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Zhao S, Chen F, Hu L, Li X, Gao Z, Chen M, Wang X, Song Z. Long non-coding rnas as key modulators of the immune microenvironment in hepatocellular carcinoma: implications for Immunotherapy. Front Immunol 2025; 16:1523190. [PMID: 40352941 PMCID: PMC12061944 DOI: 10.3389/fimmu.2025.1523190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 04/02/2025] [Indexed: 05/14/2025] Open
Abstract
Hepatocellular carcinoma (HCC) represents a major global health challenge, characterized by its complex immune microenvironment that plays a pivotal role in tumor progression and therapeutic response. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of various biological processes, including gene expression and immune cell function. This review explores the multifaceted roles of lncRNAs in modulating the immune microenvironment of HCC. We discuss how lncRNAs influence the infiltration and activation of immune cells, shape cytokine profiles, and regulate immune checkpoint molecules, thereby affecting the tumor's immunogenicity and response to immunotherapy. Furthermore, we highlight specific lncRNAs implicated in immune evasion mechanisms and their potential as biomarkers and therapeutic targets. By elucidating the intricate interplay between lncRNAs and the immune landscape in HCC, this review aims to provide insights into novel strategies for enhancing immunotherapeutic efficacy and improving patient outcomes.
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Affiliation(s)
| | | | | | | | | | - Minjie Chen
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Xiaoguang Wang
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Zhengwei Song
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
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Liu H, Wang G, Li Z, Zhang X, Zhang W, Zhang X, Liu F, Gao J. Exosome-based immunotherapy in hepatocellular carcinoma. Clin Exp Med 2025; 25:127. [PMID: 40274634 PMCID: PMC12021721 DOI: 10.1007/s10238-025-01659-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 03/29/2025] [Indexed: 04/26/2025]
Abstract
Hepatocellular carcinoma (HCC) is a significant global health concern and ranks as the third leading cause of cancer-associated mortality. Systemic therapy faces the emergence of resistance, which hinders the clinical benefits. Recent evidence suggests that exosomes, measuring between 30 and 150 nm in size, which impact the antitumor immune responses, making them a promising candidate for cancer immunotherapy. Owing to their unique physical and chemical characteristics, exosomes can be tailored and engineered for a range of therapeutic objectives. In the present review, we outline the immunomodulatory functions of exosomes in the tumor microenvironment (TME) of HCC, aiming to decipher the underlying mechanisms of exosomes in remodeling suppressive TME. Moreover, we provide detailed and intuitive resource for leveraging the potential of exosomes in immunotherapy, presenting valuable strategies to improve and optimize HCC treatment. Despite the huge therapeutic potential of exosomes, significant challenges persist, including the need for standardization in exosome production, optimization of cargo loading techniques, and the assurance of safety and effectiveness in clinical applications. Addressing these challenges may pave the way for exosome-based immunotherapy for HCC patients.
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Affiliation(s)
- Hong Liu
- Department of Pathology, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China
| | - GuoWei Wang
- Department of Radiology, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China
| | - ZhaoYi Li
- Department of Scientific Research and Education, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China
| | - XianTu Zhang
- Department of Pathology, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China
| | - WeiDong Zhang
- Department of General Surgery I, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China
| | - Xia Zhang
- Medical Laboratory, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China.
| | - Fang Liu
- Xixi Hospital Biobank, Xixi Hospital of Hangzhou, Zhejiang Province, Hangzhou, 310023, China.
| | - Jing Gao
- Department of Pathology, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China.
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Shiota M, Nemoto S, Ikegami R, Tanegashima T, Blas L, Miyake H, Takahashi M, Oya M, Tsuchiya N, Masumori N, Kobayashi K, Obara W, Shinohara N, Fujimoto K, Nozawa M, Ohba K, Ohyama C, Hashine K, Akamatsu S, Motoshima T, Mita K, Gotoh M, Tatarano S, Fujisawa M, Tomita Y, Mukai S, Ito K, Eto M. Predictive Model of Objective Response to Nivolumab Monotherapy for Advanced Renal Cell Carcinoma by Machine Learning Using Genetic and Clinical Data: The SNiP-RCC Study. JCO Clin Cancer Inform 2025; 9:e2400167. [PMID: 40279530 DOI: 10.1200/cci-24-00167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 12/10/2024] [Accepted: 02/24/2025] [Indexed: 04/27/2025] Open
Abstract
PURPOSE Anti-PD-1 antibodies are widely used for cancer treatment, including in advanced renal cell carcinoma (RCC). However, the therapeutic response varies among patients. This study aimed to predict tumor response to nivolumab anti-PD-1 antibody treatment for advanced RCC by integrating genetic and clinical data using machine learning (ML). METHODS Clinical and single-nucleotide polymorphism (SNP) data obtained in the SNPs in nivolumab PD-1 inhibitor for RCC study, which enrolled Japanese patients treated with nivolumab monotherapy for advanced clear cell RCC, were used. A point-wise linear (PWL) algorithm, logistic regression with elastic-net regularization, and eXtreme Gradient Boosting were used in this study. AUC values for objective response and C-indices for progression-free survival (PFS) were calculated to evaluate the utility of the models. RESULTS Among the three ML algorithms, the AUC values to predict objective response were highest for the PWL algorithm among all the data sets. Three predictive models (clinical model, small SNP model, and large SNP model) were created by the PWL algorithm using the clinical data alone and using eight and 49 SNPs in addition to the clinical data. C-indices for PFS by the clinical model, small SNP model, and large SNP model were 0.522, 0.600, and 0.635, respectively. CONCLUSION The results demonstrated that the SNP models created by ML produced excellent predictions of tumor response to nivolumab monotherapy for advanced clear cell RCC and will be helpful in treatment decisions.
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Affiliation(s)
- Masaki Shiota
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shota Nemoto
- Industrial & Digital Business Unit, Hitachi, Ltd, Tokyo, Japan
| | - Ryo Ikegami
- Industrial & Digital Business Unit, Hitachi, Ltd, Tokyo, Japan
| | - Tokiyoshi Tanegashima
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Leandro Blas
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hideaki Miyake
- Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Masayuki Takahashi
- Department of Urology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Mototsugu Oya
- Department of Urology, Keio University School of Medicine, Tokyo, Japan
| | - Norihiko Tsuchiya
- Department of Urology, Faculty of Medicine, Yamagata University, Yamagata, Japan
| | - Naoya Masumori
- Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Keita Kobayashi
- Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Japan
| | - Wataru Obara
- Department of Urology, Iwate Medical University School of Medicine, Iwate, Japan
| | - Nobuo Shinohara
- Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | | | - Masahiro Nozawa
- Department of Urology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kojiro Ohba
- Department of Urology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Chikara Ohyama
- Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Katsuyoshi Hashine
- Department of Urology, National Hospital Organization Shikoku Cancer Center, Ehime, Japan
| | - Shusuke Akamatsu
- Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takanobu Motoshima
- Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Koji Mita
- Department of Urology, Hiroshima City Asa Citizens Hospital, Hiroshima, Japan
| | - Momokazu Gotoh
- Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shuichi Tatarano
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Masato Fujisawa
- Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yoshihiko Tomita
- Department of Urology and Molecular Oncology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Shoichiro Mukai
- Department of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Keiichi Ito
- Department of Urology, National Defense Medical College, Saitama, Japan
| | - Masatoshi Eto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Yu Z, Fu J, Mantareva V, Blažević I, Wu Y, Wen D, Battulga T, Wang Y, Zhang J. The role of tumor-derived exosomal LncRNA in tumor metastasis. Cancer Gene Ther 2025; 32:273-285. [PMID: 40011710 DOI: 10.1038/s41417-024-00852-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 10/22/2024] [Accepted: 11/05/2024] [Indexed: 02/28/2025]
Abstract
Tumor metastasis regulated by multiple complicated pathways is closely related to variations in the tumor microenvironment. Exosomes can regulate the tumor microenvironment through various mechanisms. Exosomes derived from tumor cells carry a variety of substances, including long non-coding RNAs (lncRNAs), play important roles in intercellular communication and act as critical determinants influencing tumor metastasis. In this review, we elaborate on several pivotal processes through which lncRNAs regulate tumor metastasis, including the regulation of epithelial‒mesenchymal transition, promotion of angiogenesis and lymphangiogenesis, enhancement of the stemness of tumor cells, and evasion of immune clearance. Additionally, we comprehensively summarized a diverse array of potential tumor-derived exosomal lncRNA biomarkers to facilitate accurate diagnosis and prognosis in a clinical setting.
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Affiliation(s)
- Zhile Yu
- The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510700, PR China
| | - Jiali Fu
- The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510700, PR China
| | - Vanya Mantareva
- Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Bld. 9, 1113, Sofia, Bulgaria
| | - Ivica Blažević
- Department of Organic Chemistry, Faculty of Chemistry and Technology, University of Split, Ruđera Boškovića 35, 21000, Split, Croatia
| | - Yusong Wu
- The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510700, PR China
| | - Dianchang Wen
- The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510700, PR China
| | - Tungalag Battulga
- School of Pharmacy, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia.
| | - Yuqing Wang
- The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510700, PR China.
- The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou, 510140, PR China.
| | - Jianye Zhang
- The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510700, PR China.
- The Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, 511518, PR China.
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Ge Y, Jiang L, Dong Q, Xu Y, Yam JWP, Zhong X. Exosome-mediated Crosstalk in the Tumor Immune Microenvironment: Critical Drivers of Hepatocellular Carcinoma Progression. J Clin Transl Hepatol 2025; 13:143-161. [PMID: 39917466 PMCID: PMC11797817 DOI: 10.14218/jcth.2024.00302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 11/05/2024] [Accepted: 11/08/2024] [Indexed: 02/09/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a significant global health issue, ranking as the sixth most prevalent malignancy and the fourth leading cause of cancer-related mortality worldwide. Despite advancements in therapeutic strategies, mortality rates for HCC remain high. The tumor immune microenvironment (TIME) plays a vital role in HCC progression by influencing tumor cell survival and growth. Recent studies highlight the essential role of exosomes in mediating intercellular communication within the TIME, particularly in interactions among tumor cells, immune cells, and fibroblasts. These interactions drive critical aspects of tumor development, including immune escape, angiogenesis, drug resistance, and metastasis. A detailed understanding of the molecular mechanisms by which exosomes modulate the TIME is essential for developing targeted therapies. This review systematically evaluated the roles and regulatory mechanisms of exosomes within the TIME of HCC, examining the impact of both HCC-derived and non-HCC-derived exosomes on various cellular components within the TIME. It emphasized their regulatory effects on cell phenotypes and functions, as well as their roles in HCC progression. The review also explored the potential applications of exosome-based immunotherapies, offering new insights into improving therapeutic strategies for HCC.
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Affiliation(s)
- Yifei Ge
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Lixue Jiang
- Department of Breast Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Qingfu Dong
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, China
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fuzhou, Fujian, China
- Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, China
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Judy Wai Ping Yam
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Xiangyu Zhong
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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Shirani N, Abdi N, Chehelgerdi M, Yaghoobi H, Chehelgerdi M. Investigating the role of exosomal long non-coding RNAs in drug resistance within female reproductive system cancers. Front Cell Dev Biol 2025; 13:1485422. [PMID: 39925739 PMCID: PMC11802832 DOI: 10.3389/fcell.2025.1485422] [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: 08/23/2024] [Accepted: 01/02/2025] [Indexed: 02/11/2025] Open
Abstract
Exosomes, as key mediators of intercellular communication, have been increasingly recognized for their role in the oncogenic processes, particularly in facilitating drug resistance. This article delves into the emerging evidence linking exosomal lncRNAs to the modulation of drug resistance mechanisms in cancers such as ovarian, cervical, and endometrial cancer. It synthesizes current research findings on how these lncRNAs influence cancer cell survival, tumor microenvironment, and chemotherapy efficacy. Additionally, the review highlights potential therapeutic strategies targeting exosomal lncRNAs, proposing a new frontier in overcoming drug resistance. By mapping the interface of exosomal lncRNAs and drug resistance, this article aims to provide a comprehensive understanding that could pave the way for innovative treatments and improved patient outcomes in female reproductive system cancers.
