chen
- School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
| | - Zhixin Tian
- School of Chemical Science & Engineering, Shanghai Key Laboratory of Chemical Assessment and Sustainability, Tongji University, Shanghai 200092, China.
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Zhang T, Yu-Jing L, Ma T. Role of regulation of PD-1 and PD-L1 expression in sepsis. Front Immunol 2023; 14:1029438. [PMID: 36969168 PMCID: PMC10035551 DOI: 10.3389/fimmu.2023.1029438] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 02/27/2023] [Indexed: 03/11/2023] Open
Abstract
Long term immunosuppression is problematic during sepsis. The PD-1 and PD-L1 immune checkpoint proteins have potent immunosuppressive functions. Recent studies have revealed several features of PD-1 and PD-L1 and their roles in sepsis. Here, we summarize the overall findings of PD-1 and PD-L1 by first reviewing the biological features of PD-1 and PD-L1 and then discussing the mechanisms that control the expression of PD-1 and PD-L1. We then review the functions of PD-1 and PD-L1 in physiological settings and further discuss PD-1 and PD-L1 in sepsis, including their involvement in several sepsis-related processes and their potential therapeutic relevance in sepsis. In general, PD-1 and PD-L1 have critical roles in sepsis, indicating that their regulation may be a potential therapeutic target for sepsis.
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Affiliation(s)
- Teng Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Li Yu-Jing
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| | - Tao Ma
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- *Correspondence: Tao Ma,
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Zhang R, Zhang X, Zhang W, Cui W, Xiao Y, Liu L, Zhi S, Feng X, Liu X, Shen Y, Chai J, Hao J. Sohlh2 Regulates the Stemness and Differentiation of Colon Cancer Stem Cells by Downregulating LncRNA-H19 Transcription. Mol Cancer Res 2023; 21:115-126. [PMID: 36287177 DOI: 10.1158/1541-7786.mcr-22-0134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 07/01/2022] [Accepted: 10/13/2022] [Indexed: 02/03/2023]
Abstract
Colon cancer stem cells (CSC) are tumor-initiating cells that drive tumorigenesis and progression through self-renewal and various differentiation potency. Therefore, the identification of factors critical for colon CSC function is vital for the development of therapies. Sohlh2 belongs to the superfamily of bhlh transcription factors and serves as a tumor suppressor in several tumors. The role of Sohlh2 in CSCs remains unknown. Here we demonstrated that Sohlh2 was related to the inhibition of LncRNA-H19/miR-141/β-catenin signaling and led to the consequent suppression of colon CSC stemness and the promotion of colon CSC differentiation in vitro and in vivo. Moreover, Sohlh2 could directly bind to the promoter of LncRNA-H19 and repress its transcription activity. LncRNA-H19 mediated the effects of Sohlh2 on colon CSC stemness and differentiation. Clinically, we observed a significant inverse correlation between Sohlh2 and LncRNA-H19, β-catenin, Lgr5, CD133 expression levels, and positive correlation between Sohlh2 and MUC2, TFF2 expression in colon cancer tissues. Collectively, our findings suggest an important role of the Sohlh2/LncRNA-H19/miR-141/β-catenin pathway in regulating colon CSC stemness and differentiation, suggesting potential therapeutic targets for colon cancer. IMPLICATIONS This study identifies that Sohlh2 directly manipulates LncRNA-H19 transcription and suppresses the β-catenin signaling pathway and the Sohlh2/LncRNA-H19/miR-141/β-catenin signaling pathway plays an essential role in the stemness of colon CSCs.
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Affiliation(s)
- Ruihong Zhang
- Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China
| | - Xiaoli Zhang
- Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China
| | - Wenfang Zhang
- Department of Reproductive Medicine, Linyi Maternal and Child Health Care Hospital, Shandong, China
| | - Weiwei Cui
- Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China
| | - Yunling Xiao
- Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Shandong, China
| | - Lanlan Liu
- Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China
| | - Sujuan Zhi
- Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China
| | - Xiaoning Feng
- Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China
| | - Xuyue Liu
- Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China
| | - Ying Shen
- Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China
| | - Jie Chai
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong, China
| | - Jing Hao
- Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China
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Du W, Menjivar RE, Donahue KL, Kadiyala P, Velez-Delgado A, Brown KL, Watkoske HR, He X, Carpenter ES, Angeles CV, Zhang Y, Pasca di Magliano M. WNT signaling in the tumor microenvironment promotes immunosuppression in murine pancreatic cancer. J Exp Med 2023; 220:e20220503. [PMID: 36239683 PMCID: PMC9577101 DOI: 10.1084/jem.20220503] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 07/06/2022] [Accepted: 09/07/2022] [Indexed: 01/16/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is associated with activation of WNT signaling. Whether this signaling pathway regulates the tumor microenvironment has remained unexplored. Through single-cell RNA sequencing of human pancreatic cancer, we discovered that tumor-infiltrating CD4+ T cells express TCF7, encoding for the transcription factor TCF1. We conditionally inactivated Tcf7 in CD4 expressing T cells in a mouse model of pancreatic cancer and observed changes in the tumor immune microenvironment, including more CD8+ T cells and fewer regulatory T cells, but also compensatory upregulation of PD-L1. We then used a clinically available inhibitor of Porcupine, a key component of WNT signaling, and observed similar reprogramming of the immune response. WNT signaling inhibition has limited therapeutic window due to toxicity, and PD-L1 blockade has been ineffective in PDA. Here, we show that combination targeting reduces pancreatic cancer growth in an experimental model and might benefit the treatment of pancreatic cancer.
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Affiliation(s)
- Wenting Du
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | - Rosa E. Menjivar
- Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI
| | | | - Padma Kadiyala
- Immunology Program, University of Michigan, Ann Arbor, MI
| | - Ashley Velez-Delgado
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI
| | | | | | - Xi He
- College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI
| | - Eileen S. Carpenter
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI
| | - Christina V. Angeles
- Department of Surgery, University of Michigan, Ann Arbor, MI
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI
| | - Yaqing Zhang
- Department of Surgery, University of Michigan, Ann Arbor, MI
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI
| | - Marina Pasca di Magliano
- Department of Surgery, University of Michigan, Ann Arbor, MI
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI
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12
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Zhao L, Zhang W, Luan F, Chen X, Wu H, He Q, Weng Q, Ding L, Yang B. Butein suppresses PD-L1 expression via downregulating STAT1 in non-small cell lung cancer. Biomed Pharmacother 2023; 157:114030. [PMID: 36455456 DOI: 10.1016/j.biopha.2022.114030] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 11/13/2022] [Accepted: 11/17/2022] [Indexed: 11/29/2022] Open
Abstract
PD-L1 (programmed cell death ligand 1) is frequently up-regulated in tumors and is critical in tumor immune escape. In addition to antibodies that block the interaction between PD-L1 and PD-1 (programmed cell death protein 1), small-molecule compounds that suppress PD-L1 expression also exhibit significant anti-tumor effects, emerging as a new strategy targeting PD-L1. By using a cell-based screening model, we found that butein, a natural chalcone compound, significantly reduced the cytoplasm and cell surface expression of PD-L1. This effect was further validated in various non-small cell lung cancer (NSCLC) cell lines and primary cells derived from clinical NSCLC tissues. Butein inhibited PD-L1 transcription, but not the half-life of PD-L1 protein. Butein reduced STAT1 level and butein-induced PD-L1 suppression was eliminated by the absence of STAT1. By co-culture system, butein improved tumor elimination by increasing the killing ability of CD8+ T cells. By in vivo study, we further confirmed that butein downregulated PD-L1 expression and improved infiltration of CD8+ T cells in tumor tissues. Taken together, our study suggested that butein could suppress the transcription of PD-L1 via downregulating STAT1, providing a theoretical basis for the application of butein in anti-tumor therapy.
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Affiliation(s)
- Lin Zhao
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wenxin Zhang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Fengming Luan
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou 310009, China
| | - Xi Chen
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Honghai Wu
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qiaojun He
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310018, China; Cancer Center of Zhejiang University, Hangzhou 310058, China
| | - Qinjie Weng
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Center of Drug Safety Evaluation and Research, Zhejiang University, Hangzhou 310058, China
| | - Ling Ding
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
| | - Bo Yang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310018, China.
