|
1
|
Chen L, He Y, Jiang X, Kow ASF, Lee YZ, Tham CL, Yusof R, Lee MT. Regulation of elevated expression of Mcl-1 in hepatocellular carcinoma - a review. J Recept Signal Transduct Res 2025:1-11. [PMID: 40366802 DOI: 10.1080/10799893.2025.2503393] [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: 02/20/2025] [Revised: 04/30/2025] [Accepted: 05/04/2025] [Indexed: 05/16/2025]
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide. Mcl-1 (myeloid cell leukemia-1) is highly expressed in HCC cells and plays a critical role in chemotherapy resistance and is a major contributor to chemotherapy failure in HCC. The purpose of this study is to review the recent research progress that explores the key factors in regulating Mcl-1 overexpression in HCC cells, contributing to chemotherapy resistance. The related studies from the past decade on agents targeting Mcl-1 to inhibit HCC were also reviewed to provide insights into overcoming chemotherapy resistance in HCC. Mcl-1 overexpression in HCC is mainly regulated by transcription factors (such as STAT3, p53), non-coding RNAs (such as miRNA, lncRNA), cell cycle proteins, mitochondrial dynamics, and the hypoxic microenvironment. Targeting Mcl-1, alongside multi-target combination therapies, may overcome HCC chemotherapy resistance and improve outcomes. Future research should focus on strategies addressing multiple pathways to minimize monotherapy resistance risks and offer enhanced treatment options for the betterment of human health.
Collapse
Affiliation(s)
- Li Chen
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia
- Department of Pharmacology, College of Medicine, Guangxi University of Science and Technology, Liuzhou, PR China
| | - Yuwei He
- Department of Pharmacology, College of Medicine, Guangxi University of Science and Technology, Liuzhou, PR China
| | - Xudong Jiang
- Department of Pharmacology, College of Medicine, Guangxi University of Science and Technology, Liuzhou, PR China
| | | | - Yu Zhao Lee
- Faculty of Medicine and Health Sciences, UCSI University, Kuala Lumpur, Malaysia
| | - Chau Ling Tham
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
- Natural Medicine and Product Research Laboratory (NaturMeds), Institute of Bioscience, Universiti Putra Malaysia, Serdang, Malaysia
| | - Rohana Yusof
- Faculty of Applied Sciences, UCSI University, Kuala Lumpur, Malaysia
| | - Ming Tatt Lee
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia
- Office of Postgraduate Studies, UCSI University, Kuala Lumpur, Malaysia
- UCSI Wellbeing Research Centre, UCSI University, Kuala Lumpur, Malaysia
| |
Collapse
|
|
2
|
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.
Collapse
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
| |
Collapse
|
|
3
|
Liu R, Wang Q, Jiang Q, Chang R, Zhou Y, Ye X, Luo X, Lai Y, Su G, Yang P. Proteomic Profiles of Neutrophils from Behcet's Uveitis Patients and their Sex Differences. Inflammation 2025:10.1007/s10753-025-02305-5. [PMID: 40263198 DOI: 10.1007/s10753-025-02305-5] [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: 02/08/2025] [Revised: 04/14/2025] [Accepted: 04/15/2025] [Indexed: 04/24/2025]
Abstract
Behcet's uveitis (BU) is one of the most vision-threatening uveitis entities with male-biased incidence and severity. Neutrophil dysfunction has been implicated in the pathogenesis of this disease. However, their proteomic changes are not completely understood. We performed proteomic analysis on peripheral neutrophils from patients with active BU and identified 82 up-regulated and 516 down-regulated differentially expressed proteins (DEPs) compared to healthy controls (HCs). We further performed functional analysis on these DEPs and found that the pathway involved in neutrophil extracellular trap formation was activated, whereas nucleotide metabolism and apoptosis were suppressed. Compared with female patients, male patients presented enhanced pathways associated neutrophil-mediated inflammatory responses and suppressed apoptosis. Additionally, integrative analysis of proteomic profiles and single-cell RNA sequencing (scRNA-seq) data revealed that these sex differences might be related to the enhanced inflammatory response in primed inflammatory and inflammatory neutrophils as well as deficiencies in apoptosis and nucleotide metabolism in ROS-responsive neutrophils. Collectively, our data revealed the proteomic profiles of neutrophils from patients with BU, and their functional changes may play crucial roles in the pathogenesis of this disease and its sex differences.
Collapse
Affiliation(s)
- Rong Liu
- Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, People's Republic of China
| | - Qingfeng Wang
- Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, People's Republic of China
| | - Qingyan Jiang
- Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, People's Republic of China
| | - Rui Chang
- Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, People's Republic of China
| | - Yan Zhou
- Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, People's Republic of China
- Department of Ophthalmology, The Affiliated Yongchuan Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Xingsheng Ye
- Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, People's Republic of China
| | - Xiang Luo
- Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, People's Republic of China
| | - Yujie Lai
- Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, People's Republic of China
| | - Guannan Su
- Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, People's Republic of China
| | - Peizeng Yang
- Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, People's Republic of China.