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Affiliation(s)
- Nooshafarin Shirani
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Neda Abdi
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Matin Chehelgerdi
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Hajar Yaghoobi
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mohammad Chehelgerdi
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
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Tan Y, He Y, Xu Y, Qiu X, Liu G, Liu L, Jiang Y, Li M, Sun W, Xie Z, Huang Y, Chen X, Yang X. Identification of pain-related long non-coding RNAs for pulpitis prediction. Clin Oral Investig 2025; 29:75. [PMID: 39841251 DOI: 10.1007/s00784-025-06164-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 01/15/2025] [Indexed: 01/23/2025]
Abstract
OBJECTIVES We investigated the recently generated RNA-sequencing dataset of pulpitis to identify the potential pain-related lncRNAs for pulpitis prediction. MATERIALS AND METHODS Differential analysis was performed on the gene expression profile between normal and pulpitis samples to obtain pulpitis-related genes. The co-expressed gene modules were identified by weighted gene coexpression network analysis (WGCNA). Then the hypergeometric test was utilized to screen pain-related core modules. The functional enrichment analysis was performed on the up- and down-regulated genes in the core module of pulpitis pain to explore the underlying mechanisms. A pain-related lncRNA-based classification model was constructed using LASSO. Consensus clustering and gene set variation analysis (GSVA) on the infiltrating immunocytes was used for pulpitis subtyping. miRanda predicts miRNA-target relationship, which was filtered by expression correlation. Hallmark pathway and enrichment analysis was performed to investigate the candidate target pathways of the lncRNAs. RESULTS A total of 1830 differential RNAs were identified in pulpitis. WGCNA explored seven co-expressed modules, among which the turquoise module is pain-related with hypergeometric test. The up-regulated genes were significantly enriched in immune response related pathways. Down-regulated genes were significantly enriched in differentiation pathways. Eight lncRNAs in the pain-related module were related to inflammation. Among them, MIR181A2HG was downregulated while other seven lncRNAs were upregulated in pulpitis. The LASSO classification model revealed that MIR181A2HG and LINC00426 achieved outstanding predictive performances with perfect ROC-AUC score (AUC = 1). We differentiated the pulpitis samples into two progression subtypes and MIR181A2HG is a progressive marker for pulpitis. The miRNA-mRNA-lncRNA regulatory network of pulpitis pain was constructed, with GATA3 as a key transcription factor. NF-kappa B signaling pathway is a candidate pathway impacted by these lncRNAs. CONCLUSIONS PCED1B-AS1, MIAT, MIR181A2HG, LINC00926, LINC00861, LINC00528, LINC00426 and ITGB2-AS1 may be potential markers of pulpitis pain. A two-lncRNA signature of LINC00426 and MIR181A2HG can accurately predict pulpitis, which could facilitate the molecular diagnosis of pulpitis. GATA3 might regulate these lncRNAs and downstream NF-kappa B signaling pathway. CLINICAL RELEVANCE This study identified potential pain-related lncRNAs with underlying molecular mechanism analysis for the prediction of pulpitis. The classification model based on lncRNAs will facilitate the early diagnosis of pulpitis.
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Affiliation(s)
- Yongjie Tan
- School of Automation, Guangdong University of Technology, Guangzhou Higher Education Mega Center, No. 100 Waihuan Xi Road Panyu District, Guangzhou, 510006, China
| | - Ying He
- Department of Endodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yuexuan Xu
- School of Automation, Guangdong University of Technology, Guangzhou Higher Education Mega Center, No. 100 Waihuan Xi Road Panyu District, Guangzhou, 510006, China
| | - Xilin Qiu
- School of Automation, Guangdong University of Technology, Guangzhou Higher Education Mega Center, No. 100 Waihuan Xi Road Panyu District, Guangzhou, 510006, China
| | - Guanru Liu
- School of Automation, Guangdong University of Technology, Guangzhou Higher Education Mega Center, No. 100 Waihuan Xi Road Panyu District, Guangzhou, 510006, China
| | - Lingxian Liu
- School of Automation, Guangdong University of Technology, Guangzhou Higher Education Mega Center, No. 100 Waihuan Xi Road Panyu District, Guangzhou, 510006, China
| | - Ye Jiang
- Department of Endodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Mingyue Li
- School of Automation, Guangdong University of Technology, Guangzhou Higher Education Mega Center, No. 100 Waihuan Xi Road Panyu District, Guangzhou, 510006, China
| | - Weijun Sun
- School of Automation, Guangdong University of Technology, Guangzhou Higher Education Mega Center, No. 100 Waihuan Xi Road Panyu District, Guangzhou, 510006, China
- Guangdong Key Laboratory of IoT Information Technology, Guangdong University of Technology, Guangzhou, China
| | - Ziqiang Xie
- Department of Science and Technology, Nanchang University College of Science and Technology, Jiujiang, China
| | - Yonghui Huang
- School of Automation, Guangdong University of Technology, Guangzhou Higher Education Mega Center, No. 100 Waihuan Xi Road Panyu District, Guangzhou, 510006, China
| | - Xin Chen
- School of Automation, Guangdong University of Technology, Guangzhou Higher Education Mega Center, No. 100 Waihuan Xi Road Panyu District, Guangzhou, 510006, China.
| | - Xuechao Yang
- Department of Endodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China.
- Department of Endodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, No. 195 Dongfeng West Road Yuexiu District, Guangzhou, 510182, China.
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Yao Y, Ren Y, Hou X, Wang P, Zhu J, Liu S, Ma X, Liu T, Yang Z, Zhu H, Li N. Construction and preclinical evaluation of a 124I-labelled bispecific antibody targeting PD-L1 and PD-L2. Eur J Nucl Med Mol Imaging 2024; 52:36-47. [PMID: 39155310 DOI: 10.1007/s00259-024-06886-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 08/12/2024] [Indexed: 08/20/2024]
Abstract
PURPOSE NB12 is a bispecific antibody that consists of two anti-programmed cell death-ligand 1 (PD-L1) nanobodies and two anti-programmed cell death-ligand 2 (PD-L2) nanobodies. The aim of this study was to design a novel tracer, [124I]I-NB12, targeting PD-L1/2 and perform preclinical evaluations to dynamically monitor PD-L1/2 expression for determining cancer patient responsiveness to ICI therapy. METHODS NB12 was labelled with the radionuclide 124I at room temperature (RT). An in vitro binding assay was performed to assess the affinity of [124I]I-NB12 for PD-L1 and PD-L2. Cellular uptake, pharmacokinetic, and biodistribution experiments were performed to evaluate the biological properties. Micro-PET/CT imaging with [124I]I-NB12 was conducted at different time points. Immunohistochemical and haematoxylin and eosin (HE) staining experiments were carried out using tumour tissues. Routine blood, biochemical indices and major organ pathology were used to evaluate the biosafety of the tracers. RESULTS The radiochemical yield of [124I]I-NB12 was 84.62 ± 3.90%, and the radiochemical purity (RCP) was greater than 99%. [124I]I-NB12 had a high affinity for the PD-L1 (Kd = 19.82 nM) and PD-L2 (Kd = 2.93 nM). Cellular uptake experiments confirmed that the uptake of [124I]I-NB12 by A549-PDL1/2 cells was greater than that by A549 cells. The half-lives of the distribution phase and elimination phase were 0.26 h and 4.08 h, respectively. Micro-PET/CT showed significant [124I]I-NB12 uptake in the tumour region of A549-PDL1/2 tumour-bearing mice compared with A549 tumour-bearing mice 24 h postinjection. Immunohistochemical and HE staining experiments confirmed that tumour-bearing mice was successfully constructed. CONCLUSION We constructed a bispecific antibody that targets PD-L1 and PD-L2, namely, [124I]I-NB12. Biological evaluation revealed its specificity and affinity for PD-L1/2, and micro-PET/CT confirmed the feasibility of visualizing tumour PD-L1/2 in vivo. Using [124I]I-NB12 may be a promising strategy for identifying cancer patients that can potentially benefit from ICI therapy.
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Affiliation(s)
- Yuan Yao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Peking University, No. 52 Fu-Cheng Rd, Beijing, 100142, People's Republic of China
| | - Yanan Ren
- Guizhou University School of Medicine, Guiyang, Guizhou, 550025, People's Republic of China
| | - Xingguo Hou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Peking University, No. 52 Fu-Cheng Rd, Beijing, 100142, People's Republic of China
| | - Pei Wang
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jinyu Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Peking University, No. 52 Fu-Cheng Rd, Beijing, 100142, People's Republic of China
| | - Song Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Peking University, No. 52 Fu-Cheng Rd, Beijing, 100142, People's Republic of China
| | - Xiaokun Ma
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Peking University, No. 52 Fu-Cheng Rd, Beijing, 100142, People's Republic of China
| | - Teli Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Peking University, No. 52 Fu-Cheng Rd, Beijing, 100142, People's Republic of China
| | - Zhi Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Peking University, No. 52 Fu-Cheng Rd, Beijing, 100142, People's Republic of China.
| | - Hua Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Peking University, No. 52 Fu-Cheng Rd, Beijing, 100142, People's Republic of China.
| | - Nan Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Peking University, No. 52 Fu-Cheng Rd, Beijing, 100142, People's Republic of China.
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Kadian LK, Verma D, Lohani N, Yadav R, Ranga S, Gulshan G, Pal S, Kumari K, Chauhan SS. Long non-coding RNAs in cancer: multifaceted roles and potential targets for immunotherapy. Mol Cell Biochem 2024; 479:3229-3254. [PMID: 38413478 DOI: 10.1007/s11010-024-04933-1] [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: 06/06/2023] [Accepted: 01/05/2024] [Indexed: 02/29/2024]
Abstract
Cancer remains a major global health concern with high mortality rates mainly due to late diagnosis and poor prognosis. Long non-coding RNAs (lncRNAs) are emerging as key regulators of gene expression in human cancer, functioning through various mechanisms including as competing endogenous RNAs (ceRNAs) and indirectly regulating miRNA expression. LncRNAs have been found to have both oncogenic and tumor-suppressive roles in cancer, with the former promoting cancer cell proliferation, migration, invasion, and poor prognosis. Recent research has shown that lncRNAs are expressed in various immune cells and are involved in cancer cell immune escape and the modulation of the tumor microenvironment, thus highlighting their potential as targets for cancer immunotherapy. Targeting lncRNAs in cancer or immune cells could enhance the anti-tumor immune response and improve cancer immunotherapy outcomes. However, further research is required to fully understand the functional roles of lncRNAs in cancer and the immune system and their potential as targets for cancer immunotherapy. This review offers a comprehensive examination of the multifaceted roles of lncRNAs in human cancers, with a focus on their potential as targets for cancer immunotherapy. By exploring the intricate mechanisms underlying lncRNA-mediated regulation of cancer cell proliferation, invasion, and immune evasion, we provide insights into the diverse therapeutic applications of these molecules.
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Affiliation(s)
- Lokesh K Kadian
- Dept of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India
- Dept of Dermatology, Indiana University School of Medicine, Indianapolis, 46202, USA
| | - Deepika Verma
- Dept of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Neelam Lohani
- Dept of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Ritu Yadav
- Dept of Genetics, MD University, Rohtak, 124001, India
| | - Shalu Ranga
- Dept of Genetics, MD University, Rohtak, 124001, India
| | - Gulshan Gulshan
- Department of Biosciences and Bioengineering, IIT Bombay, Mumbai, Maharashtra, India
| | - Sanghapriya Pal
- Dept of Biochemistry, Maulana Azad Medical College and Associated Hospital, New Delhi, 110002, India
| | - Kiran Kumari
- Dept of Forensic Science, Lovely Professional University, Jalandhar, Punjab, 144411, India
| | - Shyam S Chauhan
- Dept of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India.
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10
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Bian J, Shao R, Li J, Zhu J, Shao A, Liu C, Lu LV, Pan H, Shi Y, Fang N. Mechanism research of non-coding RNA in immune checkpoint inhibitors therapy. Cancer Sci 2024; 115:3520-3531. [PMID: 39136293 PMCID: PMC11531961 DOI: 10.1111/cas.16309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 07/05/2024] [Accepted: 07/26/2024] [Indexed: 11/05/2024] Open
Abstract
Immune checkpoint inhibitor (ICI) therapies for tumors of different systems have attained significant achievements and have changed the current situation of tumor treatment due to their therapeutic characteristics of high specificity and low side effects. The immune checkpoint Programmed death 1/Programmed cell death-Ligand 1 (PD-1/PD-L1) axis exerts a vital role in the immune escape of tumor cells. As a result, it has become a key target for tumor immunotherapy. Therefore, to perfect research into potential regulatory factors for the PD-1/PD-L1 axis, in order to understand and illustrate tumor ICI therapy mechanisms, is a significant goal. Moreover, ncRNA has been verified to regulate the PD-1/PD-L1 axis in the tumor immune microenvironment to regulate tumor genesis and development. ncRNAs can improve or decrease the efficacy of ICI therapy by modulating PD-L1 expression. This review aimed to investigate the mechanisms of action of ncRNA in regulating the PD-1/PD-L1 axis in ICI therapy, to provide more efficient immunotherapy for tumors of different systems.