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13
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Chen Y, Chen M, Deng K. Blocking the Wnt/β‑catenin signaling pathway to treat colorectal cancer: Strategies to improve current therapies (Review). Int J Oncol 2022; 62:24. [PMID: 36579676 PMCID: PMC9854240 DOI: 10.3892/ijo.2022.5472] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 12/02/2022] [Indexed: 12/28/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumor types occurring in the digestive system. The incidence of CRC has exhibits yearly increases and the mortality rate among patients with CRC is high. The Wnt/β‑catenin signaling pathway, which is associated with carcinogenesis, is abnormally activated in CRC. Most patients with CRC have adenomatous polyposis coli mutations, while half of the remaining patients have β‑catenin gene mutations. Therefore, targeting the Wnt/β‑catenin signaling pathway for the treatment of CRC is of clinical value. In recent years, with in‑depth research on the Wnt/β‑catenin signaling pathway, inhibitors have been developed that are able to suppress or hinder the development and progression of CRC. In the present review, the role of the Wnt/β‑catenin signaling pathway in CRC is summarized, the research status on Wnt/β‑catenin pathway inhibitors is outlined and potential targets for inhibition of this pathway are presented.
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Affiliation(s)
- Yuxiang Chen
- Department of Gastroenterology and Hepatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China,The Laboratory of Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Mo Chen
- Department of Gerontology, Tibetan Chengdu Branch Hospital of West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China,Department of Gerontology, Hospital of Chengdu Office of People's Government of Tibetan Autonomous Region, Chengdu, Sichuan 610041, P.R. China,Professor Mo Chen, Department of Gerontology, Tibetan Chengdu Branch Hospital of West China Hospital, Sichuan University, 20 Ximianqiao Cross Street, Chengdu, Sichuan 610041, P.R. China, E-mail:
| | - Kai Deng
- Department of Gastroenterology and Hepatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China,The Laboratory of Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China,Correspondence to: Professor Kai Deng, Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, 37 Guoxue Lane, Chengdu, Sichuan 610041, P.R. China, E-mail:
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14
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Xiao L, Guan X, Xiang M, Wang Q, Long Q, Yue C, Chen L, Liu J, Liao C. B7 family protein glycosylation: Promising novel targets in tumor treatment. Front Immunol 2022; 13:1088560. [PMID: 36561746 PMCID: PMC9763287 DOI: 10.3389/fimmu.2022.1088560] [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: 11/03/2022] [Accepted: 11/22/2022] [Indexed: 12/12/2022] Open
Abstract
Cancer immunotherapy, including the inhibition of immune checkpoints, improves the tumor immune microenvironment and is an effective tool for cancer therapy. More effective and alternative inhibitory targets are critical for successful immune checkpoint blockade therapy. The interaction of the immunomodulatory ligand B7 family with corresponding receptors induces or inhibits T cell responses by sending co-stimulatory and co-inhibitory signals respectively. Blocking the glycosylation of the B7 family members PD-L1, PD-L2, B7-H3, and B7-H4 inhibited the self-stability and receptor binding of these immune checkpoint proteins, leading to immunosuppression and rapid tumor progression. Therefore, regulation of glycosylation may be the "golden key" to relieve tumor immunosuppression. The exploration of a more precise glycosylation regulation mechanism and glycan structure of B7 family proteins is conducive to the discovery and clinical application of antibodies and small molecule inhibitors.
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Affiliation(s)
- Linlin Xiao
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China,Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Xiaoyan Guan
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China,Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Mingli Xiang
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China,Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Qian Wang
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Qian Long
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China,Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Chaoyi Yue
- School of Medicine and Technology, Zunyi Medical University, Zunyi, China
| | - Lulu Chen
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China,Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Jianguo Liu
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China,*Correspondence: Chengcheng Liao, ; Jianguo Liu,
| | - Chengcheng Liao
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China,Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China,*Correspondence: Chengcheng Liao, ; Jianguo Liu,
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15
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Zheng L, Yang Q, Li F, Zhu M, Yang H, Tan T, Wu B, Liu M, Xu C, Yin J, Cao C. The Glycosylation of Immune Checkpoints and Their Applications in Oncology. Pharmaceuticals (Basel) 2022; 15:ph15121451. [PMID: 36558902 PMCID: PMC9783268 DOI: 10.3390/ph15121451] [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: 10/17/2022] [Revised: 11/16/2022] [Accepted: 11/18/2022] [Indexed: 11/24/2022] Open
Abstract
Tumor therapies have entered the immunotherapy era. Immune checkpoint inhibitors have achieved tremendous success, with some patients achieving long-term tumor control. Tumors, on the other hand, can still accomplish immune evasion, which is aided by immune checkpoints. The majority of immune checkpoints are membrane glycoproteins, and abnormal tumor glycosylation may alter how the immune system perceives tumors, affecting the body's anti-tumor immunity. Furthermore, RNA can also be glycosylated, and GlycoRNA is important to the immune system. Glycosylation has emerged as a new hallmark of tumors, with glycosylation being considered a potential therapeutic approach. The glycosylation modification of immune checkpoints and the most recent advances in glycosylation-targeted immunotherapy are discussed in this review.
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Affiliation(s)
- Linlin Zheng
- School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China
| | - Qi Yang
- Biotherapy Center, Third Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Feifei Li
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning 530021, China
| | - Min Zhu
- School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China
| | - Haochi Yang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Tian Tan
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Binghuo Wu
- Department of Oncology, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Mingxin Liu
- School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China
| | - Chuan Xu
- Department of Oncology, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Key Laboratory of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China
| | - Jun Yin
- Sichuan Key Laboratory of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China
- Correspondence: (J.Y.); (C.C.)
| | - Chenhui Cao
- Sichuan Key Laboratory of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China
- Correspondence: (J.Y.); (C.C.)
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16
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Elevation of spermine remodels immunosuppressive microenvironment through driving the modification of PD-L1 in hepatocellular carcinoma. Cell Commun Signal 2022; 20:175. [DOI: 10.1186/s12964-022-00981-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 09/27/2022] [Indexed: 11/09/2022] Open
Abstract
Abstract
Background
Spermine is frequently elevated in tumor tissues and body fluids of cancer patients and is critical for cancer cell proliferation, migration and invasion. However, the immune functions of spermine in hepatocellular carcinoma progression remains unknown. In the present study, we aimed to elucidate immunosuppressive role of spermine in hepatocellular carcinoma and to explore the underlying mechanism.
Methods
Whole-blood spermine concentration was measured using HPLC. Human primary HCC tissues were collected to examine the expression of CaSR, p-Akt, β-catenin, STT3A, PD-L1, and CD8. Mouse model of tumorigenesis and lung metastasis were established to evaluate the effects of spermine on hepatocellular carcinoma. Western blotting, immunofluorescence, real time PCR, digital Ca2+ imaging, and chromatin immunoprecipitation assay were used to investigate the underlying mechanisms by which spermine regulates PD-L1 expression and glycosylation in hepatocellular carcinoma cells.
Results
Blood spermine concentration in the HCC patient group was significantly higher than that in the normal population group. Spermine could facilitate tumor progression through inducing PD-L1 expression and decreasing the CD8+ T cell infiltration in HCC. Mechanistically, spermine activates calcium-sensing receptor (CaSR) to trigger Ca2+ entry and thereby promote Akt-dependent β-catenin stabilization and nuclear translocation. Nuclear β-catenin induced by spermine then activates transcriptional expression of PD-L1 and N-glycosyltransferase STT3A, while STT3A in turn increases the stability of PD-L1 through inducing PD-L1 protein N-glycosylation in HCC cells.
Conclusions
This study reveals the crucial function of spermine in establishing immune privilege by increasing the expression and N-glycosylation of PD-L1, providing a potential strategy for the treatment of hepatocellular carcinoma.