- Department of Ophthalmology, Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, The First Affiliated Hospital of Zhengzhou University, Henan Province Eye Hospital, Zhengzhou, People's Republic of China.
| |
Collapse
|
|
4
|
Zhang X, Bi F, Yang Q. Mechanism underlying CDC20 affecting epithelial ovarian cancer biological behavior by regulating BAG6 ubiquitination. Cell Signal 2025; 127:111577. [PMID: 39710091 DOI: 10.1016/j.cellsig.2024.111577] [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: 06/03/2024] [Revised: 12/11/2024] [Accepted: 12/17/2024] [Indexed: 12/24/2024]
Abstract
Epithelial ovarian cancer (EOC) endangers women's life and health. It is reported that cell division cycle 20 (CDC20) plays a role in EOC, but its underlying mechanisms remain unclear. Additionally, the involvement of bcl-2-associated athanogen-6 (BAG6) in EOC has not been previously reported. This study demonstrated that CDC20 was highly expressed in EOC and exhibited oncogenic properties through both in vitro and in vivo molecular biology experiments. In contrast, BAG6 was low expressed and functioned as a tumor suppressor. Both CDC20 and BAG6 were found to correlate with patient stage. Notably, the degradation of BAG6, mediated by CDC20 via ubiquitin-proteasome pathway, was shown to enhance the malignant biological behavior of EOC. Furthermore, the interaction between CDC20 and BAG6 was dependent on the WD40 domain of CDC20 and the D-box of BAG6. These findings provided valuable insights into the molecular mechanisms of EOC and established a theoretical basis for novel therapeutic targets in clinical treatment.
Collapse
Affiliation(s)
- Xiaocui Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Fangfang Bi
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Qing Yang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China.
| |
Collapse
|
|
5
|
Ou S, Nie X, Qiu X, Jin X, Wu G, Zhang R, Zhu J. Deciphering the mechanisms of long non-coding RNAs in ferroptosis: insights into its clinical significance in cancer progression and immunology. Cell Death Discov 2025; 11:14. [PMID: 39827195 PMCID: PMC11743196 DOI: 10.1038/s41420-025-02290-6] [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: 09/09/2024] [Revised: 12/12/2024] [Accepted: 01/07/2025] [Indexed: 01/22/2025] Open
Abstract
A new type of nonapoptotic, iron-dependent cell death induced by lipid peroxidation is known as ferroptosis. Numerous pathological processes, including inflammation and cancer, have been demonstrated to be influenced by changes in the ferroptosis-regulating network. Long non-coding RNAs (LncRNAs) are a group of functional RNA molecules that are not translated into proteins, which can regulate gene expression in various manners. An increasing number of studies have shown that lncRNAs can interfere with the progression of ferroptosis by modulating ferroptosis-related genes directly or indirectly. Despite evidence implicating lncRNAs in cancer and inflammation, studies on their mechanisms and therapeutic potential remain scarce. We investigate the mechanisms of lncRNA-mediated regulation of inflammation and cancer immunity, assessing the feasibility and challenges of lncRNAs as therapeutic targets in these conditions.
Collapse
Affiliation(s)
- Shengming Ou
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiaoya Nie
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiangyu Qiu
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xin Jin
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Geyan Wu
- Biomedicine Research Centre, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provicial Clinical Research Center for Obsterics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.
| | - Rongxin Zhang
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China.
| | - Jinrong Zhu
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China.
| |
Collapse
|
|
6
|
Zhang M, Huang K, Yin Q, Wu X, Zhu M, Li M. Spatial heterogeneity of the hepatocellular carcinoma microenvironment determines the efficacy of immunotherapy. Discov Oncol 2025; 16:15. [PMID: 39775241 PMCID: PMC11706828 DOI: 10.1007/s12672-025-01747-5] [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: 09/01/2024] [Accepted: 01/02/2025] [Indexed: 01/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains a global health challenge owing to its widespread incidence and high mortality. HCC has a specific immune tolerance function because of its unique physiological structure, which limits the efficacy of chemotherapy, radiotherapy, and molecular targeting. In recent years, new immune approaches, including adoptive cell therapy, tumor vaccines, and oncolytic virus therapy, have shown great potential. As the efficacy of immunotherapy mainly depends on the spatial heterogeneity of the tumor immune microenvironment, it is necessary to elucidate the crosstalk between the composition of the liver cancer immune environment, from which potential therapeutic targets can be selected to provide more appropriate individualized treatment programs. The role of spatial heterogeneity of immune cells in the microenvironment of HCC in the progression and influence of immunotherapy on improving the treatment and prognosis of HCC were comprehensively analyzed, providing new inspiration for the subsequent clinical treatment of liver cancer.
Collapse
Affiliation(s)
- Minni Zhang
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China
- The First Affiliated Hospital, Key Laboratory of Emergency and Trauma of Ministry of Education, Engineering Research Center for Hainan Biological Sample Resources of Major Diseases, The Hainan Branch of National Clinical Research Center for Cancer, Hainan Medical University, Haikou, 570102, Hainan, People's Republic of China
| | - Kailin Huang
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China
| | - Qiushi Yin
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China
| | - Xueqin Wu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China
| | - Mingyue Zhu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China.
| | - Mengsen Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China.
- Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical University, Haikou, 570023, Hainan, People's Republic of China.