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Affiliation(s)
- Jie Bian
- Department of OncologyThe Affiliated People's Hospital of Jiangsu UniversityZhenjiangChina
| | - Rui Shao
- Department of PathologyThe Affiliated People's Hospital of Jiangsu UniversityZhenjiangChina
| | - Juan Li
- Department of OncologyThe Affiliated People's Hospital of Jiangsu UniversityZhenjiangChina
| | - Jing‐Feng Zhu
- Department of Thoracic and Cardiovascular SurgeryThe Affiliated People's Hospital of Jiangsu UniversityZhenjiangChina
| | - Ai‐Zhong Shao
- Department of Thoracic and Cardiovascular SurgeryThe Affiliated People's Hospital of Jiangsu UniversityZhenjiangChina
| | - Chao Liu
- Department of Thoracic and Cardiovascular SurgeryThe Affiliated People's Hospital of Jiangsu UniversityZhenjiangChina
| | - L. V. Lu
- Department of Thoracic and Cardiovascular SurgeryThe Affiliated People's Hospital of Jiangsu UniversityZhenjiangChina
| | - Hui‐Wen Pan
- Department of Thoracic and Cardiovascular SurgeryThe Affiliated People's Hospital of Jiangsu UniversityZhenjiangChina
| | - Yi‐Jun Shi
- Department of Thoracic and Cardiovascular SurgeryThe Affiliated People's Hospital of Jiangsu UniversityZhenjiangChina
| | - Na Fang
- Department of OncologyThe Affiliated People's Hospital of Jiangsu UniversityZhenjiangChina
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11
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Zhang LN, Chen JY, Liu YX, Zhang Y, Hong LL, Li XX, Liu SH, Chen SQ, Peng L, Huang YT. Identification of lncRNA dual targeting PD-L1 and PD-L2 as a novel prognostic predictor for gastric cancer. Front Oncol 2024; 14:1341056. [PMID: 39525623 PMCID: PMC11544118 DOI: 10.3389/fonc.2024.1341056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 09/20/2024] [Indexed: 11/16/2024] Open
Abstract
Background Although breakthroughs have been achieved in gastric cancer (GC) therapy with immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1), the acquisition of high response rate remains a huge challenge for clinicians. It is imperative to identify novel biomarkers for predicting response to immunotherapy and explore alternative therapeutic strategy for GC. Methods The transcriptomic profiles and clinical information of GC patients from The Cancer Genome Atlas (TCGA)-stomach adenocarcinoma (STAD) database was used to screen differentially expressed lncRNAs between the tumor specimens and the paracancerous tissues. The TargetScan, miRDB and miRcode database were then utilized to construct competing endogenous RNA (ceRNA) networks and identify pivotal lncRNAs. An independent dataset from GEO (GSE70880) and 23 pairs of GC specimens of our cohort were subsequently performed for external validity. The relationship between clinical variables and gene expression were evaluated by Kruskal-wallis test and Wilcoxon signed-rank. The prognostic value of the candidate genes was assessed using Kaplan-Meier analysis and Cox regression models. CIBERSORT and Gene set enrichment analysis (GSEA) were used to determine immune cell infiltration. Gastric adenocarcinoma AGS cells and human embryonic kidney 293T (HEK293T) cells with knockdown of LINC01094 were generated by siRNA transfection, followed by detecting the alteration of the target miRNA and PD-L1/PD-L2 by RT-qPCR. Besides, the interaction between lncRNA and the miRNA-PD-L1/PD-L2 axis were verified by dual luciferase reporter assay. Results Twenty-two intersecting lncRNAs were identified to be PD-L1/PD-L2-related lncRNAs and LINC01094-miR-17-5p-PD-L1/PD-L2 was constructed as a potential ceRNA network. LINC01094 was increased in tumor specimens than adjacent normal samples and was positively associated with advanced tumor stages and EBV and MSI status. Furthermore, LINC01094 expression was an independent risk factor for poor overall survival (OS) in GC patients. CD8+ T cell exhaustion-related genes were enriched in high-LINC01094 tissues and high-PD-L2 group. A strong positive association of LINC01094 expression was established with M2 macrophages, IL-10+ TAM, as well as PD-L1 and PD-L2 levels, therefore a LINC01094-miR-17-5p-IL-10 network was proposed in macrophages. Using the exoRBase database, LINC01094 was assumed in blood exosomes of GC patients The results of knockdown experiments and luciferase reporter assays revealed that LINC01094 interacted with miR-17-5p and served as a miRNA sponge to regulate the expression of PD-L1 and PD-L2. Conclusion LINC01094 dually regulates the expression of PD-L1 and PD-L2 and shapes the immunosuppressive tumor microenvironment via sponging miR-17-5p. LINC01094 may serve as a potential prognostic predictor and therapeutic target in GC.
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Affiliation(s)
- Li-Na Zhang
- Department of Pathology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Jiong-Yu Chen
- Central Laboratory, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Yu-Xin Liu
- Health Care Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Yue Zhang
- Health Care Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Liang-Li Hong
- Department of Pathology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Xin-Xin Li
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Shu-Hui Liu
- Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China
| | - Shu-Qin Chen
- Biological Specimen Repository, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Lin Peng
- Central Laboratory, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Yi-Teng Huang
- Health Care Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
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12
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Marima R, Basera A, Miya T, Damane BP, Kandhavelu J, Mirza S, Penny C, Dlamini Z. Exosomal long non-coding RNAs in cancer: Interplay, modulation, and therapeutic avenues. Noncoding RNA Res 2024; 9:887-900. [PMID: 38616862 PMCID: PMC11015109 DOI: 10.1016/j.ncrna.2024.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 03/20/2024] [Accepted: 03/29/2024] [Indexed: 04/16/2024] Open
Abstract
In the intricate field of cancer biology, researchers are increasingly intrigued by the emerging role of exosomal long non-coding RNAs (lncRNAs) due to their multifaceted interactions, complex modulation mechanisms, and potential therapeutic applications. These exosomal lncRNAs, carried within extracellular vesicles, play a vital partin tumorigenesis and disease progression by facilitating communication networks between tumor cells and their local microenvironment, making them an ideal candidates for use in a liquid biopsy approach. However, exosomal lncRNAs remain an understudied area, especially in cancer biology. Therefore this review aims to comprehensively explore the dynamic interplay between exosomal lncRNAs and various cellular components, including interactions with tumor-stroma, immune modulation, and drug resistance mechanisms. Understanding the regulatory functions of exosomal lncRNAs in these processes can potentially unveil novel diagnostic markers and therapeutic targets for cancer. Additionally, the emergence of RNA-based therapeutics presents exciting opportunities for targeting exosomal lncRNAs, offering innovative strategies to combat cancer progression and improve treatment outcomes. Thus, this review provides insights into the current understanding of exosomal lncRNAs in cancer biology, highlighting their crucial roles, regulatory mechanisms, and the evolving landscape of therapeutic interventions. Furthermore, we have also discussed the advantage of exosomes as therapeutic carriers of lncRNAs for the development of personalized targeted therapy for cancer patients.
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Affiliation(s)
- Rahaba Marima
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChi Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, South Africa
| | - Afra Basera
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChi Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, South Africa
- Department of Medical Oncology, Faculty of Health Sciences, Steve Biko Academic Hospital, University of Pretoria, South Africa
| | - Thabiso Miya
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChi Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, South Africa
| | - Botle Precious Damane
- Department of Surgery, Steve Biko Academic Hospital, University of Pretoria, Pretoria, 0028, South Africa
| | - Jeyalakshmi Kandhavelu
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Sheefa Mirza
- Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Parktown, 2193, South Africa
| | - Clement Penny
- Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Parktown, 2193, South Africa
| | - Zodwa Dlamini
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChi Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, South Africa
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13
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Mahboobnia K, Beveridge DJ, Yeoh GC, Kabir TD, Leedman PJ. MicroRNAs in Hepatocellular Carcinoma Pathogenesis: Insights into Mechanisms and Therapeutic Opportunities. Int J Mol Sci 2024; 25:9393. [PMID: 39273339 PMCID: PMC11395074 DOI: 10.3390/ijms25179393] [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: 07/21/2024] [Revised: 08/18/2024] [Accepted: 08/20/2024] [Indexed: 09/15/2024] Open
Abstract
Hepatocellular carcinoma (HCC) presents a significant global health burden, with alarming statistics revealing its rising incidence and high mortality rates. Despite advances in medical care, HCC treatment remains challenging due to late-stage diagnosis, limited effective therapeutic options, tumor heterogeneity, and drug resistance. MicroRNAs (miRNAs) have attracted substantial attention as key regulators of HCC pathogenesis. These small non-coding RNA molecules play pivotal roles in modulating gene expression, implicated in various cellular processes relevant to cancer development. Understanding the intricate network of miRNA-mediated molecular pathways in HCC is essential for unraveling the complex mechanisms underlying hepatocarcinogenesis and developing novel therapeutic approaches. This manuscript aims to provide a comprehensive review of recent experimental and clinical discoveries regarding the complex role of miRNAs in influencing the key hallmarks of HCC, as well as their promising clinical utility as potential therapeutic targets.
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Affiliation(s)
- Khadijeh Mahboobnia
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - Dianne J Beveridge
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - George C Yeoh
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia
| | - Tasnuva D Kabir
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - Peter J Leedman
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
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14
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Yin Y, Feng W, Chen J, Chen X, Wang G, Wang S, Xu X, Nie Y, Fan D, Wu K, Xia L. Immunosuppressive tumor microenvironment in the progression, metastasis, and therapy of hepatocellular carcinoma: from bench to bedside. Exp Hematol Oncol 2024; 13:72. [PMID: 39085965 PMCID: PMC11292955 DOI: 10.1186/s40164-024-00539-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 07/10/2024] [Indexed: 08/02/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with high incidence, recurrence, and metastasis rates. The emergence of immunotherapy has improved the treatment of advanced HCC, but problems such as drug resistance and immune-related adverse events still exist in clinical practice. The immunosuppressive tumor microenvironment (TME) of HCC restricts the efficacy of immunotherapy and is essential for HCC progression and metastasis. Therefore, it is necessary to elucidate the mechanisms behind immunosuppressive TME to develop and apply immunotherapy. This review systematically summarizes the pathogenesis of HCC, the formation of the highly heterogeneous TME, and the mechanisms by which the immunosuppressive TME accelerates HCC progression and metastasis. We also review the status of HCC immunotherapy and further discuss the existing challenges and potential therapeutic strategies targeting immunosuppressive TME. We hope to inspire optimizing and innovating immunotherapeutic strategies by comprehensively understanding the structure and function of immunosuppressive TME in HCC.
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Affiliation(s)
- Yue Yin
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Weibo Feng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Jie Chen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Xilang Chen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Guodong Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Shuai Wang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Xiao Xu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Yongzhan Nie
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Daiming Fan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Kaichun Wu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Limin Xia
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
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15
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Jin X, Huang CX, Tian Y. The multifaceted perspectives on the regulation of lncRNAs in hepatocellular carcinoma ferroptosis: from bench-to-bedside. Clin Exp Med 2024; 24:146. [PMID: 38960924 PMCID: PMC11222271 DOI: 10.1007/s10238-024-01418-9] [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: 05/18/2024] [Accepted: 06/24/2024] [Indexed: 07/05/2024]
Abstract
Despite being characterized by high malignancy, high morbidity, and low survival rates, the underlying mechanism of hepatocellular carcinoma (HCC) has not been fully elucidated. Ferroptosis, a non-apoptotic form of regulated cell death, possesses distinct morphological, biochemical, and genetic characteristics compared to other types of cell death. Dysregulated actions within the molecular network that regulates ferroptosis have been identified as significant contributors to the progression of HCC. Long non-coding RNAs (lncRNAs) have emerged as influential contributors to diverse cellular processes, regulating gene function and expression through multiple mechanistic pathways. An increasing body of evidence indicates that deregulated lncRNAs are implicated in regulating malignant events such as cell proliferation, growth, invasion, and metabolism by influencing ferroptosis in HCC. Therefore, elucidating the inherent role of ferroptosis and the modulatory functions of lncRNAs on ferroptosis in HCC might promote the development of novel therapeutic interventions for this disease. This review provides a succinct overview of the roles of ferroptosis and ferroptosis-related lncRNAs in HCC progression and treatment, aiming to drive the development of promising therapeutic targets and biomarkers for HCC patients.
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Affiliation(s)
- Xin Jin
- Department of Gastroenterology and Hepatology, Fengdu People's Hospital, Fengdu County, Chongqing, 408200, China
| | - Chun Xia Huang
- Department of Gastroenterology and Hepatology, Fengdu People's Hospital, Fengdu County, Chongqing, 408200, China
| | - Yue Tian
- Department of Gastroenterology and Hepatology, Fengdu People's Hospital, Fengdu County, Chongqing, 408200, China.
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16
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Shi M, Jia JS, Gao GS, Hua X. Advances and challenges of exosome-derived noncoding RNAs for hepatocellular carcinoma diagnosis and treatment. Biochem Biophys Rep 2024; 38:101695. [PMID: 38560049 PMCID: PMC10979073 DOI: 10.1016/j.bbrep.2024.101695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 02/10/2024] [Accepted: 03/20/2024] [Indexed: 04/04/2024] Open
Abstract
Exosomes, also termed extracellular vesicles (EVs), are an important component of the tumor microenvironment (TME) and exert versatile effects on the molecular communications in the TME of hepatocellular carcinoma (HCC). Exosome-mediated intercellular communication is closely associated with the tumorigenesis and development of HCC. Exosomes can be extracted through ultracentrifugation and size exclusion, followed by molecular analysis through sequencing. Increasing studies have confirmed the important roles of exosome-derived ncRNAs in HCC, including tumorigenesis, progression, immune escape, and treatment resistance. Due to the protective membrane structure of exosomes, the ncRNAs carried by exosomes can evade degradation by enzymes in body fluids and maintain good expression stability. Thus, exosome-derived ncRNAs are highly suitable as biomarkers for the diagnosis and prognostic prediction of HCC, such as exosomal miR-21-5p, miR-221-3p and lncRNA-ATB. In addition, substantial studies revealed that the up-or down-regulation of exosome-derived ncRNAs had an important impact on HCC progression and response to treatment. Exosomal biomarkers, such as miR-23a, lncRNA DLX6-AS1, miR-21-5p, lncRNA TUC339, lncRNA HMMR-AS1 and hsa_circ_0004658, can reshape immune microenvironment by regulating M2-type macrophage polarization and then promote HCC development. Therefore, by controlling exosome biogenesis and modulating exosomal ncRNA levels, HCC may be inhibited or eliminated. In this current review, we summarized the recent findings on the role of exosomes in HCC progression and analyzed the relationship between exosome-derived ncRNAs and HCC diagnosis and treatment.