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17
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Gao Z, Ling X, Shi C, Wang Y, Lin A. Tumor immune checkpoints and their associated inhibitors. J Zhejiang Univ Sci B 2022; 23:823-843. [PMID: 36226537 PMCID: PMC9561405 DOI: 10.1631/jzus.b2200195] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 07/13/2022] [Indexed: 11/05/2022]
Abstract
Immunological evasion is one of the defining characteristics of cancers, as the immune modification of an immune checkpoint (IC) confers immune evasion capabilities to tumor cells. Multiple ICs, such as programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), can bind to their respective receptors and reduce tumor immunity in a variety of ways, including blocking immune cell activation signals. IC blockade (ICB) therapies targeting these checkpoint molecules have demonstrated significant clinical benefits. This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers. Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment. In this review, we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels, including epigenetic regulation, transcriptional regulation, and post-translational modifications. In addition, we provide a summary of the medications targeting various nodes in the regulatory pathway, and highlight the potential of newly identified IC molecules, focusing on their potential implications for cancer diagnostics and immunotherapy.
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Affiliation(s)
- Zerui Gao
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
- Cancer Center, Zhejiang University, Hangzhou 310058, China
- Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, China
- Chu Kochen Honors College of Zhejiang University, Hangzhou 310058, China
| | - Xingyi Ling
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
- Cancer Center, Zhejiang University, Hangzhou 310058, China
- Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, China
| | - Chengyu Shi
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
- Cancer Center, Zhejiang University, Hangzhou 310058, China
- Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, China
| | - Ying Wang
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
- Cancer Center, Zhejiang University, Hangzhou 310058, China
- Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, China
| | - Aifu Lin
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
- Cancer Center, Zhejiang University, Hangzhou 310058, China.
- Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, China.
- Breast Center of the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
- International School of Medicine, International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu 322000, China.
- ZJU-QILU Joint Research Institute, Hangzhou 310058, China.
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18
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Tang W, Pei M, Li J, Xu N, Xiao W, Yu Z, Zhang J, Hong L, Guo Z, Lin J, Dai W, Xiao Y, Wu X, Liu G, Zhi F, Li G, Xiong J, Chen Y, Zhang H, Xiang L, Li A, Liu S, Wang J. The miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop modulates the metastasis and invasion of gastric cancer cells. Oncogene 2022; 41:4823-4838. [DOI: 10.1038/s41388-022-02451-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 08/17/2022] [Accepted: 08/23/2022] [Indexed: 11/09/2022]
Abstract
AbstractAlthough the abnormal expression of miRNAs in cancer cells is a widely accepted phenomenon, the molecular mechanisms underlying miR-3648 progression and metastasis in gastric cancer (GC) remain unclear. miR-3648 expression is downregulated and its ectopic expression in GC cells significantly suppressed cell proliferation and metastasis. Mechanistic analyses indicated that miR-3648 directly targets FRAT1 or FRAT2 and inhibits FRAT1- or FRAT2-mediated invasion and motility in vitro and in vivo. Moreover, FRAT1 physically interacted with FRAT2. Furthermore, FRAT1 overexpression promoted GC cell invasion, whereas siRNA-mediated repression of FRAT2 in FRAT1-overexpressing GC cells reversed its invasive potential. Besides, miR-3648 inactivated the Wnt/β-catenin signalling pathway by downregulating FRAT1 and FRAT2 in GC. Interestingly, c-Myc, a downstream effector of Wnt/β-catenin signalling, was also downregulated by miR-3648 overexpression. In turn, c-Myc negatively regulated miR-3648 expression by binding to the miR-3648 promoter. In addition, miR-3648 expression levels were negatively correlated with c-Myc, FRAT1, and FRAT2 expression in fresh gastric samples. Our studies suggest that miR-3648 acts as a tumour-suppressive miRNA and that the miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop could be a critical regulator of GC progression.
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19
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Liu Z, Yu X, Xu L, Li Y, Zeng C. Current insight into the regulation of PD-L1 in cancer. Exp Hematol Oncol 2022; 11:44. [PMID: 35907881 PMCID: PMC9338491 DOI: 10.1186/s40164-022-00297-8] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/19/2022] [Indexed: 12/09/2023] Open
Abstract
The molecular mechanisms underlying cancer immune escape are a core topic in cancer immunology research. Cancer cells can escape T cell-mediated cellular cytotoxicity by exploiting the inhibitory programmed cell-death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1, CD274) immune checkpoint. Studying the PD-L1 regulatory pattern of tumor cells will help elucidate the molecular mechanisms of tumor immune evasion and improve cancer treatment. Recent studies have found that tumor cells regulate PD-L1 at the transcriptional, post-transcriptional, and post-translational levels and influence the anti-tumor immune response by regulating PD-L1. In this review, we focus on the regulation of PD-L1 in cancer cells and summarize the underlying mechanisms.
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Affiliation(s)
- Zhuandi Liu
- The First Affiliated Hospital, Institute of Hematology, School of Medicine, Jinan University, No.601, West Huangpu Avenue, Guangzhou, 510632, Guangzhou, China.,Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, 510632, Guangdong, China
| | - Xibao Yu
- The First Affiliated Hospital, Institute of Hematology, School of Medicine, Jinan University, No.601, West Huangpu Avenue, Guangzhou, 510632, Guangzhou, China.,Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, 510632, Guangdong, China
| | - Ling Xu
- The First Affiliated Hospital, Institute of Hematology, School of Medicine, Jinan University, No.601, West Huangpu Avenue, Guangzhou, 510632, Guangzhou, China.,Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, 510632, Guangdong, China
| | - Yangqiu Li
- The First Affiliated Hospital, Institute of Hematology, School of Medicine, Jinan University, No.601, West Huangpu Avenue, Guangzhou, 510632, Guangzhou, China. .,Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, 510632, Guangdong, China.
| | - Chengwu Zeng
- The First Affiliated Hospital, Institute of Hematology, School of Medicine, Jinan University, No.601, West Huangpu Avenue, Guangzhou, 510632, Guangzhou, China. .,Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, 510632, Guangdong, China.