- Key Laboratory of Tropical Translational Medicine, Ministry of Education, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China.
| |
Collapse
|
|
7
|
Sheng L, Lin J, Zhang Y, Chen Y, Ye X, Wang X. CAF-EVs carry lncRNA MAPKAPK5-AS1 into hepatocellular carcinoma cells and promote malignant cell proliferation. Commun Biol 2024; 7:1711. [PMID: 39739005 PMCID: PMC11685398 DOI: 10.1038/s42003-024-07428-3] [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: 05/19/2024] [Accepted: 12/18/2024] [Indexed: 01/02/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive malignancy with poor prognosis. LncRNA MAPKAPK5-AS1 is a potential oncogene and contributes to HCC cell malignant proliferation. This study explores the role of MAPKAPK5-AS1 carried by carcinoma-associated fibroblasts-derived extracellular vesicles (CAF-EVs) in HCC cell proliferation. Our findings reveal that CAF-EVs promotes HCC cell proliferation by delivering MAPKAPK5-AS1, which binds to and inhibits SMURF2 and stabilizes TCF12. SMURF2 leads to TCF12 ubiquitination and degradation. TCF12 upregulates FOXH1 expression. In animal model, CAF-EVs enhances tumor growth by stabilizing TCF12 via MAPKAPK5-AS1 and activating FOXH1 transcription. In conclusion, CAF-EVs carrying MAPKAPK5-AS1 stabilizes TCF12 expression by competitively inhibiting SMURF2, thus promoting TCF12-mediated FOXH1 transcription and driving HCC cell proliferation. Our findings may offer insights for HCC treatment and suggest potential targets for future treatments, opening avenues for HCC therapies.
Collapse
Affiliation(s)
- Lin Sheng
- The department of internal medicine, Jinhua Municipal Central Hospital, Jinhua, China
| | - Junmei Lin
- Department of Traditional Chinese Medicine, Jinhua Municipal Central Hospital, Jinhua, China
| | - Yili Zhang
- Department of Health Management Center, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Yanping Chen
- Department of Gastroenterology, Jinhua Municipal Central Hospital, Jinhua, China
| | - Xuxing Ye
- Department of Traditional Chinese Medicine, Jinhua Municipal Central Hospital, Jinhua, China
| | - Xiaobo Wang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
| |
Collapse
|
|
8
|
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.
Collapse
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.
| |
Collapse
|
|
9
|
Zhou Y, Liu D, Li H. FGL1 Promotes Tumor Immune Escape in Stomach Adenocarcinoma via the Notch Signaling Pathway. Mol Biotechnol 2024; 66:3203-3212. [PMID: 37902887 DOI: 10.1007/s12033-023-00928-3] [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: 01/17/2023] [Accepted: 10/05/2023] [Indexed: 11/01/2023]
Abstract
Immune escape is the major reason for immunotherapy failure in stomach adenocarcinoma (STAD). We tried to reveal the underlying mechanism of FGL1 influencing STAD in this study. Bioinformatics analyses were conducted to analyze the expression of FGL1, the signaling pathways affected by FGL1, and the relation between FGL1 and immune cell infiltration. Quantitative real-time PCR (qRT-PCR), cell counting kit-8 assay, colony formation assay, flow cytometry and Transwell assay were adopted to analyze FGL1 expression, cell viability, cell proliferation, cell apoptosis, and cell invasion, respectively. Enzyme-linked immunosorbent assay, lactate dehydrogenase method, qRT-PCR and Western blot were adopted to reveal proinflammatory cytokine expression, cytotoxicity and mRNA and protein expression of the Notch signaling-related genes, respectively, after co-culture of STAD cells and CD8+T cells. Nude mice experiment was conducted to validate the results obtained above. FGL1 expressed highly in STAD and could activate the Notch signaling pathway, and it was negatively correlated with CD8+T cell infiltration. Cell experiments confirmed that high expression of FGL1 facilitated proliferation and hindered apoptosis of STAD cells. Knockdown of FGL1 could facilitate expression of pro-inflammatory factors and the cytotoxicity of CD8+T cells in co-culture system of STAD and CD8+ T cells. Knockdown of FGL1 could suppress the expression of the Notch signaling pathway-related genes, and the addition of Notch inhibitor proved that FGL1 promoted immune escape via the Notch signaling pathway. This study investigated the influence of FGL1 on STAD immune escape and demonstrated that FGL1 inhibited CD8+ T cell activation by activating the Notch signaling pathway and thus promoted tumor immune escape in STAD, providing a new potential diagnostic marker and therapeutic target for the immunotherapy of STAD patients.
Collapse
Affiliation(s)
- Yani Zhou
- School of Health Management, Shangluo University, Shangluo, 726000, China
| | - Dan Liu
- Department of Rheumatology, First Affiliated Hospital of Xi'an Medical College, Xi'an, 710077, China
| | - Huirong Li
- Department of Mathematics and Computer Application, Shangluo University, No. 10, Beixin Street, Shangzhou District, Shangluo, 726000, Shaanxi Province, China.