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Affiliation(s)
- Min Shi
- Department of Clinical Laboratory, Ningbo No.2 Hospital, Ningbo, Zhejiang, China
| | - Jun-Su Jia
- Department of Clinical Laboratory, Ningbo No.2 Hospital, Ningbo, Zhejiang, China
| | - Guo-Sheng Gao
- Department of Clinical Laboratory, Ningbo No.2 Hospital, Ningbo, Zhejiang, China
| | - Xin Hua
- Department of Clinical Laboratory, Ningbo No.2 Hospital, Ningbo, Zhejiang, China
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17
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Mi J, Zhang H, Jiang X, Yi Y, Cao W, Song C, Yuan C. lncRNA MIAT promotes luminal B breast cancer cell proliferation, migration, and invasion in vitro. J Appl Genet 2024; 65:309-319. [PMID: 37987972 DOI: 10.1007/s13353-023-00807-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 11/03/2023] [Accepted: 11/05/2023] [Indexed: 11/22/2023]
Abstract
Long noncoding RNAs (lncRNAs) play a role in the emergence and progression of several human tumors, including luminal B breast cancer (BC). The biological functions and potential mechanisms of lncRNA myocardial infarction-associated transcripts (MIAT) in luminal B BC, on the contrary, are unknown. In this work, we used UALCAN database analysis to find high expression of lncRNA MIAT in luminal BC tissues and also confirmed high levels of lncRNA MIAT expression in luminal B BC tissues and cells. In vitro knockdown of MIAT inhibited the proliferation, migration, and invasion of BT474 cells. In addition, we found that miR-150-5p levels were significantly reduced in luminal B BC specimens and cells, and miR-150-5p levels were significantly increased when MIAT was knocked down. And TIMER database analysis showed that MIAT was positively associated with PDL1. Through bioinformatic tools and in vitro experiments, lncRNA MIAT could function as a competitive endogenous RNA (CeRNA) to further regulate programmed cell death ligand 1 (PDL1) expression by directly sponging miR-150-5p. In conclusion, our data suggest that MIAT, an oncogene, may sponge miR-150-5p to regulate PDL1 expression and affect proliferation, migration, and invasion in luminal B BC in vitro.
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Affiliation(s)
- Jintao Mi
- Molecular Immunology, College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, China
| | - Hongsheng Zhang
- Molecular Immunology, College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, China
| | - Xuemei Jiang
- Department of Breast Surgery, People's Hospital of Deyang City, Deyang, 618000, Sichuan, China
| | - Ying Yi
- Department of Breast Surgery, People's Hospital of Deyang City, Deyang, 618000, Sichuan, China
| | - Weiwei Cao
- Department of Clinical Laboratory, People's Hospital of Deyang City, Deyang, 618000, Sichuan, China
| | - Chunjiao Song
- Department of Clinical Laboratory, People's Hospital of Deyang City, Deyang, 618000, Sichuan, China
| | - Chengliang Yuan
- Department of Clinical Laboratory, People's Hospital of Deyang City, Deyang, 618000, Sichuan, China.
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18
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Augello G, Cusimano A, Cervello M, Cusimano A. Extracellular Vesicle-Related Non-Coding RNAs in Hepatocellular Carcinoma: An Overview. Cancers (Basel) 2024; 16:1415. [PMID: 38611093 PMCID: PMC11011022 DOI: 10.3390/cancers16071415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 04/02/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer. It is a major public health problem worldwide, and it is often diagnosed at advanced stages, when no effective treatment options are available. Extracellular vesicles (EVs) are nanosized double-layer lipid vesicles containing various biomolecule cargoes, such as lipids, proteins, and nucleic acids. EVs are released from nearly all types of cells and have been shown to play an important role in cell-to-cell communication. In recent years, many studies have investigated the role of EVs in cancer, including HCC. Emerging studies have shown that EVs play primary roles in the development and progression of cancer, modulating tumor growth and metastasis formation. Moreover, it has been observed that non-coding RNAs (ncRNAs) carried by tumor cell-derived EVs promote tumorigenesis, regulating the tumor microenvironment (TME) and playing critical roles in the progression, angiogenesis, metastasis, immune escape, and drug resistance of HCC. EV-related ncRNAs can provide information regarding disease status, thus encompassing a role as biomarkers. In this review, we discuss the main roles of ncRNAs present in HCC-derived EVs, including micro(mi) RNAs, long non-coding (lnc) RNAs, and circular (circ) RNAs, and their potential clinical value as biomarkers and therapeutic targets.
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Affiliation(s)
- Giuseppa Augello
- Institute for Biomedical Research and Innovation, National Research Council (CNR), 90146 Palermo, Italy; (A.C.); (M.C.)
| | - Alessandra Cusimano
- Institute for Biomedical Research and Innovation, National Research Council (CNR), 90146 Palermo, Italy; (A.C.); (M.C.)
- Department of Biological, Chemical and Pharmaceutical Science and Technology (STEBICEF), University of Palermo, 90128 Palermo, Italy
| | - Melchiorre Cervello
- Institute for Biomedical Research and Innovation, National Research Council (CNR), 90146 Palermo, Italy; (A.C.); (M.C.)
| | - Antonella Cusimano
- Institute for Biomedical Research and Innovation, National Research Council (CNR), 90146 Palermo, Italy; (A.C.); (M.C.)
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Huang Q, Zhong X, Li J, Hu R, Yi J, Sun J, Xu Y, Zhou X. Exosomal ncRNAs: Multifunctional contributors to the immunosuppressive tumor microenvironment of hepatocellular carcinoma. Biomed Pharmacother 2024; 173:116409. [PMID: 38460375 DOI: 10.1016/j.biopha.2024.116409] [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: 12/05/2023] [Revised: 02/23/2024] [Accepted: 03/06/2024] [Indexed: 03/11/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignant liver cancer characterized by aggressive progression, unfavorable prognosis, and an increasing global health burden. Therapies that precisely target immunological checkpoints and immune cells have gained significant attention as possible therapeutics in recent years. In truth, the efficacy of immunotherapy is heavily contingent upon the tumor microenvironment (TME). Recent studies have indicated that exosomes serve as a sophisticated means of communication among biomolecules, executing an essential part in the TME of immune suppression. Exosomal non-coding RNAs (ncRNAs) can induce the activation of tumor cells and immunosuppressive immune cells that suppress the immune system, such as cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), CD+8 T cells, regulatory T cells (Tregs), and regulatory B cells (Bregs). This cell-cell crosstalk triggered by exosomal ncRNAs promotes tumor proliferation and metastasis, angiogenesis, malignant phenotype transformation, and drug resistance. Hence, it is imperative to comprehend how exosomal ncRNAs regulate tumor cells or immune cells within the TME to devise more comprehensive and productive immunotherapy programs. This study discusses the features of exosomal ncRNAs in HCC and how the activation of the exosomes redefines the tumor's immunosuppressive microenvironment, hence facilitating the advancement of HCC. Furthermore, we also explored the potential of exosomal ncRNAs as a viable biological target or natural vehicle for HCC therapy.
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Affiliation(s)
- Qi Huang
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao PR China; Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, PR China; Department of Liver Disease, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, PR China
| | - Xin Zhong
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, PR China; Department of Liver Disease, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, PR China
| | - Jing Li
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao PR China; Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, PR China; Department of Liver Disease, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, PR China
| | - Rui Hu
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao PR China; Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, PR China; Department of Liver Disease, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, PR China
| | - Jinyu Yi
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao PR China; Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, PR China; Department of Liver Disease, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, PR China
| | - Jialing Sun
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, PR China; Department of Liver Disease, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, PR China
| | - Youhua Xu
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao PR China.
| | - Xiaozhou Zhou
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, PR China; Department of Liver Disease, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, PR China.
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20
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Yang Y, Yan X, Bai X, Yang J, Song J. Programmed cell death-ligand 2: new insights in cancer. Front Immunol 2024; 15:1359532. [PMID: 38605944 PMCID: PMC11006960 DOI: 10.3389/fimmu.2024.1359532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 03/18/2024] [Indexed: 04/13/2024] Open
Abstract
Immunotherapy has revolutionized cancer treatment, with the anti-PD-1/PD-L1 axis therapy demonstrating significant clinical efficacy across various tumor types. However, it should be noted that this therapy is not universally effective for all PD-L1-positive patients, highlighting the need to expedite research on the second ligand of PD-1, known as Programmed Cell Death Receptor Ligand 2 (PD-L2). As an immune checkpoint molecule, PD-L2 was reported to be associated with patient's prognosis and plays a pivotal role in cancer cell immune escape. An in-depth understanding of the regulatory process of PD-L2 expression may stratify patients to benefit from anti-PD-1 immunotherapy. Our review focuses on exploring PD-L2 expression in different tumors, its correlation with prognosis, regulatory factors, and the interplay between PD-L2 and tumor treatment, which may provide a notable avenue in developing immune combination therapy and improving the clinical efficacy of anti-PD-1 therapies.
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Affiliation(s)
- Yukang Yang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
| | - Xia Yan
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Xueqi Bai
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Jiayang Yang
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Jianbo Song
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
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21
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Zou W, Luo X, Gao M, Yu C, Wan X, Yu S, Wu Y, Wang A, Fenical W, Wei Z, Zhao Y, Lu Y. Optimization of cancer immunotherapy on the basis of programmed death ligand-1 distribution and function. Br J Pharmacol 2024; 181:257-272. [PMID: 36775813 PMCID: PMC11080663 DOI: 10.1111/bph.16054] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 02/04/2023] [Indexed: 02/14/2023] Open
Abstract
Programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) immune checkpoint blockade as a breakthrough in cancer immunotherapy has shown unprecedented positive outcomes in the clinic. However, the overall effectiveness of PD-L1 antibody is less than expected. An increasing number of studies have demonstrated that PD-L1 is widely distributed and expressed not only on the cell membrane but also on the inside of the cells as well as on the extracellular vesicles secreted by tumour cells. Both endogenous and exogenous PD-L1 play significant roles in influencing the therapeutic effect of anti-tumour immunity. Herein, we mainly focused on the distribution and function of PD-L1 and further summarized the potential targeted therapeutic strategies. More importantly, in addition to taking the overall expression abundance of PD-L1 as a predictive indicator for selecting corresponding PD-1/PD-L1 monoclonal antibodies (mAbs), we also proposed that personalized combination therapies based on the different distribution of PD-L1 are worth attention to achieve more efficient and effective therapeutic outcomes in cancer patients. LINKED ARTICLES: This article is part of a themed issue on Cancer Microenvironment and Pharmacological Interventions. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.2/issuetoc.
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Affiliation(s)
- Wei Zou
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xin Luo
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Mengyuan Gao
- Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Chang Yu
- Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xueting Wan
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Suyun Yu
- Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuanyuan Wu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, China
| | - Aiyun Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, China
| | - William Fenical
- Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, California, USA
| | - Zhonghong Wei
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yang Zhao
- Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yin Lu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, China
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22
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Shi H, Liu Y, Liu Z, Ge X, Wu J, Tang H, Zhang Y, Lu S. Prediction Model for Immunotherapy Efficacy in Hepatocellular Carcinoma Based on Alternative Splicing Sequencing Data. Technol Cancer Res Treat 2024; 23:15330338241265962. [PMID: 39118591 PMCID: PMC11311179 DOI: 10.1177/15330338241265962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 05/08/2024] [Accepted: 05/28/2024] [Indexed: 08/10/2024] Open
Abstract
Background: Integrating immune checkpoint inhibitors with multi-target tyrosine kinase inhibitors presents an innovative and hopeful strategy in liver cancer treatment. Nonetheless, a degree of resistance to this treatment is noticeable in certain patients. Alternative splicing (AS) represents a common biological process that controls the variety of life functions via isoforms. Purpose: Investigating how gene AS affects the effectiveness of combined immunotherapy in treating hepatocellular carcinoma (HCC). Methods: Our retrospective examination focused on AS's effect on immune therapy effectiveness, utilizing accessible tissue sequencing and clinical records for HCC. For corroborating our results, we gathered samples of drug-resistant HCC tissue, nearby tissues, HCC tissue with high drug responsiveness, and healthy liver tissue from clinical studies. Results: The study revealed a link between the frequency of AS occurrences, the expression levels of programmed cell death 1 ligand 1, and the resistance to tumor medications. Our study detailed the AS occurrences in HCC, leading to the creation of a risk-assessment function and a predictive model using AS data. The results of our study revealed that the risk score effectively distinguished between various immune subtypes and the effectiveness of immune therapy. Additional examination of the chosen AS occurrences uncovered their effects on both the immune microenvironment and cellular immunity. Our investigation also delved into the regulatory framework of AS, uncovering the role of stringently controlled splicing factors in the emergence of tumors and the modulation of the body's immune response. Conclusions: Increased AS in HCC diminishes the efficacy of immunotherapy; conversely, more AS in peritumoral tissue elevates the likelihood of tumor immune evasion.
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Affiliation(s)
- Huizhong Shi
- Medical School of China PLA, Beijing, China
- The First Medical Centre, Chinese PLA General Hospital, Beijing, China
- Institute of Hepatobiliary Surgery of Chinese PLAGH, Beijing, China
| | - Yang Liu
- Medical School of China PLA, Beijing, China
- The First Medical Centre, Chinese PLA General Hospital, Beijing, China
- Institute of Hepatobiliary Surgery of Chinese PLAGH, Beijing, China
| | - Zhao Liu
- Qingdao Central Hospital, University of Health and Rehabilitation Sciences(Qingdao Central Hospital) Qingdao, China
| | - Xinlan Ge
- The First Medical Centre, Chinese PLA General Hospital, Beijing, China
- Key Laboratory of Digital Hepatobiliary Surgery, PLA, Beijing, China
| | - Jushan Wu
- General Surgery Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Haowen Tang
- The First Medical Centre, Chinese PLA General Hospital, Beijing, China
- Institute of Hepatobiliary Surgery of Chinese PLAGH, Beijing, China
| | - Yi Zhang
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Beijing, China
| | - Shichun Lu
- The First Medical Centre, Chinese PLA General Hospital, Beijing, China
- Institute of Hepatobiliary Surgery of Chinese PLAGH, Beijing, China
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Hao L, Li S, Deng J, Li N, Yu F, Jiang Z, Zhang J, Shi X, Hu X. The current status and future of PD-L1 in liver cancer. Front Immunol 2023; 14:1323581. [PMID: 38155974 PMCID: PMC10754529 DOI: 10.3389/fimmu.2023.1323581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 11/27/2023] [Indexed: 12/30/2023] Open
Abstract
The application of immunotherapy in tumor, especially immune checkpoint inhibitors (ICIs), has played an important role in the treatment of advanced unresectable liver cancer. However, the efficacy of ICIs varies greatly among different patients, which has aroused people's attention to the regulatory mechanism of programmed death ligand-1 (PD-L1) in the immune escape of liver cancer. PD-L1 is regulated by multiple levels and signaling pathways in hepatocellular carcinoma (HCC), including gene variation, epigenetic inheritance, transcriptional regulation, post-transcriptional regulation, and post-translational modification. More studies have also found that the high expression of PD-L1 may be the main factor affecting the immunotherapy of liver cancer. However, what is the difference of PD-L1 expressed by different types of cells in the microenvironment of HCC, and which type of cells expressed PD-L1 determines the effect of tumor immunotherapy remains unclear. Therefore, clarifying the regulatory mechanism of PD-L1 in liver cancer can provide more basis for liver cancer immunotherapy and combined immune treatment strategy. In addition to its well-known role in immune regulation, PD-L1 also plays a role in regulating cancer cell proliferation and promoting drug resistance of tumor cells, which will be reviewed in this paper. In addition, we also summarized the natural products and drugs that regulated the expression of PD-L1 in HCC.