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20
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Cao P, Yang X, Liu D, Ye S, Yang W, Xie Z, Lei X. Research progress of
PD‐L1
non‐glycosylation in cancer immunotherapy. Scand J Immunol 2022. [DOI: 10.1111/sji.13205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Pu Cao
- School of Pharmacy, Hengyang Medical College, University of South China Hengyang Hunan P.R. China
| | - Xiaoyan Yang
- School of Pharmacy, Hengyang Medical College, University of South China Hengyang Hunan P.R. China
| | - Daquan Liu
- School of Pharmacy, Hengyang Medical College, University of South China Hengyang Hunan P.R. China
| | - Simin Ye
- School of Pharmacy, Hengyang Medical College, University of South China Hengyang Hunan P.R. China
| | - Wei Yang
- School of Pharmacy, Hengyang Medical College, University of South China Hengyang Hunan P.R. China
| | - Zhizhong Xie
- School of Pharmacy, Hengyang Medical College, University of South China Hengyang Hunan P.R. China
| | - Xiaoyong Lei
- School of Pharmacy, Hengyang Medical College, University of South China Hengyang Hunan P.R. China
- The Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China Hengyang Hunan P.R. China
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21
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Tang Y, Nan N, Gui C, Zhou X, Jiang W, Zhou X. Blockage of PD-L1 by FERMT3-mediated Wnt/β-catenin signaling regulates chemoresistance and immune evasion of colorectal cancer cells. Clin Exp Pharmacol Physiol 2022; 49:988-997. [PMID: 35672907 DOI: 10.1111/1440-1681.13685] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/20/2022] [Accepted: 06/02/2022] [Indexed: 11/27/2022]
Abstract
Colorectal cancer (CRC) constitutes a major public health problem due to the high rate of morbidity and mortality. Chemotherapy and immunotherapy are the major and promising strategies for cancer patients including CRC; nevertheless, chemoresistance and immune escape limit the final efficacy of above approaches. FERMT3 has been proved to exert the critical role in immune system and contradictive effects on cancer progression. In this study, bioinformatics database analysis and clinical specimen detection both corroborated the down-regulation of FERMT3 in CRC tissues and cells. Of interest, overexpression of FERMT3 suppressed CRC cell invasion and sensitized cells to 5-fluorouracil (5-FU) by reducing cell viability and increasing cell apoptosis and caspase-3 activity. Noticeably, FERMT3 up-regulation enhanced natural killer (NK) cells activation by increasing secretions of IFN-γ and TNF-α when NK cells were co-cultured with CRC cells. Importantly, up-regulation of FERMT3 promoted NK cell-mediated killing of CRC cells. Mechanically, FERMT3 inhibited the aberrant activation of Wnt/β-catenin signaling and the subsequent PD-L1 expression in CRC cells. Moreover, targeting PD-L1 suppressed CRC cell invasion, 5-FU resistance and NK cells-mediated tumor killing. Additionally, reactivating the Wnt/β-catenin signaling with a specific WNT agonist CAS 853220-52-7 overturned the efficacy of FERMT3 overexpression against CRC cell invasion, 5-FU chemoresistance and cell susceptibility to NK cell-mediated cytotoxicity. Thus, the current findings substantiate that FERMT3 elevation may attenuate CRC cell chemoresistance and NK cell-mediated immune response to tumor cells by inhibiting Wnt/β-catenin-PD-L1 signaling. Therefore, FERMT3 elevation may be a promising therapeutic approach to overcome chemoresistance and immune evasion in CRC. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Yanhua Tang
- Department of Gastrointestinal Surgery, The First People's Hospital of Gui Yang, Gui Yang, P.R. China
| | - Nan Nan
- Department of Pathology, The First People's Hospital of Gui Yang, Gui Yang, P.R. China
| | - Chuanzhi Gui
- Department of Pathology, The First People's Hospital of Gui Yang, Gui Yang, P.R. China
| | - Xuan Zhou
- Department of Science and education, The First People's Hospital of Gui Yang, Gui Yang, P.R. China
| | - Wenyong Jiang
- Department of Nephrology, The First People's Hospital of Gui Yang, Gui Yang, P.R. China
| | - Xiaoqian Zhou
- Department of Gastroenterology, The First People's Hospital of Gui Yang, Gui Yang, P.R. China
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22
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Lv W, Yu H, Han M, Tan Y, Wu M, Zhang J, Wu Y, Zhang Q. Analysis of Tumor Glycosylation Characteristics and Implications for Immune Checkpoint Inhibitor’s Efficacy for Breast Cancer. Front Immunol 2022; 13:830158. [PMID: 35444644 PMCID: PMC9013822 DOI: 10.3389/fimmu.2022.830158] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 03/08/2022] [Indexed: 12/14/2022] Open
Abstract
The alterations of glycosylation, which is a common post-translational modification of proteins, have been acknowledged as key events in breast cancer (BC) oncogenesis and progression. The aberrant expression of glycosyltransferases leads to aberrant glycosylation patterns, posing the diagnostic potential in BC outcomes. The present study aims to establish a glycosyltransferase-based signature to predict BC prognosis and response to immune checkpoint inhibitors. We firstly screened 9 glycosyltransferase genes from The Cancer Genome Atlas (TCGA) database and accordingly established a glyco-signature for predicting the prognosis in BC patients. Patients with BC were successfully divided into high-risk and low-risk groups based on the median cutoff point for risk scores in this signature. Next, the combinational analyses of univariate and multivariate Cox regression, Kaplan–Meier, and receiver operating characteristic (ROC) curves were used to prove that this glyco-signature possessed excellent predictive performance for prognosis of BC patients, as the high-risk group possessed worse outcomes, in comparison to the low-risk group. Additionally, the Gene Set Enrichment Analysis (GSEA) and immunologic infiltration analysis were adopted and indicated that there was a more immunosuppressive state in the high-risk group than that in the low-risk group. The clinical sample validation verified that glycosyltransferase genes were differentially expressed in patients in the low- and high-risk groups, while the biomarkers of antitumor M1 macrophages were increased and N-glycosyltransferase STT3A decreased in the low-risk group. The final in vitro assay showed that the silencing of STT3A suppressed the proliferation and migration of BC cells. Collectively, our well-constructed glyco-signature is able to distinguish the high- and low-risk groups and accordingly predict BC prognosis, which will synergistically promote the prognosis evaluation and provide new immunotherapeutic targets for combating BC.
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Affiliation(s)
- Wenchang Lv
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Honghao Yu
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mei Han
- Department of Anesthesiology, The People’s Hospital of China Three Gorges, China Three Gorges University, Yichang, China
| | - Yufang Tan
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Wu
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Zhang
- Department of Thyroid and Breast Surgery, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, China
- *Correspondence: Jun Zhang, ; Yiping Wu, ; Qi Zhang,
| | - Yiping Wu
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Jun Zhang, ; Yiping Wu, ; Qi Zhang,
| | - Qi Zhang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Jun Zhang, ; Yiping Wu, ; Qi Zhang,
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23
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Yamaguchi H, Hsu JM, Yang WH, Hung MC. Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics. Nat Rev Clin Oncol 2022; 19:287-305. [DOI: 10.1038/s41571-022-00601-9] [Citation(s) in RCA: 294] [Impact Index Per Article: 98.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2022] [Indexed: 02/06/2023]
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24
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Azcue P, Guerrero Setas D, Encío I, Ibáñez-Beroiz B, Mercado M, Vera R, Gómez-Dorronsoro ML. A Novel Prognostic Biomarker Panel for Early-Stage Colon Carcinoma. Cancers (Basel) 2021; 13:5909. [PMID: 34885019 PMCID: PMC8656725 DOI: 10.3390/cancers13235909] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/18/2021] [Accepted: 11/22/2021] [Indexed: 12/09/2022] Open
Abstract
Molecular characterization of colorectal cancer has helped us understand better the biology of the disease. However, previous efforts have yet to provide significant clinical value in order to be integrated into clinical practice for patients with early-stage colon cancer (CC). The purpose of this study was to assess PD-L1, GLUT-1, e-cadherin, MUC2, CDX2, and microsatellite instability (dMMR) and to propose a risk-panel with prognostic capabilities. Biomarkers were immunohistochemically assessed through tissue microarrays in a cohort of 144 patients with stage II/III colon cancer. A biomarker panel consisting of PD-L1, GLUT-1, dMMR, and potentially CDX2 was constructed that divided patients into low, medium, and high risk of overall survival or disease-free survival (DFS) in equally sized groups. Compared with low-risk patients, medium-risk patients have almost twice the risk of death (HR = 2.10 (0.99-4.46), p = 0.054), while high-risk patients have almost four times the risk (HR = 3.79 (1.77-8.11), p = 0.001). The multivariate goodness of fit was 0.756 and was correlated with Kaplan-Meier curves (p = 0.002). Consistent results were found for DFS. This study provides a critical basis for the future development of an immunohistochemical assessment capable of discerning early-stage CC patients as a function of their prognosis. This tool may aid with treatment personalization in daily clinical practice and improve survival outcomes.
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Affiliation(s)
- Pablo Azcue
- Department of Health Science, Public University of Navarra, 31008 Pamplona, Spain; (I.E.); (B.I.-B.)
| | - David Guerrero Setas
- Department of Pathology, University Hospital of Navarra, 31008 Pamplona, Spain; (D.G.S.); (M.M.)
- Campus Arrosadia, Public University of Navarra, 31006 Pamplona, Spain
- Molecular Pathology of Cancer Group–Navarrabiomed, 31008 Pamplona, Spain
- Department of Medical Oncology, University Hospital of Navarra, 31008 Pamplona, Spain;
| | - Ignacio Encío
- Department of Health Science, Public University of Navarra, 31008 Pamplona, Spain; (I.E.); (B.I.-B.)
- Institute for Health Research Navarra (IdISNA), 31008 Pamplona, Spain
| | - Berta Ibáñez-Beroiz
- Department of Health Science, Public University of Navarra, 31008 Pamplona, Spain; (I.E.); (B.I.-B.)
- Institute for Health Research Navarra (IdISNA), 31008 Pamplona, Spain
- Unit of Methodology-Navarrabiomed-University Hospital of Navarra, 31008 Pamplona, Spain
- Research Network on Health Services Research and Chronic Diseases (REDISSEC), 31008 Pamplona, Spain
| | - María Mercado
- Department of Pathology, University Hospital of Navarra, 31008 Pamplona, Spain; (D.G.S.); (M.M.)
| | - Ruth Vera
- Department of Medical Oncology, University Hospital of Navarra, 31008 Pamplona, Spain;
- Institute for Health Research Navarra (IdISNA), 31008 Pamplona, Spain
| | - María Luisa Gómez-Dorronsoro
- Department of Pathology, University Hospital of Navarra, 31008 Pamplona, Spain; (D.G.S.); (M.M.)