| |
Collapse
|
|
10
|
Chen H, Hou G, Lan T, Xue S, Xu L, Feng Q, Zeng Y, Wang H. Identification and validation of a five-necroptosis-related lncRNAs signature for prognostic prediction in hepatocellular carcinoma. Heliyon 2024; 10:e37403. [PMID: 39309864 PMCID: PMC11415698 DOI: 10.1016/j.heliyon.2024.e37403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 09/02/2024] [Accepted: 09/03/2024] [Indexed: 09/25/2024] Open
Abstract
Background Hepatocellular carcinoma (HCC) is among the most prevalent digestive system malignancies and is associated with a poor prognosis. Necroptosis, a form of regulated death mediated by death receptors, exhibits characteristics of both necrosis and apoptosis. Long non-coding RNAs (lncRNAs) have been identified as crucial regulators in tumor necroptosis. This study aims to identify the necroptosis-related lncRNAs (np-lncRNA) in HCC and investigate their relationships with prognosis. Method The RNA-sequencing data, along with clinicopathological and survival information of HCC patients were sourced from The Cancer Genome Atlas (TCGA) database. The np-lncRNAs were analyzed to assess their potential in predicting HCC prognosis. Prognostic signatures related to necroptosis were constructed using stepwise multivariate Cox regression analysis. The prognosis of patients was compared using Kaplan-Meier (KM) analysis. The accuracy of the prognostic signature was evaluated using Receiver operating characteristic (ROC) analysis and decision curve analysis (DCA). Quantitative real-time polymerase chain reaction(qPCR) was employed to validate the lncRNAs expression levels of lncRNAs among samples from an independent cohort. Results The np-lncRNAs ZFPM2-AS1, AC099850.3, BACE1-AS, KDM4A-AS1 and MKLN1-AS were identified as potential prognostic biomarkers. The prognostic signature constructed from these np-lncRNAs achieved an Area Under the Curve (AUC) of 0.773. Based on the risk score derived from the signature, patients were divided into two groups, with the high-risk group exhibiting poorer overall survival. Gene Set Enrichment Analysis (GSEA) revealed significantly different between the low risk and high risk groups in tumor-related pathways (such as mTOR, MAPK and p53 signaling pathways) and immune-related functions (like T cell receptor signaling pathway and natural killer cell mediated cytotoxicity). The increased expression of np-lncRNAs was confirmed in another independent HCC cohort. Conclusions This signature offers a dependable method for forecasting the prognosis of HCC patients. Our findings indicate a subset of np-lncRNA biomarkers that could be utilized for prognosis prediction and personalized treatment strategies of HCC patients.
Collapse
Affiliation(s)
- Hao Chen
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital, Southwest Medical University, Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, Luzhou, 646000, China
| | - Guimin Hou
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Hepato-Biliary-Pancreatic Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Tian Lan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Shuai Xue
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lin Xu
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qingbo Feng
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yong Zeng
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Haichuan Wang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| |
Collapse
|
|
11
|
Ye G, Ye M, Jin X. Roles of clinical application of lenvatinib and its resistance mechanism in advanced hepatocellular carcinoma (Review). Am J Cancer Res 2024; 14:4113-4171. [PMID: 39417171 PMCID: PMC11477829 DOI: 10.62347/ujvp4361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 09/03/2024] [Indexed: 10/19/2024] Open
Abstract
Lenvatinib (LEN) is a multi-target TKI, which plays a pivotal role in the treatment of advanced hepatocellular carcinoma (HCC). The inevitable occurrence of drug resistance still prevents curative potential and is deleterious for the prognosis, and a growing body of studies is accumulating, which have devoted themselves to unveiling its underlying resistance mechanism and made some progress. The dysregulation of crucial signaling pathways, non-coding RNA and RNA modifications were proven to be associated with LEN resistance. A range of drugs were found to influence LEN therapeutic efficacy. In addition, the superiority of LEN combination therapy has been shown to potentially overcome the limitations of LEN monotherapy in a series of research, and a range of promising indicators for predicting treatment response and prognosis have been discovered in recent years. In this review, we summarize the latest developments in LEN resistance, the efficacy and safety of LEN combination therapy as well as associated indicators, which may provide new insight into its resistance as well as ideas in the treatment of advanced HCC.
Collapse
Affiliation(s)
- Ganghui Ye
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo UniversityNingbo 315211, Zhejiang, P. R. China
- Department of Oncology, The First Hospital of Ningbo UniversityNingbo 315020, Zhejiang, P. R. China
- Department of Radiation Oncology, Taizhou Central Hospital (Taizhou University Hospital)Taizhou 318000, Zhejiang, P. R. China
| | - Meng Ye
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo UniversityNingbo 315211, Zhejiang, P. R. China
- Department of Oncology, The First Hospital of Ningbo UniversityNingbo 315020, Zhejiang, P. R. China
| | - Xiaofeng Jin
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo UniversityNingbo 315211, Zhejiang, P. R. China
- Department of Oncology, The First Hospital of Ningbo UniversityNingbo 315020, Zhejiang, P. R. China
| |
Collapse
|
|
12
|
Dong G, Wang X, Wang X, Jia Y, Jia Y, Zhao W, Tong Z. Circ_0084653 promotes the tumor progression and immune escape in triple-negative breast cancer via the deubiquitination of MYC and upregulation of SOX5. Int J Biol Macromol 2024; 280:135655. [PMID: 39278446 DOI: 10.1016/j.ijbiomac.2024.135655] [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: 07/18/2024] [Revised: 09/03/2024] [Accepted: 09/12/2024] [Indexed: 09/18/2024]
Abstract
The role of circular RNAs (circRNAs) in cancers is gaining more and more attention, yet related reporters are limited. In triple-negative breast cancer (TNBC), circRNA circ_0084653 originated from COP9 signalosome subunit 5 (COPS5), and COPS5 has been validated to be upregulated in breast cancer before. In our research, COPS5 was also upregulated in TNBC cells, and knockdown of it repressed cell proliferation, invasion, EMT, stemness and PDL-1 protein expression but increased T-cell percentage. Further, circ_0084653 was an aberrantly upregulated circRNA in TNBC cells, and similarly, circ_0084653 silence inhibited TNBC development. Besides, circ_0084653 expression was distributed in both cytoplasm and nucleus. COPS5 overexpression partially rescued the suppressing effects of circ_0084653 depletion in TNBC. Subsequently, circ_0084653 triggered deubiquitination of MYC, the upstream transcription factor of COPS5, via recruiting ubiquitin specific peptidase 36 (USP36). Moreover, circ_0084653 served as the sponge of miR-1323 to release the expression the target gene SRY-box transcription factor 5 (SOX5). SOX5 upregulation completely remedied the inhibiting influence of circ_0084653 downregulation in TNBC. Meanwhile, transcription factor SOX5 activated transcriptionally circ_0084653. To sum up, SOX5-induced circ_0084653 promotes TNBC via the deubiquitination of USP36, which may provide some fresh ideas for TNBC-related molecular mechanisms.