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Affiliation(s)
- Liyuan Hao
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Shenghao Li
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Clinical Research Center, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei, China
| | - Jiali Deng
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Na Li
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Fei Yu
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Zhi Jiang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Junli Zhang
- Department of Infectious Diseases, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xinli Shi
- Center of Experimental Management, Shanxi University of Chinese Medicine, Jinzhong, China
| | - Xiaoyu Hu
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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Arab I, Park J, Shin JJ, Shin HS, Suk K, Lee WH. Macrophage lncRNAs in cancer development: Long-awaited therapeutic targets. Biochem Pharmacol 2023; 218:115890. [PMID: 37884197 DOI: 10.1016/j.bcp.2023.115890] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 10/23/2023] [Indexed: 10/28/2023]
Abstract
In the tumor microenvironment, the interplay among macrophages, cancer cells, and endothelial cells is multifaceted. Tumor-associated macrophages (TAMs), which often exhibit an M2 phenotype, contribute to tumor growth and angiogenesis, while cancer cells and endothelial cells reciprocally influence macrophage behavior. This complex interrelationship highlights the importance of targeting these interactions for the development of novel cancer therapies aimed at disrupting tumor progression and angiogenesis. Accumulating evidence underscores the indispensable involvement of lncRNAs in shaping macrophage functionality and contributing to the development of cancer. Animal studies have further validated the therapeutic potential of manipulating macrophage lncRNA activity to ameliorate disease severity and reduce morbidity rates. This review provides a survey of our current understanding of macrophage-associated lncRNAs, with a specific emphasis on their molecular targets and their regulatory impact on cancer progression. These lncRNAs predominantly govern macrophage polarization, favoring the dominance of M2 macrophages or TAMs. Exosomes or extracellular vesicles mediate lncRNA transfer between macrophages and cancer cells, affecting cellular functions of each other. Moreover, this review presents therapeutic strategies targeting cancer-associated lncRNAs. The insights and findings presented in this review pertaining to macrophage lncRNAs can offer valuable information for the development of treatments against cancer.
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Affiliation(s)
- Imene Arab
- School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Jeongkwang Park
- School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Jae-Joon Shin
- School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Hyeung-Seob Shin
- School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Kyoungho Suk
- Department of Pharmacology, Brain Science & Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Won-Ha Lee
- School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea.
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Wu W, He J. Unveiling the functional paradigm of exosome-derived long non-coding RNAs (lncRNAs) in cancer: based on a narrative review and systematic review. J Cancer Res Clin Oncol 2023; 149:15219-15247. [PMID: 37578522 DOI: 10.1007/s00432-023-05273-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 08/10/2023] [Indexed: 08/15/2023]
Abstract
BACKGROUND AND PURPOSE The intricate mechanisms underlying intercellular communication within the tumor microenvironment remain largely elusive. Recently, attention has shifted towards exploring the intercellular signaling mediated by exosomal long non-coding RNAs (lncRNAs) within this context. This comprehensive systematic review aims to elucidate the functional paradigm of exosome-derived lncRNAs in cancer. MATERIALS AND METHODS The review provides a comprehensive narrative of lncRNA definition, characteristics, as well as the formation, sorting, and uptake processes of exosome-derived lncRNAs. Additionally, it describes comprehensive technology for exosome research and nucleic acid drug loading. This review further systematically examines the cellular origins, functional roles, and underlying mechanisms of exosome-derived lncRNAs in recipient cells within the cancer setting. RESULTS The functional paradigm of exosome-derived lncRNAs in cancer mainly depends on the source cells and sorting mechanism of exosomal lncRNAs, the recipient cells and uptake mechanisms of exosomal lncRNAs, and the specific molecular mechanisms of lncRNAs in recipient cells. The source cells of exosomal lncRNAs mainly involved in the current review included tumor cells, cancer stem cells, normal cells, macrophages, and cancer-associated fibroblasts. CONCLUSION This synthesis of knowledge offers valuable insights for accurately identifying exosomal lncRNAs with potential as tumor biomarkers. Moreover, it aids in the selection of appropriate targeting strategies and preclinical models, thereby facilitating the clinical translation of exosomal lncRNAs as promising therapeutic targets against cancer. Through a comprehensive understanding of the functional role of exosome-derived lncRNAs in cancer, this review paves the way for advancements in personalized medicine and improved treatment outcomes.
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Affiliation(s)
- Wenhan Wu
- Department of General Surgery (Gastrointestinal Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China.
| | - Jia He
- Faculty Affairs and Human Resources Management Department, Southwest Medical University, Luzhou, China
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Chen Y, Xu H, Tang H, Li H, Zhang C, Jin S, Bai D. miR-9-5p expression is associated with vascular invasion and prognosis in hepatocellular carcinoma, and in vitro verification. J Cancer Res Clin Oncol 2023; 149:14657-14671. [PMID: 37584711 DOI: 10.1007/s00432-023-05257-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 08/07/2023] [Indexed: 08/17/2023]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is a common liver malignancy. Early vascular invasion (VI) has been associated with poor prognosis in HCC patients. MicroRNAs (miRNAs) play a significant role in the emergence and development of many tumor types. METHODS Differential expression analysis of miRNAs related to VI was performed based on data from the TCGA database, and survival-associated miRNAs identified. We identified miR-9-5p as a survival-related miRNA and verified its expression in 61 clinical samples using quantitative real-time PCR. We further performed functional enrichment analysis, protein-protein interaction analysis, univariate and multivariate analysis of the survival-related miRNAs, and cell function assays. RESULTS In this study, we identified miR-9-5p that could predict VI and prognosis in HCC patients. Cellular experiments demonstrated that downregulation of miR‑9‑5p inhibits migration, invasion, and angiogenesis of HCC cells. Further, we explored and verified the possible mechanism through which miR-9-5p is involved in HCC progression. Univariate and multivariate analysis revealed that miR-9-5p was an independent risk factor for HCC. Finally, the nomogram based on miR-9-5p showed a good predictive value of HCC survival. CONCLUSIONS MiR-9-5p is associated with VI in HCC, and higher expression of miR-9-5p indicates poor prognosis in HCC.
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Affiliation(s)
- Yuan Chen
- Yangzhou University Medical College, Yangzhou, Jiangsu, China
| | - Hao Xu
- Yangzhou University Medical College, Yangzhou, Jiangsu, China
- General Surgery Department of Siyang Hospital, Suqian, Jiangsu, China
| | - Hao Tang
- Yangzhou University Medical College, Yangzhou, Jiangsu, China
| | - Hongyuan Li
- Dalian Medical University, Dalian, Liaoning, China
| | - Chi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, China
| | - Shengjie Jin
- Department of Hepatobiliary and Pancreatic Surgery, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, China
| | - Dousheng Bai
- Department of Hepatobiliary and Pancreatic Surgery, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, China.
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Wu J, Yao J, Jia S, Yao X, Shao J, Cao W, Ma S, Yao X, Li H. A cuproptosis-related lncRNA signature for predicting prognosis and immune response in hepatocellular carcinoma. Heliyon 2023; 9:e19352. [PMID: 37810122 PMCID: PMC10558351 DOI: 10.1016/j.heliyon.2023.e19352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 08/09/2023] [Accepted: 08/20/2023] [Indexed: 10/10/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) has a high incidence and poor prognosis. Cuproptosis is a novel type of cell death, which differs from previously reported types of cell death such as apoptosis, autophagy, proptosis, ferroptosis, necroptosis, etc. Long non-coding RNAs (lncRNAs) play multiple roles in HCC. Methods We downloaded information from The Cancer Genome Atlas (TCGA) database, and obtained cuproptosis-related genes from published studies. The cuproptosis-related lncRNAs were obtained by correlation analysis, and subsequently used to construct a prognostic cuproptosis-related lncRNA signature. Analyses of overall survival (OS), progression-free survival (PFS), receiver operating characteristic (ROC) curve with the area under the curve (AUC) values and the index of concordance (c-index) curve were used to evaluate the signature. The tumor microenvironment (TME) was analyzed by ESTIMATE algorithm. The immune cell data was downloaded from the Tumor Immune Estimation Resource (TIMER) 2.0 database. Immune-related pathways were analyzed by single-sample gene set enrichment analysis (ssGSEA) algorithm. Immunophenoscore (IPS) scores from The Cancer Immunome (TCIA) database were used to evaluate immunotherapy response. The "pRRophetic" was employed to screen drugs for high-risk patients. The candidate lncRNA expression levels were detected by Real Time Quantitative PCR. Results We constructed a cuproptosis-related lncRNA signature containing seven lncRNAs: AC125437.1, PCED1B-AS1, PICSAR, AP001372.2, AC027097.1, LINC00479, and SLC6A1-AS1. This signature had excellent accuracy, and was independent of the stratification of clinicopathological features. Further study showed that high-risk tumors under this signature had higher TMB, fewer TME components and higher tumor purity. The tumors with high risk were not enriched in immune cell infiltration or immune process pathways, and high-risk patients had a poor response to immunotherapy. Moreover, 29 drugs such as sorafenib, dasatinib and paclitaxel were screened for high-risk HCC patients to improve their prognosis. The expression levels of the candidate lncRNAs in HCC tissue were significantly increased (except PCED1B-AS1). Conclusions Our prognostic cuproptosis-related lncRNA signature was accurate and effective for predicting the prognosis of HCC. The immunotherapy was unsuitable for high-risk HCC patients with this signature.
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Affiliation(s)
- Jingyi Wu
- Faculty of Pharmacy, Zhejiang Pharmaceutical University, Ningbo, 315100, PR China
| | - Jianzuo Yao
- Department of Hepatobiliary and Pancreatic Surgery, Li Huili Hospital Affiliated to Ningbo University, Ningbo, 315040, PR China
| | - Shu Jia
- Faculty of Pharmacy, Zhejiang Pharmaceutical University, Ningbo, 315100, PR China
| | - Xiaokun Yao
- Faculty of Pharmacy, Zhejiang Pharmaceutical University, Ningbo, 315100, PR China
| | - Jingping Shao
- Faculty of Pharmacy, Zhejiang Pharmaceutical University, Ningbo, 315100, PR China
| | - Weijuan Cao
- Faculty of Pharmacy, Zhejiang Pharmaceutical University, Ningbo, 315100, PR China
| | - Shuwei Ma
- Faculty of Pharmacy, Zhejiang Pharmaceutical University, Ningbo, 315100, PR China
| | - Xiaomin Yao
- Faculty of Pharmacy, Zhejiang Pharmaceutical University, Ningbo, 315100, PR China
| | - Hong Li
- Department of Hepatobiliary and Pancreatic Surgery, Li Huili Hospital Affiliated to Ningbo University, Ningbo, 315040, PR China
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Afra F, Mahboobipour AA, Salehi Farid A, Ala M. Recent progress in the immunotherapy of hepatocellular carcinoma: Non-coding RNA-based immunotherapy may improve the outcome. Biomed Pharmacother 2023; 165:115104. [PMID: 37393866 DOI: 10.1016/j.biopha.2023.115104] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 07/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second most lethal cancer and a leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) significantly improved the prognosis of HCC; however, the therapeutic response remains unsatisfactory in a substantial proportion of patients or needs to be further improved in responders. Herein, other methods of immunotherapy, including vaccine-based immunotherapy, adoptive cell therapy, cytokine delivery, kynurenine pathway inhibition, and gene delivery, have been adopted in clinical trials. Although the results were not encouraging enough to expedite their marketing. A major proportion of human genome is transcribed into non-coding RNAs (ncRNAs). Preclinical studies have extensively investigated the roles of ncRNAs in different aspects of HCC biology. HCC cells reprogram the expression pattern of numerous ncRNAs to decrease the immunogenicity of HCC, exhaust the cytotoxic and anti-cancer function of CD8 + T cells, natural killer (NK) cells, dendritic cells (DCs), and M1 macrophages, and promote the immunosuppressive function of T Reg cells, M2 macrophages, and myeloid-derived suppressor cells (MDSCs). Mechanistically, cancer cells recruit ncRNAs to interact with immune cells, thereby regulating the expression of immune checkpoints, functional receptors of immune cells, cytotoxic enzymes, and inflammatory and anti-inflammatory cytokines. Interestingly, prediction models based on the tissue expression or even serum levels of ncRNAs could predict response to immunotherapy in HCC. Moreover, ncRNAs markedly potentiated the efficacy of ICIs in murine models of HCC. This review article first discusses recent advances in the immunotherapy of HCC, then dissects the involvement and potential application of ncRNAs in the immunotherapy of HCC.