- Institute for Health Research Navarra (IdISNA), 31008 Pamplona, Spain
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25
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Shadbad MA, Asadzadeh Z, Derakhshani A, Hosseinkhani N, Mokhtarzadeh A, Baghbanzadeh A, Hajiasgharzadeh K, Brunetti O, Argentiero A, Racanelli V, Silvestris N, Baradaran B. A scoping review on the potentiality of PD-L1-inhibiting microRNAs in treating colorectal cancer: Toward single-cell sequencing-guided biocompatible-based delivery. Biomed Pharmacother 2021; 143:112213. [PMID: 34560556 DOI: 10.1016/j.biopha.2021.112213] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/13/2021] [Accepted: 09/15/2021] [Indexed: 12/15/2022] Open
Abstract
Tumoral programmed cell death ligand 1 (PD-L1) has been implicated in the immune evasion and development of colorectal cancer. Although monoclonal immune checkpoint inhibitors can exclusively improve the prognosis of patients with microsatellite instability-high (MSI-H) and tumor mutational burden-high (TMB-H) colorectal cancer, specific tumor-suppressive microRNAs (miRs) can regulate multiple oncogenic pathways and inhibit the de novo expression of oncoproteins, like PD-L1, both in microsatellite stable (MSS) and MSI-H colorectal cancer cells. This scoping review aimed to discuss the currently available evidence regarding the therapeutic potentiality of PD-L1-inhibiting miRs for colorectal cancer. For this purpose, the Web of Science, Scopus, and PubMed databases were systematically searched to obtain peer-reviewed studies published before 17 March 2021. We have found that miR-191-5p, miR-382-3p, miR-148a-3p, miR-93-5p, miR-200a-3p, miR-200c-3p, miR-138-5p, miR-140-3p, and miR-15b-5p can inhibit tumoral PD-L1 in colorectal cancer cells. Besides inhibiting PD-L1, miR-140-3p, miR-382-3p, miR-148a-3p, miR-93-5p, miR-200a-3p, miR-200c-3p, miR-138-5p, and miR-15b-5p can substantially reduce tumor migration, inhibit tumor development, stimulate anti-tumoral immune responses, decrease tumor viability, and enhance the chemosensitivity of colorectal cancer cells regardless of the microsatellite state. Concerning the specific, effective, and safe delivery of these miRs, the single-cell sequencing-guided biocompatible-based delivery of these miRs can increase the specificity of miR delivery, decrease the toxicity of traditional nanoparticles, transform the immunosuppressive tumor microenvironment into the proinflammatory one, suppress tumor development, decrease tumor migration, and enhance the chemosensitivity of tumoral cells regardless of the microsatellite state.
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Affiliation(s)
- Mahdi Abdoli Shadbad
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Iran
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Iran
| | - Afshin Derakhshani
- Laboratory of Experimental Pharmacology, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| | | | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Iran
| | | | - Oronzo Brunetti
- Istituto Tumori BariGiovanni Paolo II, Istituto Nazionale dei Tumori (IRCCS), Bari, Italy
| | - Antonella Argentiero
- Istituto Tumori BariGiovanni Paolo II, Istituto Nazionale dei Tumori (IRCCS), Bari, Italy
| | - Vito Racanelli
- Department of Biomedical Sciences and Human Oncology, School of Medicine, University of Bari Aldo Moro, Bari, Italy
| | - Nicola Silvestris
- Istituto Tumori BariGiovanni Paolo II, Istituto Nazionale dei Tumori (IRCCS), Bari, Italy; Department of Biomedical Sciences and Human Oncology, School of Medicine, University of Bari Aldo Moro, Bari, Italy.
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Iran.
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26
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Ma Y, Xia P, Wang Z, Xu J, Zhang L, Jiang Y. PDIA6 promotes pancreatic cancer progression and immune escape through CSN5-mediated deubiquitination of β-catenin and PD-L1. Neoplasia 2021; 23:912-928. [PMID: 34325342 PMCID: PMC8329431 DOI: 10.1016/j.neo.2021.07.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 01/15/2023]
Abstract
Protein Disulfide Isomerase Family A Member 6 (PDIA6) is an endoplasmic reticulum protein that is capable of catalyzing protein folding and disulfide bond formation. Abnormally elevated expression of PDIA6 has been reported to predict poor outcomes in various cancers. Herein, gain-of- and loss-of-function experiments were performed to investigate how PDIA6 participated in the carcinogenesis of pancreatic cancer (PC). By analyzing the protein expression of PDIA6 in 28 paired PC and para carcinoma specimens, we first found that PDIA6 expression was higher in PC samples. Both the overall survival and disease-free survival rates of PC patients with higher PDIA6 expression were poorer than those with lower PDIA6 (n = 178). Furthermore, knockdown of PDIA6 impaired the malignancies of PC cells - suppressed cell proliferation, invasion, migration, cisplatin resistance, and xenografted tumor growth. PDIA6-silenced PC cells were more sensitive to cytotoxic natural killer (NK) cells. Overexpression of PDIA6 had opposite effects on PC cells. Interestingly, COP9 signalosome subunit 5 (CSN5), a regulator of E3 ubiquitin ligases known to promote deubiquitination of its downstream targets, was demonstrated to interact with PDIA6, and its expression was increased in PC cells overexpressing PDIA6. Additionally, PDIA6 overexpression promoted deubiquitination of β-catenin and PD-L1 and subsequently upregulated their expression in PC cells. These alterations were partly reversed by CSN5 shRNA. Collectively, the above results demonstrate that PDIA6 contributes to PC progression, which may be associated with CSN5-regulated deubiquitination of β-catenin and PD-L1. Our findings suggest PDIA6 as a potential target for the treatment of PC.
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Affiliation(s)
- Yihui Ma
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Peiyi Xia
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhengyang Wang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jingjing Xu
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lan Zhang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanan Jiang
- Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
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27
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Guo JN, Xia BR, Deng SH, Yang C, Pi YN, Cui BB, Jin WL. Deubiquitinating Enzymes Orchestrate the Cancer Stem Cell-Immunosuppressive Niche Dialogue: New Perspectives and Therapeutic Potential. Front Cell Dev Biol 2021; 9:680100. [PMID: 34179009 PMCID: PMC8220152 DOI: 10.3389/fcell.2021.680100] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 05/17/2021] [Indexed: 11/13/2022] Open
Abstract
Cancer stem cells (CSCs) are sparks for igniting tumor recurrence and the instigators of low response to immunotherapy and drug resistance. As one of the important components of tumor microenvironment, the tumor associated immune microenvironment (TAIM) is driving force for the heterogeneity, plasticity and evolution of CSCs. CSCs create the inhibitory TAIM (ITAIM) mainly through four stemness-related signals (SRSs), including Notch-nuclear factor-κB axis, Hedgehog, Wnt and signal transducer and activator of transcription. Ubiquitination and deubiquitination in proteins related to the specific stemness of the CSCs have a profound impact on the regulation of ITAIM. In regulating the balance between ubiquitination and deubiquitination, it is crucial for deubiquitinating enzymes (DUBs) to cleave ubiquitin chains from substrates. Ubiquitin-specific peptidases (USPs) comprise the largest family of DUBs. Growing evidence suggests that they play novel functions in contribution of ITAIM, including regulating tumor immunogenicity, activating stem cell factors, upregulating the SRSs, stabilizing anti-inflammatory receptors, and regulating anti-inflammatory cytokines. These overactive or abnormal signaling may dampen antitumor immune responses. The inhibition of USPs could play a regulatory role in SRSs and reversing ITAIM, and also have great potential in improving immune killing ability against tumor cells, including CSCs. In this review, we focus on the USPs involved in CSCs signaling pathways and regulating ITAIM, which are promising therapeutic targets in antitumor therapy.