Collapse
Affiliation(s)
- Guolei Dong
- Department of Breast Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin Medical University, Ministry of Education, Tianjin 300060, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin 300060, China
| | - Xiaorui Wang
- Department of Breast Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin Medical University, Ministry of Education, Tianjin 300060, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin 300060, China
| | - Xu Wang
- Department of Breast Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin Medical University, Ministry of Education, Tianjin 300060, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin 300060, China
| | - Yan Jia
- Department of Breast Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin Medical University, Ministry of Education, Tianjin 300060, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin 300060, China
| | - Yongsheng Jia
- Department of Breast Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin Medical University, Ministry of Education, Tianjin 300060, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin 300060, China
| | - Weipeng Zhao
- Department of Breast Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin Medical University, Ministry of Education, Tianjin 300060, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin 300060, China
| | - Zhongsheng Tong
- Department of Breast Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin Medical University, Ministry of Education, Tianjin 300060, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin 300060, China.
| |
Collapse
|
|
13
|
Arshi A, Mahmoudi E, Raeisi F, Dehghan Tezerjani M, Bahramian E, Ahmed Y, Peng C. Exploring potential roles of long non-coding RNAs in cancer immunotherapy: a comprehensive review. Front Immunol 2024; 15:1446937. [PMID: 39257589 PMCID: PMC11384988 DOI: 10.3389/fimmu.2024.1446937] [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: 06/10/2024] [Accepted: 08/05/2024] [Indexed: 09/12/2024] Open
Abstract
Cancer treatment has long been fraught with challenges, including drug resistance, metastasis, and recurrence, making it one of the most difficult diseases to treat effectively. Traditional therapeutic approaches often fall short due to their inability to target cancer stem cells and the complex genetic and epigenetic landscape of tumors. In recent years, cancer immunotherapy has revolutionized the field, offering new hope and viable alternatives to conventional treatments. A particularly promising area of research focuses on non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), and their role in cancer resistance and the modulation of signaling pathways. To address these challenges, we performed a comprehensive review of recent studies on lncRNAs and their impact on cancer immunotherapy. Our review highlights the crucial roles that lncRNAs play in affecting both innate and adaptive immunity, thereby influencing the outcomes of cancer treatments. Key observations from our review indicate that lncRNAs can modify the tumor immune microenvironment, enhance immune cell infiltration, and regulate cytokine production, all of which contribute to tumor growth and resistance to therapies. These insights suggest that lncRNAs could serve as potential targets for precision medicine, opening up new avenues for developing more effective cancer immunotherapies. By compiling recent research on lncRNAs across various cancers, this review aims to shed light on their mechanisms within the tumor immune microenvironment.
Collapse
Affiliation(s)
- Asghar Arshi
- Department of Biology, York University, Toronto, ON, Canada
| | - Esmaeil Mahmoudi
- Young Researchers and Elite Club, Islamic Azad University, Shahrekord, Iran
| | | | - Masoud Dehghan Tezerjani
- Department of bioinformatics, School of Advanced Medical Technologies, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Elham Bahramian
- Department of Biological Sciences, University of Arkansas, Fayetteville, AR, United States
| | - Yeasin Ahmed
- Department of Biological Sciences, University of Arkansas, Fayetteville, AR, United States
| | - Chun Peng
- Department of Biology, York University, Toronto, ON, Canada
| |
Collapse
|
|
14
|
Luo H, Jing H, Chen W. An extensive overview of the role of lncRNAs generated from immune cells in the etiology of cancer. Int Immunopharmacol 2024; 133:112063. [PMID: 38677091 DOI: 10.1016/j.intimp.2024.112063] [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: 02/03/2024] [Revised: 04/07/2024] [Accepted: 04/08/2024] [Indexed: 04/29/2024]
Abstract
Long non-coding RNAs (lncRNAs) are involved in the control of critical tumor-suppressor and oncogenic pathways in cancer. These types of non-coding RNAs could affect both immune and cancer cells. The thorough analysis of lncRNAs derived from immune cells and the incorporation of new findings significantly advance our understanding of the complex role of lncRNAs in the context of cancer. This work highlights the promise of lncRNAs for translational therapeutic approaches while also establishing a solid foundation for comprehending the complex link between lncRNAs and cancer through a coherent narrative. The main findings of this article are that types of lncRNAs derived from immune cells, such as MM2P and MALAT1, can affect the behaviors of cancer cells, like invasion, angiogenesis, and proliferation. As research in this area grows, the therapeutic potential of targeting these lncRNAs offers promising opportunities for expanding our understanding of cancer biology and developing cutting-edge, precision-based therapies for cancer therapy.