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Affiliation(s)
- Fatemeh Afra
- Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ali Mahboobipour
- Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Salehi Farid
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Moein Ala
- Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Papadakos SP, Machairas N, Stergiou IE, Arvanitakis K, Germanidis G, Frampton AE, Theocharis S. Unveiling the Yin-Yang Balance of M1 and M2 Macrophages in Hepatocellular Carcinoma: Role of Exosomes in Tumor Microenvironment and Immune Modulation. Cells 2023; 12:2036. [PMID: 37626849 PMCID: PMC10453902 DOI: 10.3390/cells12162036] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/03/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer with a high mortality rate and limited treatment options. Recent research has brought attention to the significant importance of intercellular communication in the progression of HCC, wherein exosomes have been identified as critical agents facilitating cell-to-cell signaling. In this article, we investigate the impact of macrophages as both sources and targets of exosomes in HCC, shedding light on the intricate interplay between exosome-mediated communication and macrophage involvement in HCC pathogenesis. It investigates how exosomes derived from HCC cells and other cell types within the tumor microenvironment (TME) can influence macrophage behavior, polarization, and recruitment. Furthermore, the section explores the reciprocal interactions between macrophage-derived exosomes and HCC cells, stromal cells, and other immune cells, elucidating their role in tumor growth, angiogenesis, metastasis, and immune evasion. The findings presented here contribute to a better understanding of the role of macrophage-derived exosomes in HCC progression and offer new avenues for targeted interventions and improved patient outcomes.
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Affiliation(s)
- Stavros P. Papadakos
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 10679 Athens, Greece;
| | - Nikolaos Machairas
- Second Department of Propaedeutic Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 11527 Athens, Greece;
| | - Ioanna E. Stergiou
- Pathophysiology Department, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Konstantinos Arvanitakis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636 Thessaloniki, Greece; (K.A.); (G.G.)
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Georgios Germanidis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636 Thessaloniki, Greece; (K.A.); (G.G.)
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Adam Enver Frampton
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
- Oncology Section, Surrey Cancer Research Institute, Department of Clinical and Experimental Medicine, FHMS, University of Surrey, The Leggett Building, Daphne Jackson Road, Guildford GU2 7WG, UK
- HPB Surgical Unit, Royal Surrey NHS Foundation Trust, Guildford GU2 7XX, UK
| | - Stamatios Theocharis
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 10679 Athens, Greece;
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Li T, Jiao J, Ke H, Ouyang W, Wang L, Pan J, Li X. Role of exosomes in the development of the immune microenvironment in hepatocellular carcinoma. Front Immunol 2023; 14:1200201. [PMID: 37457718 PMCID: PMC10339802 DOI: 10.3389/fimmu.2023.1200201] [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: 04/04/2023] [Accepted: 06/12/2023] [Indexed: 07/18/2023] Open
Abstract
Despite numerous improved treatment methods used in recent years, hepatocellular carcinoma (HCC) is still a disease with a high mortality rate. Many recent studies have shown that immunotherapy has great potential for cancer treatment. Exosomes play a significant role in negatively regulating the immune system in HCC. Understanding how these exosomes play a role in innate and adaptive immunity in HCC can significantly improve the immunotherapeutic effects on HCC. Further, engineered exosomes can deliver different drugs and RNA molecules to regulate the immune microenvironment of HCC by regulating the aforementioned immune pathway, thereby significantly improving the mortality rate of HCC. This study aimed to declare the role of exosomes in the development of the immune microenvironment in HCC and list engineered exosomes that could be used for clinical transformation therapy. These findings might be beneficial for clinical patients.
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Affiliation(s)
- Tanghua Li
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Jiapeng Jiao
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Haoteng Ke
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Wenshan Ouyang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Luobin Wang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Jin Pan
- The Department of Electronic Engineering, The Chinese University of Hong Kong, Hongkong, Hongkong SAR, China
| | - Xin Li
- Zhujiang Hospital, Southern Medical University, Guangzhou, China
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31
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Pan X, Li C, Feng J. The role of LncRNAs in tumor immunotherapy. Cancer Cell Int 2023; 23:30. [PMID: 36810034 PMCID: PMC9942365 DOI: 10.1186/s12935-023-02872-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 02/13/2023] [Indexed: 02/23/2023] Open
Abstract
Cancer immunotherapy is a major breakthrough in the history of tumor therapy in the last decade. Immune checkpoint inhibitors blocking CTLA-4/B7 or PD-1/PD-L1 pathways have greatly prolonged the survival of patients with different cancers. Long non-coding RNAs (lncRNAs) are abnormally expressed in tumors and play an important role in tumor immunotherapy through immune regulation and immunotherapy resistance. In this review, we summarized the mechanisms of lncRNAs in regulating gene expression and well-studied immune checkpoint pathways. The crucial regulatory function of immune-related lncRNAs in cancer immunotherapy was also described. Further understanding of the underlying mechanisms of these lncRNAs is of great importance to the development of taking lncRNAs as novel biomarkers and therapeutic targets for immunotherapy.
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Affiliation(s)
- Xuan Pan
- Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
| | - Chenchen Li
- grid.89957.3a0000 0000 9255 8984Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Jifeng Feng
- Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
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32
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The Interaction of Programmed Cell Death Protein and Its Ligands with Non-Coding RNAs in Neoplasms: Emerging Anticancer Immunotherapeutics. Processes (Basel) 2023. [DOI: 10.3390/pr11020538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/12/2023] Open
Abstract
Recent studies have demonstrated that cancer cells can elude immune cells by creating a sanctuary within the tumor’s microenvironment. Large amounts of immune-suppressing signaling proteins can be expressed by cancer cells. One of the most important mechanisms in this system is immune suppression caused by tumors and the modulation of the immune checkpoint. The immune checkpoint is modulated by both the programmed cell death protein 1 (PD-1) and its ligands, programmed death ligand 1 (PD-L1) and PD-L2. Non-coding RNAs (ncRNA), including the more well-known microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), all play roles in the regulation of biological processes and extensive diseases such as cancer. Thus, the focus of this study is on the interactions between the programmed death protein and its ligands with miRNAs, lncRNAs, and circRNAs during tumorigenesis and tumor progression. Furthermore, some FDA-approved drugs for the treatment of various cancers were based on their interactions with PD-1, PD-Ls, and ncRNAs. This promising strategy is still in the production stages, with additional results and clinical trials being processed.
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Dutta S, Ganguly A, Chatterjee K, Spada S, Mukherjee S. Targets of Immune Escape Mechanisms in Cancer: Basis for Development and Evolution of Cancer Immune Checkpoint Inhibitors. BIOLOGY 2023; 12:biology12020218. [PMID: 36829496 PMCID: PMC9952779 DOI: 10.3390/biology12020218] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/22/2023] [Accepted: 01/27/2023] [Indexed: 02/03/2023]
Abstract
Immune checkpoint blockade (ICB) has emerged as a novel therapeutic tool for cancer therapy in the last decade. Unfortunately, a small number of patients benefit from approved immune checkpoint inhibitors (ICIs). Therefore, multiple studies are being conducted to find new ICIs and combination strategies to improve the current ICIs. In this review, we discuss some approved immune checkpoints, such as PD-L1, PD-1, and CTLA-4, and also highlight newer emerging ICIs. For instance, HLA-E, overexpressed by tumor cells, represents an immune-suppressive feature by binding CD94/NKG2A, on NK and T cells. NKG2A blockade recruits CD8+ T cells and activates NK cells to decrease the tumor burden. NKG2D acts as an NK cell activating receptor that can also be a potential ICI. The adenosine A2A and A2B receptors, CD47-SIRPα, TIM-3, LAG-3, TIGIT, and VISTA are targets that also contribute to cancer immunoresistance and have been considered for clinical trials. Their antitumor immunosuppressive functions can be used to develop blocking antibodies. PARPs, mARTs, and B7-H3 are also other potential targets for immunosuppression. Additionally, miRNA, mRNA, and CRISPR-Cas9-mediated immunotherapeutic approaches are being investigated with great interest. Pre-clinical and clinical studies project these targets as potential immunotherapeutic candidates in different cancer types for their robust antitumor modulation.
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Affiliation(s)
- Shovan Dutta
- The Center for Immunotherapy & Precision Immuno-Oncology (CITI), Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Anirban Ganguly
- Department of Biochemistry, All India Institute of Medical Sciences, Deoghar 814152, India
| | | | - Sheila Spada
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA
- Correspondence: (S.S.); (S.M.)
| | - Sumit Mukherjee
- Department of Cardiothoracic and Vascular Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Correspondence: (S.S.); (S.M.)
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34
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The Long Noncoding RNA Gm9866/Nuclear Factor- κB Axis Promotes Macrophage Polarization. Mediators Inflamm 2023; 2023:9991916. [PMID: 36756088 PMCID: PMC9899594 DOI: 10.1155/2023/9991916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/17/2023] [Accepted: 01/18/2023] [Indexed: 02/03/2023] Open
Abstract
Macrophages are a type of immune cells with high levels of plasticity and heterogeneity. They can polarize into M1 or M2 functional phenotypes. These two phenotypes exhibit a dynamic balance during polarization-related diseases and play opposing roles. Long noncoding RNAs (lncRNAs) play an important role in biological processes such as cell proliferation, death, and differentiation; however, how long noncoding RNAs affect the cellular functionality of macrophages remains to be studied. Long noncoding RNA Gm9866 was found to be closely related to macrophage polarization through bioinformatics analysis. In this study, by conducting real-time polymerase chain reaction analysis, it was observed that long noncoding RNA Gm9866 expression significantly increased after treatment with interleukin-4 but significantly decreased after treatment with lipopolysaccharide. Fluorescence in situ hybridization revealed that long noncoding RNA Gm9866 was expressed mainly in the nucleus. Real-time polymerase chain reaction analysis showed that overexpression of long noncoding RNA Gm9866 in RAW264.7 cells further promoted the expression of M2 markers MRC1 (macrophage mannose receptor 1) and MRC2 (macrophage mannose receptor 2). Western blotting analysis demonstrated inhibition of nuclear factor-κB (NF-κB) expression. EdU (5-ethynyl-2'-deoxyuridine) and TUNEL (TdT-mediated dUTP nick-end labeling) staining assays revealed that overexpression of long noncoding RNA Gm9866 promoted cell proliferation and inhibited apoptosis. These findings thus indicated that long noncoding RNA Gm9866 promoted macrophage polarization and inhibited the nuclear factor-κB signaling pathway. Thus, long noncoding RNA Gm9866 may serve as a potential diagnostic and therapeutic target for polarization-related diseases such as infectious diseases, inflammatory diseases, liver fibrosis, and tumors.
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35
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Zhang W, Yan Y, Peng J, Thakur A, Bai N, Yang K, Xu Z. Decoding Roles of Exosomal lncRNAs in Tumor-Immune Regulation and Therapeutic Potential. Cancers (Basel) 2022; 15:286. [PMID: 36612282 PMCID: PMC9818565 DOI: 10.3390/cancers15010286] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 12/12/2022] [Accepted: 12/29/2022] [Indexed: 01/03/2023] Open
Abstract
Exosomes are nanovesicles secreted into biofluids by various cell types and have been implicated in different physiological and pathological processes. Interestingly, a plethora of studies emphasized the mediating role of exosomes in the bidirectional communication between donor and recipient cells. Among the various cargoes of exosomes, long non-coding RNAs (lncRNAs) have been identified as crucial regulators between cancer cells and immune cells in the tumor microenvironment (TME) that can interfere with innate and adaptive immune responses to affect the therapeutic efficiency. Recently, a few major studies have focused on the exosomal lncRNA-mediated interaction between cancer cells and immune cells infiltrated into TME. Nevertheless, a dearth of studies pertains to the immune regulating role of exosomal lncRNAs in cancer and is still in the early stages. Comprehensive mechanisms of exosomal lncRNAs in tumor immunity are not well understood. Herein, we provide an overview of the immunomodulatory function of exosomal lncRNAs in cancer and treatment resistance. In addition, we also summarize the potential therapeutic strategies toward exosomal lncRNAs in TME.
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Affiliation(s)
- Wenqin Zhang
- Department of Pathology, Xiangya Changde Hospital, Changde 415000, China
| | - Yuanliang Yan
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Jinwu Peng
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Abhimanyu Thakur
- Ben May Department for Cancer Research, Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
| | - Ning Bai
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Keda Yang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Zhijie Xu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
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36
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Saadi W, Fatmi A, Pallardó FV, García-Giménez JL, Mena-Molla S. Long Non-Coding RNAs as Epigenetic Regulators of Immune Checkpoints in Cancer Immunity. Cancers (Basel) 2022; 15:cancers15010184. [PMID: 36612180 PMCID: PMC9819025 DOI: 10.3390/cancers15010184] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/19/2022] [Accepted: 12/25/2022] [Indexed: 12/30/2022] Open
Abstract
In recent years, cancer treatment has undergone significant changes, predominantly in the shift towards immunotherapeutic strategies using immune checkpoint inhibitors. Despite the clinical efficacy of many of these inhibitors, the overall response rate remains modest, and immunotherapies for many cancers have proved ineffective, highlighting the importance of knowing the tumor microenvironment and heterogeneity of each malignancy in patients. Long non-coding RNAs (lncRNAs) have attracted increasing attention for their ability to control various biological processes by targeting different molecular pathways. Some lncRNAs have a regulatory role in immune checkpoints, suggesting they might be utilized as a target for immune checkpoint treatment. The focus of this review is to describe relevant lncRNAs and their targets and functions to understand key regulatory mechanisms that may contribute in regulating immune checkpoints. We also provide the state of the art on super-enhancers lncRNAs (selncRNAs) and circular RNAs (circRNAs), which have recently been reported as modulators of immune checkpoint molecules within the framework of human cancer. Other feasible mechanisms of interaction between lncRNAs and immune checkpoints are also reported, along with the use of miRNAs and circRNAs, in generating new tumor immune microenvironments, which can further help avoid tumor evasion.