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Affiliation(s)
- Jun-Nan Guo
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Bai-Rong Xia
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, Anhui Provincial Cancer Hospital, University of Science and Technology of China, Hefei, China
| | - Shen-Hui Deng
- Department of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chang Yang
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ya-Nan Pi
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Bin-Bin Cui
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Wei-Lin Jin
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Institute of Cancer Neuroscience, The First Clinical Medical College of Lanzhou University, Lanzhou, China
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28
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Zhang Y, Meng H, Guo K. Inhibition of MicroRNA-302c on Stemness of Colon Cancer Stem Cells via the CARF/Wnt/β-Catenin Axis. Dig Dis Sci 2021; 66:1906-1915. [PMID: 32617772 DOI: 10.1007/s10620-020-06435-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 06/21/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND Even though the relevance of microRNA (miR)-302c has been studied, little is known about its involvement in colon cancer (CC). AIMS Our aim here was to investigate the role of miR-302c in the cancer stem cells (CSCs) of CC. METHODS Firstly, the CSCs were screened out from cultured SW1116 and SW480 cells by flow cytometry, and the differentially expressed miRNAs in cell were obtained by microarray analysis. The expression of miR-302c, collaborator of ARF (CARF), and Wnt/β-catenin-related genes in CSCs was determined by means of RT-qPCR and Western blot. A dual-luciferase reporter assay was conducted to authenticate the binding relationship between miR-302c and CARF. Proliferation, migration, invasion, sphere formation as well as apoptosis of CSCs were assessed by cell counting kit-8, Transwell assay, sphere formation assay as well as flow cytometric analysis, respectively. The roles of miR-302c and CARF in tumor growth were determined in vivo. RESULTS The expression of miR-302c in CC cells was reduced versus that in normal cells. The overexpression of miR-302c weakened the stemness, proliferation, invasion, and migration abilities while induced apoptosis of CSCs in CC. Also, miR-302c reduced tumor size and weight in mice, accompanied with lowered CARF expression. The mechanistic analysis manifested that miR-302c bound to CARF and suppressed its expression and disrupted the Wnt/β-catenin signaling. CONCLUSION This study offers a novel characterization of miR-302c function in CSCs in CC, which may be beneficial to the development of capable therapeutic options for CC.
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Affiliation(s)
- Yun Zhang
- Department of Gastroenterology, Caoxian People's Hospital, Development Zone, Fumin Avenue, Caoxian, 274400, Shandong, People's Republic of China
| | - Hua Meng
- Department of Gastroenterology, Caoxian People's Hospital, Development Zone, Fumin Avenue, Caoxian, 274400, Shandong, People's Republic of China
| | - Kun Guo
- Department of Gastroenterology, Caoxian People's Hospital, Development Zone, Fumin Avenue, Caoxian, 274400, Shandong, People's Republic of China.
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29
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The Role of Glycosyltransferases in Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22115822. [PMID: 34070747 PMCID: PMC8198577 DOI: 10.3390/ijms22115822] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 05/25/2021] [Accepted: 05/27/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the main causes of cancer death in the world. Post-translational modifications (PTMs) have been extensively studied in malignancies due to its relevance in tumor pathogenesis and therapy. This review is focused on the dysregulation of glycosyltransferase expression in CRC and its impact in cell function and in several biological pathways associated with CRC pathogenesis, prognosis and therapeutic approaches. Glycan structures act as interface molecules between cells and their environment and in several cases facilitate molecule function. CRC tissue shows alterations in glycan structures decorating molecules, such as annexin-1, mucins, heat shock protein 90 (Hsp90), β1 integrin, carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), insulin-like growth factor-binding protein 3 (IGFBP3), transforming growth factor beta (TGF-β) receptors, Fas (CD95), PD-L1, decorin, sorbin and SH3 domain-containing protein 1 (SORBS1), CD147 and glycosphingolipids. All of these are described as key molecules in oncogenesis and metastasis. Therefore, glycosylation in CRC can affect cell migration, cell–cell adhesion, actin polymerization, mitosis, cell membrane repair, apoptosis, cell differentiation, stemness regulation, intestinal mucosal barrier integrity, immune system regulation, T cell polarization and gut microbiota composition; all such functions are associated with the prognosis and evolution of the disease. According to these findings, multiple strategies have been evaluated to alter oligosaccharide processing and to modify glycoconjugate structures in order to control CRC progression and prevent metastasis. Additionally, immunotherapy approaches have contemplated the use of neo-antigens, generated by altered glycosylation, as targets for tumor-specific T cells or engineered CAR (Chimeric antigen receptors) T cells.
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30
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Liu J, Zhao Z, Qiu N, Zhou Q, Wang G, Jiang H, Piao Y, Zhou Z, Tang J, Shen Y. Co-delivery of IOX1 and doxorubicin for antibody-independent cancer chemo-immunotherapy. Nat Commun 2021; 12:2425. [PMID: 33893275 PMCID: PMC8065121 DOI: 10.1038/s41467-021-22407-6] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 03/10/2021] [Indexed: 12/12/2022] Open
Abstract
Anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibodies are currently used in the clinic to interupt the PD-1/PD-L1 immune checkpoint, which reverses T cell dysfunction/exhaustion and shows success in treating cancer. Here, we report a histone demethylase inhibitor, 5-carboxy-8-hydroxyquinoline (IOX1), which inhibits tumour histone demethylase Jumonji domain-containing 1A (JMJD1A) and thus downregulates its downstream β-catenin and subsequent PD-L1, providing an antibody-independent paradigm interrupting the PD-1/PD-L1 checkpoint. Synergistically, IOX1 inhibits cancer cells’ P-glycoproteins (P-gp) through the JMJD1A/β-catenin/P-gp pathway and greatly enhances doxorubicin (DOX)-induced immune-stimulatory immunogenic cell death. As a result, the IOX1 and DOX combination greatly promotes T cell infiltration and activity and significantly reduces tumour immunosuppressive factors. Their liposomal combination reduces the growth of various murine tumours, including subcutaneous, orthotopic, and lung metastasis tumours, and offers a long-term immunological memory function against tumour rechallenging. This work provides a small molecule-based potent cancer chemo-immunotherapy. Some chemotherapeutic drugs, such as doxorubicin, induce immunogenic cell death (ICD) and promote anti-tumor immune responses. Here the authors report that the histone demethylase inhibitor 5-carboxy-8-hydroxyquinoline (IOX1) reduces the expression of PD-L1 in cancer cells and enhances doxorubicin-induced ICD, promoting T cell infiltration and reducing tumor growth in preclinical models.
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Affiliation(s)
- Jing Liu
- Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.,Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, China
| | - Zhihao Zhao
- Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.,Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, China
| | - Nasha Qiu
- Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China
| | - Quan Zhou
- Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China
| | - Guowei Wang
- Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China
| | - Haiping Jiang
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ying Piao
- Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.,Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, China
| | - Zhuxian Zhou
- Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.,Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, China
| | - Jianbin Tang
- Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China
| | - Youqing Shen
- Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China. .,Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, China.
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Azcue P, Encío I, Guerrero Setas D, Suarez Alecha J, Galbete A, Mercado M, Vera R, Gomez-Dorronsoro ML. PD-L1 as a Prognostic Factor in Early-Stage Colon Carcinoma within the Immunohistochemical Molecular Subtype Classification. Cancers (Basel) 2021; 13:1943. [PMID: 33920689 PMCID: PMC8073668 DOI: 10.3390/cancers13081943] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 04/10/2021] [Accepted: 04/12/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND There is a patent need to better characterize early-stage colorectal cancer (CRC) patients. PD-1 ligand (PD-L1) expression has been proposed as a prognostic factor but yields mixed results in different settings. The Consensus Molecular Subtype (CMS) classification has yet to be integrated into clinical practice. We sought to evaluate the prognostic value of PD-L1 expression overall and within CMS in early-stage colon cancer patients, in the hope of assisting treatment choice in this setting. METHODS Tissue-microarrays were constructed from tumor samples of 162 stage II/III CRC patients. They underwent automatic immunohistochemical staining for PD-L1 and the proposed CMS panel. Primary endpoints were overall survival (OS) and disease-free survival (DFS). RESULTS PD-L1 expression was significantly and independently associated with better prognosis (HR = 0.46 (0.26-0.82), p = 0.009) and was mostly seen in immune cells of the tumor-related stroma. CMS4 five-folds the risk of mortalitycompared with CMS1 (HR = 5.58 (1.36, 22.0), p = 0.034). In the subgroup CMS2/CMS3 analysis, PD-L1 expression significantly differentiated individuals with better OS (p = 0.004) and DFS (p < 0.001). CONCLUSIONS Our study suggests that PD-L1 expression is an independent prognostic factor in patients with stage II/III colon cancer. Additionally, it successfully differentiates patients with better prognosis in the CMS2/CMS3 group and may prove significant for the clinical relevance of the CMS classification.