Collapse
Affiliation(s)
- Hong Luo
- Department of Oncology, Yancheng Branch of Nanjing Drum Tower Hospital, Yancheng, Jiangsu Province, China.
| | - Hailiang Jing
- Department of Integrative Medicine, Yancheng Branch of Nanjing Drum Tower Hospital, Yancheng, Jiangsu Province, China
| | - Wei Chen
- Department of Oncology, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| |
Collapse
|
|
15
|
Li W, Zhang H, You Z, Guo B. LncRNAs in Immune and Stromal Cells Remodel Phenotype of Cancer Cell and Tumor Microenvironment. J Inflamm Res 2024; 17:3173-3185. [PMID: 38774447 PMCID: PMC11108079 DOI: 10.2147/jir.s460730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 05/07/2024] [Indexed: 05/24/2024] Open
Abstract
Emerging studies suggest that long non-coding RNAs (lncRNAs) participate in the mutual regulation of cells in tumor microenvironment, thereby affecting the anti-tumor immune activity of immune cells. Additionally, the intracellular pathways mediated by lncRNAs can affect the expression of immune checkpoints or change the cell functions, including cytokines secretion, of immune and stromal cells in tumor microenvironment, which further influences cancer patients' prognosis and treatment response. With the in-depth research, lncRNAs have shown great potency as a new immunotherapy target and predict immunotherapy response. The research on lncRNAs provides us with a new insight into developing new immunotherapy drugs and predicting the outcome of immunotherapy. With development of RNA sequencing technology, amounts of lncRNAs were found to be dysregulated in immune and stromal cells rather than tumor cells. These lncRNAs function through ceRNA network or regulating transcript factor activity, thus leading abnormal differentiation and activation of immune and stromal cells. Here, we review the function of lncRNAs in the immune microenvironment and focus on the alteration of lncRNAs in immune and stromal cells, and discuss how these alterations affect tumor growth, metastasis and treatment response.
Collapse
Affiliation(s)
- Wenbin Li
- Department of Clinical Oncology, Qianjiang Hospital Affiliated to Renmin Hospital of Wuhan University, Qianjiang, Hubei, People’s Republic of China
- Department of Clinical Oncology, Qianjiang Central Hospital of Hubei Province, Qianjiang, Hubei, People’s Republic of China
| | - Haohan Zhang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China
| | - Zuo You
- Department of Traditional Chinese Medicine, Xianfeng County People’s Hospital, Enshi, Hubei, People’s Republic of China
| | - Baozhu Guo
- Department of Pain, Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China
| |
Collapse
|
|
16
|
Rashwan HH, Taher AM, Hassan HA, Awaji AA, Kiriacos CJ, Assal RA, Youness RA. Harnessing the supremacy of MEG3 LncRNA to defeat gastrointestinal malignancies. Pathol Res Pract 2024; 256:155223. [PMID: 38452587 DOI: 10.1016/j.prp.2024.155223] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/16/2024] [Accepted: 02/21/2024] [Indexed: 03/09/2024]
Abstract
Evidence suggests that long non-coding RNAs (lncRNAs) play a pivotal role in the carcinogenesis and progression of various human malignancies including gastrointestinal malignancies. This comprehensive review reports the functions and mechanisms of the lncRNA maternally expressed gene 3 (MEG3) involved in gastrointestinal malignancies. It summarizes its roles in mediating the regulation of cellular proliferation, apoptosis, migration, invasiveness, epithelial-to-mesenchymal transition, and drug resistance in several gastrointestinal cancers such as colorectal cancer, gall bladder cancer, pancreatic cancer, gastric cancer, esophageal cancer, cholangiocarcinoma, gastrointestinal stromal tumors and most importantly, hepatocellular carcinoma. In addition, the authors briefly highlight its implicated mechanistic role and interactions with different non-coding RNAs and oncogenic signaling cascades. This review presents the rationale for developing non coding RNA-based anticancer therapy via harnessing the power of MEG3 in gastrointestinal malignancies.
Collapse
Affiliation(s)
- H H Rashwan
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; Bioinformatics Group, Center for Informatics Science (CIS), School of Information Technology and Computer Science (ITCS), Nile University, 12677, Giza, Egypt
| | - A M Taher
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt
| | - H A Hassan
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt
| | - A A Awaji
- Department of Biology, Faculty of Science, University College of Taymaa, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - C J Kiriacos
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt
| | - R A Assal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt
| | - R A Youness
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt.
| |
Collapse
|
|
17
|
Ebrahimi N, Abdulwahid AHRR, Mansouri A, Karimi N, Bostani RJ, Beiranvand S, Adelian S, Khorram R, Vafadar R, Hamblin MR, Aref AR. Targeting the NF-κB pathway as a potential regulator of immune checkpoints in cancer immunotherapy. Cell Mol Life Sci 2024; 81:106. [PMID: 38418707 PMCID: PMC10902086 DOI: 10.1007/s00018-023-05098-8] [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: 07/02/2023] [Revised: 10/01/2023] [Accepted: 10/29/2023] [Indexed: 03/02/2024]
Abstract
Advances in cancer immunotherapy over the last decade have led to the development of several agents that affect immune checkpoints. Inhibitory receptors expressed on T cells that negatively regulate the immune response include cytotoxic T‑lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD1), which have been studied more than similar receptors. Inhibition of these proteins and other immune checkpoints can stimulate the immune system to attack cancer cells, and prevent the tumor from escaping the immune response. However, the administration of anti-PD1 and anti-CTLA4 antibodies has been associated with adverse inflammatory responses similar to autoimmune diseases. The current review discussed the role of the NF-κB pathway as a tumor promoter, and how it can govern inflammatory responses and affect various immune checkpoints. More precise knowledge about the communication between immune checkpoints and NF-κB pathways could increase the effectiveness of immunotherapy and reduce the adverse effects of checkpoint inhibitor therapy.