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Affiliation(s)
- Wiam Saadi
- Department of Biology, Faculty of Nature, Life and Earth Sciences, University of Djillali Bounaama, Khemis Miliana 44225, Algeria
- Correspondence: (W.S.); (S.M.-M.)
| | - Ahlam Fatmi
- INCLIVA Health Research Institute, INCLIVA, 46010 Valencia, Spain
| | - Federico V. Pallardó
- INCLIVA Health Research Institute, INCLIVA, 46010 Valencia, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III, 46010 Valencia, Spain
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain
| | - José Luis García-Giménez
- INCLIVA Health Research Institute, INCLIVA, 46010 Valencia, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III, 46010 Valencia, Spain
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain
| | - Salvador Mena-Molla
- INCLIVA Health Research Institute, INCLIVA, 46010 Valencia, Spain
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain
- Correspondence: (W.S.); (S.M.-M.)
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37
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Wang Y, Du J, Gao Z, Sun H, Mei M, Wang Y, Ren Y, Zhou X. Evolving landscape of PD-L2: bring new light to checkpoint immunotherapy. Br J Cancer 2022; 128:1196-1207. [PMID: 36522474 PMCID: PMC10050415 DOI: 10.1038/s41416-022-02084-y] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 11/16/2022] [Accepted: 11/18/2022] [Indexed: 12/23/2022] Open
Abstract
AbstractImmune checkpoint blockade therapy targeting programmed cell death protein 1 (PD-1) has revolutionized the landscape of multiple human cancer types, including head and neck squamous carcinoma (HNSCC). Programmed death ligand-2 (PD-L2), a PD-1 ligand, mediates cancer cell immune escape (or tolerance independent of PD-L1) and predicts poor prognosis of patients with HNSCC. Therefore, an in-depth understanding of the regulatory process of PD-L2 expression may stratify patients with HNSCC to benefit from anti-PD-1 immunotherapy. In this review, we summarised the PD-L2 expression and its immune-dependent and independent functions in HNSCC and other solid tumours. We focused on recent findings on the mechanisms that regulate PD-L2 at the genomic, transcriptional, post-transcriptional, translational, and post-translational levels, also in intercellular communication of tumour microenvironment (TME). We also discussed the prospects of using small molecular agents indirectly targeting PD-L2 in cancer therapy. These findings may provide a notable avenue in developing novel and effective PD-L2-targeted therapeutic strategies for immune combination therapy and uncovering biomarkers that improve the clinical efficacy of anti-PD-1 therapies.
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Roshani M, Baniebrahimi G, Mousavi M, Zare N, Sadeghi R, Salarinia R, Sheida A, Molavizadeh D, Sadeghi S, Moammer F, Zolfaghari MR, Mirzaei H. Exosomal long non-coding RNAs: novel molecules in gastrointestinal cancers' progression and diagnosis. Front Oncol 2022; 12:1014949. [PMID: 36591473 PMCID: PMC9795196 DOI: 10.3389/fonc.2022.1014949] [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: 08/09/2022] [Accepted: 11/10/2022] [Indexed: 12/15/2022] Open
Abstract
Gastrointestinal (GI) cancers arise in the GI tract and accessory organs, including the mouth, esophagus, stomach, liver, biliary tract, pancreas, small intestine, large intestine, and rectum. GI cancers are a major cause of cancer-related morbidity and mortality worldwide. Exosomes act as mediators of cell-to-cell communication, with pleiotropic activity in the regulation of homeostasis, and can be markers for diseases. Non-coding RNAs (ncRNAs), such as long non-coding RNAs (lncRNAs), can be transported by exosomes derived from tumor cells or non-tumor cells. They can be taken by recipient cells to alter their function or remodel the tumor microenvironment. Moreover, due to their uniquely low immunogenicity and excellent stability, exosomes can be used as natural carriers for therapeutic ncRNAs in vivo. Exosomal lncRNAs have a crucial role in regulating several cancer processes, including angiogenesis, proliferation, drug resistance, metastasis, and immunomodulation. Exosomal lncRNA levels frequently alter according to the onset and progression of cancer. Exosomal lncRNAs can therefore be employed as biomarkers for the diagnosis and prognosis of cancer. Exosomal lncRNAs can also monitor the patient's response to chemotherapy while also serving as potential targets for cancer treatment. Here, we discuss the role of exosomal lncRNAs in the biology and possible future treatment of GI cancer.
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Affiliation(s)
- Mohammad Roshani
- Internal Medicine and Gastroenterology, Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ghazaleh Baniebrahimi
- Department of Pediatric Dentistry, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahboubeh Mousavi
- Department of Anatomy, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Noushid Zare
- Faculty of Pharmacy, Tehran University of Medical Science, Tehran, Iran
| | - Reza Sadeghi
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Salarinia
- Department of Advanced Technologies, School of Medicine, North Khorasan University of Sciences, Bojnurd, Iran
| | - Amirhossein Sheida
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Danial Molavizadeh
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Sara Sadeghi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Farzaneh Moammer
- Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | | | - Hamed Mirzaei
- Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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39
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Reprograming immune microenvironment modulates CD47 cancer stem cells in hepatocellular carcinoma. Int Immunopharmacol 2022; 113:109475. [PMID: 36435064 DOI: 10.1016/j.intimp.2022.109475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/13/2022] [Accepted: 11/14/2022] [Indexed: 11/24/2022]
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40
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Wang G, Luo G, Zhao M, Miao H. Significance of exosomes in hepatocellular carcinoma. Front Oncol 2022; 12:1056379. [PMID: 36531059 PMCID: PMC9748478 DOI: 10.3389/fonc.2022.1056379] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 11/11/2022] [Indexed: 09/28/2023] Open
Abstract
Among the most prevalent cancers in the world, hepatocellular carcinoma (HCC) has a high mortality rate. The diagnosis and management of HCC are presently hindered by difficulties in early detection and suboptimal treatment outcomes. Exosomes have been shown to play an important role in hepatocarcinogenesis and can also be used for diagnosis and treatment. In this review, we discussed the research progress on exosomes in hepatocarcinogenesis development, tumor microenvironment remodeling, treatment resistance, and immunosuppression. HCC can be diagnosed and treated by understanding the pathogenesis and identifying early diagnostic markers. This review will be a significant reference for scholars with an initial understanding of the field to fully understand the role of exosomes in the organism.
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Affiliation(s)
- GuoYun Wang
- Department of Hepatobiliary Surgery, The Second Hospital of Guangdong Medical University, Zhanjiang, China
| | - GaiXiang Luo
- The First Clinical Medical College of Lanzhou University, Gansu Provincial People’s Hospital, Lanzhou, China
| | - MeiJing Zhao
- Department of Hepatobiliary Surgery, The Second Hospital of Guangdong Medical University, Zhanjiang, China
| | - HuiLai Miao
- Department of Hepatobiliary Surgery, The Second Hospital of Guangdong Medical University, Zhanjiang, China
- Key Laboratory of Liver Injury Diagnosis and Repair, Guangdong Medical University, Zhanjiang, China
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41
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Wang X, Chen W, Lao W, Chen Y. Upregulation of PCED1B-AS1 in proliferative diabetic retinopathy and its involvement in retinal vascular endothelial cell proliferation. BMC Ophthalmol 2022; 22:450. [PMID: 36418980 PMCID: PMC9685937 DOI: 10.1186/s12886-022-02683-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 11/14/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND This study was to assess the diagnostic value of PCED1B-AS1 for proliferative diabetic retinopathy (PDR) and investigate the involvement of PCED1B-AS1 in PDR. METHODS The vitreous and blood specimens from 37 subjects with PDR and 21 non-diabetics were examined by reverse transcription quantitative PCR to determine the PCED1B-AS1 level. The two groups were age- and gender-matched. Receiver operating characteristic (ROC) curves were plotted to visually illustrate the diagnostic ability of PCED1B-AS1. Human retinal Müller glial cells were studied by ELISA. Proliferation and migration of human retinal microvascular endothelial cells (HRMECs) were assessed in vitro. RESULTS Significant increases of PCED1B-AS1 levels were observed in the vitreous samples and CD34 + VEGFR-2 + cells from blood samples of diabetic subjects with PDR, compared with those of non-diabetics. The ROC curve based on the vitreous PCED1B-AS1 levels revealed an AUC of 0.812, while the ROC curve based on the PCED1B-AS1 levels in CD34 + VEGFR-2 + cells from blood samples revealed an AUC of 0.870. In Müller cell cultures, PCED1B-AS1 siRNA significantly attenuated VEGF and MCP-1 upregulation which were induced by CoCl2 and TNF-α. Additionally, PCED1B-AS1 siRNA attenuated VEGF-induced proliferation and migration in HRMECs. CONCLUSION This study revealed the potential of PCED1B-AS1 as a diagnostic biomarker for PDR. In vitro data point to the anti-angiogenic and anti-proliferation effects of PCED1B-AS1.
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Affiliation(s)
- Xuyang Wang
- grid.12981.330000 0001 2360 039XHainan Eye Hospital and Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 19 Xiuhua Road, 570311 Haikou, Hainan China
| | - Wangling Chen
- grid.12981.330000 0001 2360 039XHainan Eye Hospital and Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 19 Xiuhua Road, 570311 Haikou, Hainan China
| | - Wei Lao
- grid.12981.330000 0001 2360 039XHainan Eye Hospital and Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 19 Xiuhua Road, 570311 Haikou, Hainan China
| | - Yunxin Chen
- grid.12981.330000 0001 2360 039XHainan Eye Hospital and Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 19 Xiuhua Road, 570311 Haikou, Hainan China
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Liu T, Zhao H. Long Non-Coding RNAs: A Double-Edged Sword in Renal Cell Carcinoma Carcinogenesis. INT J PHARMACOL 2022. [DOI: 10.3923/ijp.2022.1537.1549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Zheng LM, Ye JQ, Li HF, Liu Q. Construction of a potentially functional lncRNA-miRNA-mRNA network in sepsis by bioinformatics analysis. Front Genet 2022; 13:1031589. [PMID: 36457745 PMCID: PMC9707798 DOI: 10.3389/fgene.2022.1031589] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 10/28/2022] [Indexed: 11/11/2024] Open
Abstract
Objective: Sepsis is a common disease in internal medicine, with a high incidence and dangerous condition. Due to the limited understanding of its pathogenesis, the prognosis is poor. The goal of this project is to screen potential biomarkers for the diagnosis of sepsis and to identify competitive endogenous RNA (ceRNA) networks associated with sepsis. Methods: The expression profiles of long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and messenger RNAs (mRNAs) were derived from the Gene Expression Omnibus (GEO) dataset. The differentially expressed lncRNAs (DElncRNAs), miRNAs (DEmiRNAs) and mRNAs (DEmRNAs) were screened by bioinformatics analysis. DEmRNAs were analyzed by protein-protein interaction (PPI) network analysis, transcription factor enrichment analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Set Enrichment Analysis (GSEA). After the prediction of the relevant database, the competitive ceRNA network is built in Cytoscape. The gene-drug interaction was predicted by DGIgb. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was used to confirm five lncRNAs from the ceRNA network. Results: Through Venn diagram analysis, we found that 57 DElncRNAs, 6 DEmiRNAs and 317 DEmRNAs expressed abnormally in patients with sepsis. GO analysis and KEGG pathway analysis showed that 789 GO terms and 36 KEGG pathways were enriched. Through intersection analysis and data mining, 5 key KEGG pathways and related core genes were revealed by GSEA. The PPI network consists of 247 nodes and 1,163 edges, and 50 hub genes are screened by the MCODE plug-in. In addition, there are 5 DElncRNAs, 6 DEmiRNAs and 28 DEmRNAs in the ceRNA network. Drug action analysis showed that 7 genes were predicted to be molecular targets of drugs. Five lncRNAs in ceRNA network are verified by qRT-PCR, and the results showed that the relative expression of five lncRNAs was significantly different between sepsis patients and healthy control subjects. Conclusion: A sepsis-specific ceRNA network has been effectively created, which is helpful to understand the interaction between lncRNAs, miRNAs and mRNAs. We discovered prospective sepsis peripheral blood indicators and proposed potential treatment medicines, providing new insights into the progression and development of sepsis.