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Affiliation(s)
- Pablo Azcue
- Department of Health Science, Public University of Navarra (UPNA), 31008 Pamplona, Spain;
| | - Ignacio Encío
- Department of Health Science, Public University of Navarra (UPNA), 31008 Pamplona, Spain;
- Institute for Health Research Navarra (IdISNA), 31008 Pamplona, Spain; (A.G.); (R.V.)
| | - David Guerrero Setas
- Department of Molecular Pathology, Hospital Complex of Navarra (CHN), 31008 Pamplona, Spain; (D.G.S.); (M.M.)
- Campus Arrosadia, Public University of Navarra (UPNA), 31006 Pamplona, Spain
- Molecular Pathology of Cancer Group–Navarrabiomed, 31008 Pamplona, Spain
- Department of Medical Oncology, Hospital Complex of Navarra (CHN), 31008 Pamplona, Spain
| | - Javier Suarez Alecha
- Department of Surgery, Hospital Complex of Navarra (CHN), 31008 Pamplona, Spain;
| | - Arkaitz Galbete
- Institute for Health Research Navarra (IdISNA), 31008 Pamplona, Spain; (A.G.); (R.V.)
- Campus Arrosadia, Public University of Navarra (UPNA), 31006 Pamplona, Spain
- Navarrabiomed-Hospital Complex of Navarra (CHN), Redissec, 31008 Pamplona, Spain
| | - María Mercado
- Department of Molecular Pathology, Hospital Complex of Navarra (CHN), 31008 Pamplona, Spain; (D.G.S.); (M.M.)
| | - Ruth Vera
- Institute for Health Research Navarra (IdISNA), 31008 Pamplona, Spain; (A.G.); (R.V.)
- Department of Medical Oncology, Hospital Complex of Navarra (CHN), 31008 Pamplona, Spain
| | - Maria Luisa Gomez-Dorronsoro
- Institute for Health Research Navarra (IdISNA), 31008 Pamplona, Spain; (A.G.); (R.V.)
- Department of Molecular Pathology, Hospital Complex of Navarra (CHN), 31008 Pamplona, Spain; (D.G.S.); (M.M.)
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Han C, Chen S, Ma H, Wen X, Wang Z, Xu Y, Jin X, Yu X, Wang M. RPN2 Predicts Poor Prognosis and Promotes Bladder Cancer Growth and Metastasis via the PI3K-Akt Pathway. Onco Targets Ther 2021; 14:1643-1657. [PMID: 33727825 PMCID: PMC7953128 DOI: 10.2147/ott.s300480] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 02/20/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Ribophorin II (RPN2) is a highly conserved glycoprotein involved in the N-linked glycosylation of multiple proteins. RPN2 was reported to be associated with malignant phenotype in several tumors. However, the function of RPN2 in bladder cancer (BCa) remains unclear. METHODS Expression of RPN2 in BCa and adjacent tissues was compared by bioinformatics analysis, immunohistochemistry, and Western blotting. qRT-PCR was performed to explore the correlation between RPN2 expression and various clinical features in 38 patients. We assessed the effects of RPN2 on the biological activity of BCa both in vitro and in vivo, and explored its potential mechanisms based on gene set enrichment analysis (GSEA). RESULTS We found that RPN2 was highly expressed in human BCa compared with normal adjacent tissues. There was a significant positive correlation between higher RPN2 mRNA levels and tumor T stage, lymph node (LN) metastasis and the degree of pathological differentiation in 38 patients with BCa. We further demonstrated that RPN2 silencing inhibited the growth and metastasis of BCa both in vitro and in vivo. Western blotting revealed that RPN2 knockdown suppressed epithelial-mesenchymal transition (EMT) and inhibited the PI3K-Akt pathway. CONCLUSION These data suggest that RPN2 functions as an oncogene to promote tumor development and is a promising prognostic factor and therapeutic target in BCa.
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Affiliation(s)
- Chenglin Han
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China
| | - Shuxiao Chen
- Department of Vascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China
| | - Haiyang Ma
- Department of Thoracic Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China
| | - Xiangchuan Wen
- Department of Neurology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China
| | - Zilong Wang
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China
| | - Yingkun Xu
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China
| | - Xunbo Jin
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China
| | - Xiao Yu
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China
| | - Muwen Wang
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China
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Ryu WJ, Han G, Lee SH, Choi KY. Suppression of Wnt/β-catenin and RAS/ERK pathways provides a therapeutic strategy for gemcitabine-resistant pancreatic cancer. Biochem Biophys Res Commun 2021; 549:40-46. [PMID: 33662667 DOI: 10.1016/j.bbrc.2021.02.076] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 02/17/2021] [Indexed: 01/17/2023]
Abstract
Pancreatic cancer is a major malignant tumor without an effective treatment. KRAS mutations occur in 90% of the pancreatic cancer patients and are a major obstacle for treatment of pancreatic cancer. Pancreatic cancer patients have been treated with limited chemotherapeutic agents such as gemcitabine. However, patients often develop resistance to gemcitabine that is attributed to KRAS mutations. Gemcitabine treatment activates both the Wnt/β-catenin and RAS/ERK pathways. These signaling pathways are also activated in the gemcitabine-resistant pancreatic cancer cell lines, suggesting that they play an important role in gemcitabine resistance in pancreatic cancer. The gemcitabine-resistant cell lines show enhanced migratory and invasive capabilities than their parental lines. Therefore, we investigated the effects of a small molecule, KYA1797K that degrades both β-catenin and RAS, on pancreatic cancer. KYA1797K decreased the expression level of both β-catenin and KRAS in pancreatic cancer cell lines expressing either wild-type or mutant KRAS. It also suppressed migration and invasion of gemcitabine-resistant and parental pancreatic cancer cells. Overall, we demonstrated that inhibiting the Wnt/β-catenin and RAS/ERK pathways by destabilizing β-catenin and RAS could be a therapeutic approach to overcome gemcitabine resistance in pancreatic cancer.
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Affiliation(s)
- Won-Ji Ryu
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, South Korea
| | - Gyoonhee Han
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, South Korea
| | - Soung-Hoon Lee
- CK Biotechnology Inc., Building 117, 50 Yonsei Ro, Seodaemun-Gu, Seoul, 03722, South Korea.
| | - Kang-Yell Choi
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, South Korea; CK Biotechnology Inc., Building 117, 50 Yonsei Ro, Seodaemun-Gu, Seoul, 03722, South Korea.
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Liu L, Yu T, Jin Y, Mai W, Zhou J, Zhao C. MicroRNA-15a Carried by Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibits the Immune Evasion of Colorectal Cancer Cells by Regulating the KDM4B/HOXC4/PD-L1 Axis. Front Cell Dev Biol 2021; 9:629893. [PMID: 33732698 PMCID: PMC7959841 DOI: 10.3389/fcell.2021.629893] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 02/08/2021] [Indexed: 12/24/2022] Open
Abstract
The relevance of microRNA-15a (miR-15a) to autoimmunity has been reported. Herein, we intended to probe the potential roles of miR-15a shuttled by adipose-derived mesenchymal stem cells (adMSCs)-derived extracellular vesicles (Evs) in colorectal cancer (CRC). Initially, CRC cells were treated with interferon gamma (IFN-γ) to screen out differentially expressed genes by transcriptome sequencing. Following a 24-h co-culture with 20 μM adMSCs-derived Evs, CRC cell viability, migration, invasion, and apoptosis were assessed. After the determination of histone lysine demethylase 4B (KDM4B) as our target, its regulatory miRNA was predicted by the bioinformatics websites and verified by dual-luciferase and RNA pull-down assays. Intriguingly, KDM4B downregulated homeobox C4 (HOXC4) expression, while HOXC4 bound to the promoter sequence of programmed death-ligand 1 (PD-L1). Thus, we conducted rescue experiments to study the role of KDM4B and HOXC4. Finally, we evaluated the effects of adMSCs on CRC cell growth and immune evasion through in vivo tumorigenesis experiments. AdMSCs-derived Evs overexpressing miR-15a repressed proliferation, migration, and invasion, while it promoted the apoptosis of CRC cells via downregulation of KDM4B. These in vivo findings were reproduced in vitro on CRC immune evasion. Collectively, adMSCs-derived Evs overexpressing miR-15a restricted the immune evasion of CRC via the KDM4B/HOXC4/PD-L1 axis.