Collapse
Affiliation(s)
- Nasim Ebrahimi
- Genetics Division, Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran
| | | | - Atena Mansouri
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Nasrin Karimi
- Department of Biology, Faculty of Basic Science, Islamic Azad University Damghan Branch, Damghan, Iran
| | | | - Sheida Beiranvand
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Samaneh Adelian
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Roya Khorram
- Bone and Joint Diseases Research Center, Department of Orthopedic Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Vafadar
- Department of Orthopeadic Surgery, Kerman University of Medical Sciences, Kerman, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028, South Africa.
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Amir Reza Aref
- Xsphera Biosciences, Translational Medicine Group, 6 Tide Street, Boston, MA, 02210, USA.
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
| |
Collapse
|
|
18
|
Cianciotti BC, Magnani ZI, Ugolini A, Camisa B, Merelli I, Vavassori V, Potenza A, Imparato A, Manfredi F, Abbati D, Perani L, Spinelli A, Shifrut E, Ciceri F, Vago L, Di Micco R, Naldini L, Genovese P, Ruggiero E, Bonini C. TIM-3, LAG-3, or 2B4 gene disruptions increase the anti-tumor response of engineered T cells. Front Immunol 2024; 15:1315283. [PMID: 38510235 PMCID: PMC10953820 DOI: 10.3389/fimmu.2024.1315283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 02/05/2024] [Indexed: 03/22/2024] Open
Abstract
Background In adoptive T cell therapy, the long term therapeutic benefits in patients treated with engineered tumor specific T cells are limited by the lack of long term persistence of the infused cellular products and by the immunosuppressive mechanisms active in the tumor microenvironment. Exhausted T cells infiltrating the tumor are characterized by loss of effector functions triggered by multiple inhibitory receptors (IRs). In patients, IR blockade reverts T cell exhaustion but has low selectivity, potentially unleashing autoreactive clones and resulting in clinical autoimmune side effects. Furthermore, loss of long term protective immunity in cell therapy has been ascribed to the effector memory phenotype of the infused cells. Methods We simultaneously redirected T cell specificity towards the NY-ESO-1 antigen via TCR gene editing (TCRED) and permanently disrupted LAG3, TIM-3 or 2B4 genes (IRKO) via CRISPR/Cas9 in a protocol to expand early differentiated long-living memory stem T cells. The effector functions of the TCRED-IRKO and IR competent (TCRED-IRCOMP) cells were tested in short-term co-culture assays and under a chronic stimulation setting in vitro. Finally, the therapeutic efficacy of the developed cellular products were evaluated in multiple myeloma xenograft models. Results We show that upon chronic stimulation, TCRED-IRKO cells are superior to TCRED-IRCOMP cells in resisting functional exhaustion through different mechanisms and efficiently eliminate cancer cells upon tumor re-challenge in vivo. Our data indicate that TIM-3 and 2B4-disruption preserve T-cell degranulation capacity, while LAG-3 disruption prevents the upregulation of additional inhibitory receptors in T cells. Conclusion These results highlight that TIM-3, LAG-3, and 2B4 disruptions increase the therapeutic benefit of tumor specific cellular products and suggest distinct, non-redundant roles for IRs in anti-tumor responses.
Collapse
Affiliation(s)
| | - Zulma Irene Magnani
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alessia Ugolini
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Barbara Camisa
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Innovative Immunotherapies Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Ivan Merelli
- Institute for Biomedical Technologies, National Research Council, Segrate, Italy
| | - Valentina Vavassori
- Gene Transfer Technologies and New Gene Therapy Strategies Unit, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alessia Potenza
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Antonio Imparato
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Francesco Manfredi
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Danilo Abbati
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Laura Perani
- Experimental Imaging Centre, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Antonello Spinelli
- Experimental Imaging Centre, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Eric Shifrut
- The School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
- Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Dotan Center for Advanced Therapies, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Fabio Ciceri
- Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Luca Vago
- Università Vita-Salute San Raffaele, Milan, Italy
- Unit of Immunogenetics, Leukemia Genomics and Immunobiology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Raffaella Di Micco
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Luigi Naldini
- Gene Transfer Technologies and New Gene Therapy Strategies Unit, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Pietro Genovese
- Gene Transfer Technologies and New Gene Therapy Strategies Unit, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
- Gene Therapy Program, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Department of Pediatric Oncology, Harvard Medical School, Boston, MA, United States
| | - Eliana Ruggiero
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Chiara Bonini
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| |
Collapse
|
|
19
|
Fitzgerald KA, Shmuel-Galia L. Lnc-ing RNA to intestinal homeostasis and inflammation. Trends Immunol 2024; 45:127-137. [PMID: 38220553 DOI: 10.1016/j.it.2023.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/14/2023] [Accepted: 12/21/2023] [Indexed: 01/16/2024]
Abstract
Long noncoding RNAs (lncRNAs) play important roles in numerous biological processes, including the immune system. Initial research in this area focused on cell-based studies, but recent advances underscore the profound significance of lncRNAs at the organismal level, providing invaluable insights into their roles in inflammatory diseases. In this rapidly evolving field, lncRNAs have been described with pivotal roles in the intestinal tract where they regulate intestinal homeostasis and inflammation by influencing processes such as immune cell development, inflammatory signaling pathways, epithelial barrier function, and cellular metabolism. Understanding the regulation and function of lncRNAs in this tissue may position lncRNAs not only as potential disease biomarkers but also as promising targets for therapeutic intervention in inflammatory bowel disease and related diseases.