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Affiliation(s)
- Li-ming Zheng
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, China
| | - Jun-qiu Ye
- Department of Infection, Hubei Provincial Hospital of Traditional Chinese Medicine, Affiliated to Hubei University of Chinese Medicine, Wuhan, China
- Hubei Provincial Academy of Traditional Chinese Medicine, Wuhan, China
| | - Heng-fei Li
- Department of Infection, Hubei Provincial Hospital of Traditional Chinese Medicine, Affiliated to Hubei University of Chinese Medicine, Wuhan, China
- Hubei Provincial Academy of Traditional Chinese Medicine, Wuhan, China
| | - Quan Liu
- Hubei Provincial Academy of Traditional Chinese Medicine, Wuhan, China
- Department of Pulmonary Disease, Hubei Provincial Hospital of Traditional Chinese Medicine, Affiliated to Hubei University of Chinese Medicine, Wuhan, China
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Ghafouri-Fard S, Shoorei H, Hussen BM, Poornajaf Y, Taheri M, Sharifi G. Interplay between programmed death-ligand 1 and non-coding RNAs. Front Immunol 2022; 13:982902. [PMID: 36405753 PMCID: PMC9667550 DOI: 10.3389/fimmu.2022.982902] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 10/21/2022] [Indexed: 01/25/2023] Open
Abstract
Programmed death-ligand 1 (PD-L1) is a transmembrane protein with essential roles in the suppression of adaptive immune responses. As an immune checkpoint molecule, PD-L1 can be exploited by cancer cells to evade the anti-tumor attacks initiated by the immune system. Thus, blockade of the PD1/PD-L1 axis can eliminate the suppressive signals and release the antitumor immune responses. Identification of the underlying mechanisms of modulation of the activity of the PD1/PD-L1 axis would facilitate the design of more efficacious therapeutic options and better assignment of patients for each option. Recent studies have confirmed the interactions between miRNAs/lncRNAs/circ-RNAs and the PD1/PD-L1 axis. In the current review, we give a summary of interactions between these transcripts and PD-L1 in the context of cancer. We also overview the consequences of these interactions in the determination of the response of patients to anti-cancer drugs.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Shoorei
- Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran,Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan, Iraq,Center of Research and Strategic Studies, Lebanese French University, Erbil, Kurdistan, Iraq
| | - Yadollah Poornajaf
- Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran,Institute of Human Genetics, Jena University Hospital, Jena, Germany,*Correspondence: Mohammad Taheri, ; Guive Sharifi,
| | - Guive Sharifi
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran,*Correspondence: Mohammad Taheri, ; Guive Sharifi,
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Wang B, Yao L, Dong Y, Liu J, Wu J. LncRNA PCED1B-AS1 knockdown inhibits osteosarcoma via methylation-mediated miR-10a downregulation. J Orthop Surg Res 2022; 17:464. [PMID: 36274134 PMCID: PMC9590122 DOI: 10.1186/s13018-022-03284-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 08/04/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND LncRNA PCED1B-AS1 (PCED1B-AS1) promotes glioma. This study aimed to investigate its role in osteosarcoma (OS). METHODS The study included 60 OS patients. Accumulation of miR-10a and PCED1B-AS1 in tissues from OS patients and cell lines was determined by RT-qPCR. Cell transfections were performed for interaction analysis. Participation of PCED1B-AS1 siRNA silencing and miR-10a overexpression in proliferation, invasion, and migration of U2OS and MG-63 cells was analyzed by cell proliferation assay and Transwell assay. RESULTS PCED1B-AS1 level was increased in OS and positively correlated with miR-10a level. In OS cells, PCED1B-AS1 siRNA silencing downregulated miR-10a. Methylation-specific PCR analysis showed that PCED1B-AS1 siRNA silencing decreased the methylation of miR-10a gene promoter. Moreover, PCED1B-AS1 siRNA silencing suppressed OS cell proliferation, invasion, and migration. In addition, miR-10a overexpression attenuated the effects of PCED1B-AS1 siRNA silencing. CONCLUSION PCED1B-AS1 knockdown may inhibit OS cell proliferation and movement by regulating miR-10 gene methylation.
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Affiliation(s)
- Bing Wang
- Joint Surgery Department, The First People's Hospital of Lianyungang, No.6 Zhenhua East Road, Lianyungang City, 222061, Jiangsu Province, People's Republic of China
| | - Li Yao
- Joint Surgery Department, The First People's Hospital of Lianyungang, No.6 Zhenhua East Road, Lianyungang City, 222061, Jiangsu Province, People's Republic of China
| | - Yuefu Dong
- Joint Surgery Department, The First People's Hospital of Lianyungang, No.6 Zhenhua East Road, Lianyungang City, 222061, Jiangsu Province, People's Republic of China
| | - Jian Liu
- Joint Surgery Department, The First People's Hospital of Lianyungang, No.6 Zhenhua East Road, Lianyungang City, 222061, Jiangsu Province, People's Republic of China
| | - Jian Wu
- Joint Surgery Department, The First People's Hospital of Lianyungang, No.6 Zhenhua East Road, Lianyungang City, 222061, Jiangsu Province, People's Republic of China.
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Han Q, Wang M, Dong X, Wei F, Luo Y, Sun X. Non-coding RNAs in hepatocellular carcinoma: Insights into regulatory mechanisms, clinical significance, and therapeutic potential. Front Immunol 2022; 13:985815. [PMID: 36300115 PMCID: PMC9590653 DOI: 10.3389/fimmu.2022.985815] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 09/23/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a complex and heterogeneous malignancy with high incidence and poor prognosis. In addition, owing to the lack of diagnostic and prognostic markers, current multimodal treatment options fail to achieve satisfactory outcomes. Tumor immune microenvironment (TIME), angiogenesis, epithelial-mesenchymal transition (EMT), invasion, metastasis, metabolism, and drug resistance are important factors influencing tumor development and therapy. The intercellular communication of these important processes is mediated by a variety of bioactive molecules to regulate pathophysiological processes in recipient cells. Among these bioactive molecules, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), account for a large part of the human transcriptome, and their dysregulation affects the progression of HCC. The purpose of this review is to evaluate the potential regulatory mechanisms of ncRNAs in HCC, summarize novel biomarkers from somatic fluids (plasma/serum/urine), and explore the potential of some small-molecule modulators as drugs. Thus, through this review, we aim to contribute to a deeper understanding of the regulatory mechanisms, early diagnosis, prognosis, and precise treatment of HCC.
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Affiliation(s)
- Qin Han
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Mengchen Wang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xi Dong
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Fei Wei
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yun Luo
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- *Correspondence: Yun Luo, ; Xiaobo Sun,
| | - Xiaobo Sun
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- *Correspondence: Yun Luo, ; Xiaobo Sun,
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Xu Z, Chen Y, Ma L, Chen Y, Liu J, Guo Y, Yu T, Zhang L, Zhu L, Shu Y. Role of exosomal non-coding RNAs from tumor cells and tumor-associated macrophages in the tumor microenvironment. Mol Ther 2022; 30:3133-3154. [PMID: 35405312 PMCID: PMC9552915 DOI: 10.1016/j.ymthe.2022.01.046] [Citation(s) in RCA: 176] [Impact Index Per Article: 58.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 12/21/2021] [Accepted: 01/27/2022] [Indexed: 12/13/2022] Open
Abstract
Exosomes have a crucial role in intercellular communication and mediate interactions between tumor cells and tumor-associated macrophages (TAMs). Exosome-encapsulated non-coding RNAs (ncRNAs) are involved in various physiological processes. Tumor-derived exosomal ncRNAs induce M2 macrophage polarization through signaling pathway activation, signal transduction, and transcriptional and post-transcriptional regulation. Conversely, TAM-derived exosomal ncRNAs promote tumor proliferation, metastasis, angiogenesis, chemoresistance, and immunosuppression. MicroRNAs induce gene silencing by directly targeting mRNAs, whereas lncRNAs and circRNAs act as miRNA sponges to indirectly regulate protein expressions. The role of ncRNAs in tumor-host interactions is ubiquitous. Current research is increasingly focused on the tumor microenvironment. On the basis of the "cancer-immunity cycle" hypothesis, we discuss the effects of exosomal ncRNAs on immune cells to induce T cell exhaustion, overexpression of programmed cell death ligands, and create a tumor immunosuppressive microenvironment. Furthermore, we discuss potential applications and prospects of exosomal ncRNAs as clinical biomarkers and drug delivery systems.
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Affiliation(s)
- Zijie Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Yi Chen
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Ling Ma
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Yizhang Chen
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Jingya Liu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Yuchen Guo
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Ting Yu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Lianghui Zhang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Lingjun Zhu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; Department of Oncology, The Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu 211112, China.
| | - Yongqian Shu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
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Immune-related 3-lncRNA signature with prognostic connotation in a multi-cancer setting. J Transl Med 2022; 20:442. [PMID: 36180904 PMCID: PMC9523969 DOI: 10.1186/s12967-022-03654-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 09/19/2022] [Indexed: 11/27/2022] Open
Abstract
Background Advances in our understanding of the tumor microenvironment have radically changed the cancer field, highlighting the emerging need for biomarkers of an active, favorable tumor immune phenotype to aid treatment stratification and clinical prognostication. Numerous immune-related gene signatures have been defined; however, their prognostic value is often limited to one or few cancer types. Moreover, the area of non-coding RNA as biomarkers remains largely unexplored although their number and biological roles are rapidly expanding. Methods We developed a multi-step process to identify immune-related long non-coding RNA signatures with prognostic connotation in multiple TCGA solid cancer datasets. Results Using the breast cancer dataset as a discovery cohort we found 2988 differentially expressed lncRNAs between immune favorable and unfavorable tumors, as defined by the immunologic constant of rejection (ICR) gene signature. Mapping of the lncRNAs to a coding-non-coding network identified 127 proxy protein-coding genes that are enriched in immune-related diseases and functions. Next, we defined two distinct 20-lncRNA prognostic signatures that show a stronger effect on overall survival than the ICR signature in multiple solid cancers. Furthermore, we found a 3 lncRNA signature that demonstrated prognostic significance across 5 solid cancer types with a stronger association with clinical outcome than ICR. Moreover, this 3 lncRNA signature showed additional prognostic significance in uterine corpus endometrial carcinoma and cervical squamous cell carcinoma and endocervical adenocarcinoma as compared to ICR. Conclusion We identified an immune-related 3-lncRNA signature with prognostic connotation in multiple solid cancer types which performed equally well and in some cases better than the 20-gene ICR signature, indicating that it could be used as a minimal informative signature for clinical implementation. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03654-7.
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Pallozzi M, Di Tommaso N, Maccauro V, Santopaolo F, Gasbarrini A, Ponziani FR, Pompili M. Non-Invasive Biomarkers for Immunotherapy in Patients with Hepatocellular Carcinoma: Current Knowledge and Future Perspectives. Cancers (Basel) 2022; 14:cancers14194631. [PMID: 36230554 PMCID: PMC9559710 DOI: 10.3390/cancers14194631] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/18/2022] [Accepted: 09/20/2022] [Indexed: 12/16/2022] Open
Abstract
Simple Summary The search for non-invasive biomarkers is a hot topic in modern oncology, since a tissue biopsy has significant limitations in terms of cost and invasiveness. The treatment perspectives have been significantly improved after the approval of immunotherapy for patients with hepatocellular carcinoma; therefore, the quick identification of responders is crucial to define the best therapeutic strategy. In this review, the current knowledge on the available non-invasive biomarkers of the response to immunotherapy is described. Abstract The treatment perspectives of advanced hepatocellular carcinoma (HCC) have deeply changed after the introduction of immunotherapy. The results in responders show improved survival compared with Sorafenib, but only one-third of patients achieve a significant benefit from treatment. As the tumor microenvironment exerts a central role in shaping the response to immunotherapy, the future goal of HCC treatment should be to identify a proxy of the hepatic tissue condition that is easy to use in clinical practice. Therefore, the search for biomarkers that are accurate in predicting prognosis will be the hot topic in the therapeutic management of HCC in the near future. Understanding the mechanisms of resistance to immunotherapy may expand the patient population that will benefit from it, and help researchers to find new combination regimens to improve patients’ outcomes. In this review, we describe the current knowledge on the prognostic non-invasive biomarkers related to treatment with immune checkpoint inhibitors, focusing on serological markers and gut microbiota.
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Affiliation(s)
- Maria Pallozzi
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Natalia Di Tommaso
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Valeria Maccauro
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Correspondence: (F.R.P.); (M.P.)
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Correspondence: (F.R.P.); (M.P.)
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Li S, Xie X, Peng F, Du J, Peng C. Regulation of temozolomide resistance via lncRNAs: Clinical and biological properties of lncRNAs in gliomas (Review). Int J Oncol 2022; 61:101. [PMID: 35796022 PMCID: PMC9291250 DOI: 10.3892/ijo.2022.5391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 06/10/2022] [Indexed: 11/05/2022] Open
Abstract
Gliomas are a primary types of intracranial malignancies and are characterized by a poor prognosis due to aggressive recurrence profiles. Temozolomide (TMZ) is an auxiliary alkylating agent that is extensively used in conjunction with surgical resection and forms the mainstay of clinical treatment strategies for gliomas. However, the frequent occurrence of TMZ resistance in clinical practice limits its therapeutic efficacy. Accumulating evidence has demonstrated that long non‑coding RNAs (lncRNAs) can play key and varied roles in glioma progression. lncRNAs have been reported to inhibit glioma progression by targeting various signaling pathways. In addition, the differential expression of lncRNAs has also been found to mediate the resistance of glioma to several chemotherapeutic agents, particularly to TMZ. The present review article therefore summarizes the findings of previous studies in an aim to report the significance and function of lncRNAs in regulating the chemoresistance of gliomas. The present review may provide further insight into the clinical treatment of gliomas.
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Affiliation(s)
- Sui Li
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of The Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xiaofang Xie
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, P.R. China
| | - Fu Peng
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of The Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, P.R. China
- Correspondence to: Dr Fu Peng or Professor Junrong Du, Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of The Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, 17 Renmin South Road, Chengdu, Sichuan 610041, P.R. China, E-mail: , E-mail:
| | - Junrong Du
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of The Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, P.R. China
- Correspondence to: Dr Fu Peng or Professor Junrong Du, Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of The Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, 17 Renmin South Road, Chengdu, Sichuan 610041, P.R. China, E-mail: , E-mail:
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, P.R. China
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