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Affiliation(s)
- Lei Liu
- Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ting Yu
- Department of Pharmacy Intravenous Admixture Services, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yanping Jin
- Harbin Maternal and Child Health Care and Family Planning Service Center, Harbin, China
| | - Wei Mai
- Department of Orthopedics, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jing Zhou
- Department of Gastrointestinal Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Chunbo Zhao
- Department of Gastrointestinal Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China
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Liu Y, Peng FX. Research progress on O-GlcNAcylation in the occurrence, development, and treatment of colorectal cancer. World J Gastrointest Surg 2021; 13:96-115. [PMID: 33643531 PMCID: PMC7898190 DOI: 10.4240/wjgs.v13.i2.96] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 12/21/2020] [Accepted: 12/29/2020] [Indexed: 02/06/2023] Open
Abstract
For a long time, colorectal cancer (CRC) has been ranked among the top cancer-related mortality rates, threatening human health. As a significant post-translational modification, O-GlcNAcylation plays an essential role in complex life activities. Related studies have found that the occurrence, development, and metastasis of CRC are all related to abnormal O-GlcNAcylation and participate in many critical biological processes, such as gene transcription, signal transduction, cell growth, and differentiation. Recently, nucleotide sugar analogs, tumor-specific carbohydrate vaccine, SIRT1 longevity gene, dendritic cells as targets, and NOTCH gene have become effective methods to induce antitumor therapy. Not long ago, checkpoint kinase 1 and checkpoint kinase 2 were used as therapeutic targets for CRC, but there are still many problems to be solved. With an in-depth study of protein chip, mass spectrometry, chromatography, and other technologies, O-GlcNAcylation research will accelerate rapidly, which may provide new ideas for the research and development of antitumor drugs and the discovery of new CRC diagnostic markers.
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Affiliation(s)
- Yao Liu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of North Sichuan Medical College, Mianyang 621000, Sichuan Province, China
- Department of Gastrointestinal Surgery, Sichuan Mianyang 404 Hospital, Mianyang 621000, Sichuan Province, China
| | - Fang-Xing Peng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of North Sichuan Medical College, Mianyang 621000, Sichuan Province, China
- Department of Gastrointestinal Surgery, Sichuan Mianyang 404 Hospital, Mianyang 621000, Sichuan Province, China
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Spatial and Temporal Changes in PD-L1 Expression in Cancer: The Role of Genetic Drivers, Tumor Microenvironment and Resistance to Therapy. Int J Mol Sci 2020; 21:ijms21197139. [PMID: 32992658 PMCID: PMC7583014 DOI: 10.3390/ijms21197139] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 09/18/2020] [Accepted: 09/24/2020] [Indexed: 12/14/2022] Open
Abstract
Immunotherapies blocking immune inhibitory receptors programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) on T-cells have dramatically improved patient outcomes in a range of advanced cancers. However, the lack of response, and the development of resistance remain major obstacles to long-term improvements in patient outcomes. There is significant interest in the clinical use of biomarkers to improve patient selection, and the expression of PD-1 ligand 1 (PD-L1) is often reported as a potential biomarker of response. However, accumulating evidence suggests that the predictive value of PD-L1 expression in tumor biopsies is relatively low due, in part, to its complex biology. In this review, we discuss the biological consequences of PD-L1 expression by various cell types within the tumor microenvironment, and the complex mechanisms that regulate PD-L1 expression at the genomic, transcriptomic and proteomic levels.
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37
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Sun J, Zheng Y, Mamun M, Li X, Chen X, Gao Y. Research progress of PD-1/PD-L1 immunotherapy in gastrointestinal tumors. Biomed Pharmacother 2020; 129:110504. [PMID: 32768978 DOI: 10.1016/j.biopha.2020.110504] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/30/2020] [Accepted: 07/02/2020] [Indexed: 12/24/2022] Open
Abstract
Gastrointestinal tumor (GIT) is a common malignant tumor of the digestive system, which seriously threatens people's health and life. With the deepening of the study on the mechanism of tumor immune escape, programmed death receptor ligand 1 (PD-L1) has been proved to interact with the tumor microenvironment to mediate tumor immune escape. PD-L1 inhibitor is a hot spot in tumor immunotherapy in recent years, which can restore the activity of T cells, enhance the body's ability of immune response, and ultimately enable the immune system to effectively identify and kill gastric cancer cells, then achieve long-term tumor remission in patients with GITs. At present, variety of PD-L1 inhibitors such as pembrolizumab, nivolumab and avelumab have been approved for the market, and they have achieved good results in clinical studies on the GIT. This paper reviews the progress of PD-1/PD-L1 immunotherapy in GITs which include gastric cancer, colon cancer and rectal cancer.
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Affiliation(s)
- Jiangang Sun
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yichao Zheng
- Zhengzhou University School of Pharmaceutical Science, Zhengzhou, Henan 450001, China
| | - Maa Mamun
- Zhengzhou University School of Pharmaceutical Science, Zhengzhou, Henan 450001, China
| | - Xiaojing Li
- Zhengzhou University School of Pharmaceutical Science, Zhengzhou, Henan 450001, China
| | - Xiaoping Chen
- Department of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yongshun Gao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
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He XY, Ren XH, Peng Y, Zhang JP, Ai SL, Liu BY, Xu C, Cheng SX. Aptamer/Peptide-Functionalized Genome-Editing System for Effective Immune Restoration through Reversal of PD-L1-Mediated Cancer Immunosuppression. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2020; 32:e2000208. [PMID: 32147886 DOI: 10.1002/adma.202000208] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 02/09/2020] [Accepted: 02/24/2020] [Indexed: 06/10/2023]
Abstract
Effective reversal of tumor immunosuppression is of critical importance in cancer therapy. A multifunctional delivery vector that can effectively deliver CRISPR-Cas9 plasmid for β-catenin knockout to reverse tumor immunosuppression is constructed. The multi-functionalized delivery vector is decorated with aptamer-conjugated hyaluronic acid and peptide-conjugated hyaluronic acid to combine the tumor cell/nuclear targeting function of AS1411 with the cell penetrating/nuclear translocation function of TAT-NLS. Due to the significantly enhanced plasmid enrichment in malignant cell nuclei, the genome editing system can induce effective β-catenin knockout and suppress Wnt/β-catenin pathway, resulting in notably downregulated proteins involved in tumor progression and immunosuppression. Programmed death-ligand 1 (PD-L1) downregulation in edited tumor cells not only releases the PD-1/PD-L1 brake to improve the cancer killing capability of CD8+ T cells, but also enhances antitumor immune responses of immune cells. This provides a facile strategy to reverse tumor immunosuppression and to restore immunosurveillance and activate anti-tumor immunity.
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Affiliation(s)
- Xiao-Yan He
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
- School of Life Sciences, Anhui Medical University, Hefei, 230032, P. R. China
| | - Xiao-He Ren
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Yan Peng
- Department of Pharmacy, The Renmin Hospital of Wuhan University, Wuhan, 430060, P. R. China
| | - Jian-Ping Zhang
- Neurology Clinic, The Renmin Hospital of Wuhan University, Wuhan, 430060, P. R. China
| | - Shu-Lun Ai
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Bo-Ya Liu
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Chang Xu
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Si-Xue Cheng
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
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