Collapse
Affiliation(s)
- Katherine A Fitzgerald
- Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
| | - Liraz Shmuel-Galia
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
| |
Collapse
|
|
20
|
Al-Hawary SIS, Saleh RO, Taher SG, Ahmed SM, Hjazi A, Yumashev A, Ghildiyal P, Qasim MT, Alawadi A, Ihsan A. Tumor-derived lncRNAs: Behind-the-scenes mediators that modulate the immune system and play a role in cancer pathogenesis. Pathol Res Pract 2024; 254:155123. [PMID: 38277740 DOI: 10.1016/j.prp.2024.155123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 01/07/2024] [Accepted: 01/08/2024] [Indexed: 01/28/2024]
Abstract
Having been involved in complex cellular regulatory networks and cell-to-cell communications, non-coding RNAs (lncRNAs) have become functional carriers that transmit information between cells and tissues, modulate tumor microenvironments, encourage angiogenesis and invasion, and make tumor cells more resistant to drugs. Immune cells' exosomal lncRNAs may be introduced into tumor cells to influence the tumor's course and the treatment's effectiveness. Research has focused on determining if non-coding RNAs affect many target genes to mediate regulating recipient cells. The tumor microenvironment's immune and cancer cells are influenced by lncRNAs, which may impact a treatment's efficacy. The lncRNA-mediated interaction between cancer cells and immune cells invading the tumor microenvironment has been the subject of numerous recent studies. On the other hand, tumor-derived lncRNAs' control over the immune system has not gotten much attention and is still a relatively new area of study. Tumor-derived lncRNAs are recognized to contribute to tumor immunity, while the exact mechanism is unclear.
Collapse
Affiliation(s)
| | - Raed Obaid Saleh
- Department of Medical Laboratory Techniques, Al-Maarif University College, Al-Anbar, Iraq.
| | - Sada Gh Taher
- National University of Science and Technology, Dhi Qar, Iraq
| | | | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Alexey Yumashev
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Pallavi Ghildiyal
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Maytham T Qasim
- College of Health and Medical Technology, Al-Ayen University, Thi-Qar 64001, Iraq
| | - Ahmed Alawadi
- College of Health and Medical Technology, Al-Ayen University, Thi-Qar 64001, Iraq; College of Technical Engineering, the Islamic University, Najaf, Iraq; College of Technical Engineering, the Islamic University of Al Diwaniyah, Iraq
| | - Ali Ihsan
- College of Technical Engineering, the Islamic University of Babylon, Iraq; Department of Pediatrics, General Medicine Practice Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia; Department of Medical Laboratory Technique, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
| |
Collapse
|
|
21
|
Zhang D, Zhang M, Zhang L, Wang W, Hua S, Zhou C, Sun X. Long non-coding RNAs and immune cells: Unveiling the role in viral infections. Biomed Pharmacother 2024; 170:115978. [PMID: 38056234 DOI: 10.1016/j.biopha.2023.115978] [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: 10/01/2023] [Revised: 11/26/2023] [Accepted: 11/29/2023] [Indexed: 12/08/2023] Open
Abstract
Viral infections present significant challenges to human health, underscoring the importance of understanding the immune response for effective therapeutic strategies. Immune cell activation leads to dynamic changes in gene expression. Numerous studies have demonstrated the crucial role of long noncoding RNAs (lncRNAs) in immune activation and disease processes, including viral infections. This review provides a comprehensive overview of lncRNAs expressed in immune cells, including CD8 T cells, CD4 T cells, B cells, monocytes, macrophages, dendritic cells, and granulocytes, during both acute and chronic viral infections. LncRNA-mediated gene regulation encompasses various mechanisms, including the modulation of viral replication, the establishment of latency, activation of interferon pathways and other critical signaling pathways, regulation of immune exhaustion and aging, and control of cytokine and chemokine production, as well as the modulation of interferon-stimulated genes. By highlighting specific lncRNAs in different immune cell types, this review enhances our understanding of immune responses to viral infections from a lncRNA perspective and suggests potential avenues for exploring lncRNAs as therapeutic targets against viral diseases.
Collapse
Affiliation(s)
- Dan Zhang
- Department of Immunology and Pathogen Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
| | - Mengna Zhang
- Department of Immunology and Pathogen Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
| | - Liqin Zhang
- Department of Immunology and Pathogen Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
| | - Weijuan Wang
- Department of Immunology and Pathogen Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
| | - Stéphane Hua
- Laboratory of Cellular Immunology and Biotechnology, Molecular Engineering for Health Unit CEA Saclay, 91191 Gif-sur-Yvette cedex, France
| | - Chan Zhou
- Department of Population and Quantitative Health Sciences, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Xiaoming Sun
- Department of Immunology and Pathogen Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
| |
Collapse
|
|
22
|
Xiao Y, Hu Y, Liu S. Non-coding RNAs: a promising target for early metastasis intervention. Chin Med J (Engl) 2023; 136:2538-2550. [PMID: 37442775 PMCID: PMC10617820 DOI: 10.1097/cm9.0000000000002619] [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: 12/01/2022] [Indexed: 07/15/2023] Open
Abstract
ABSTRACT Metastases account for the overwhelming majority of cancer-associated deaths. The dissemination of cancer cells from the primary tumor to distant organs involves a complex process known as the invasion-metastasis cascade. The underlying biological mechanisms of metastasis, however, remain largely elusive. Recently, the discovery and characterization of non-coding RNAs (ncRNAs) have revealed the diversity of their regulatory roles, especially as key contributors throughout the metastatic cascade. Here, we review recent progress in how three major types of ncRNAs (microRNAs, long non-coding RNAs, and circular RNAs) are involved in the multistep procedure of metastasis. We further examine interactions among the three ncRNAs as well as current progress in their regulatory mechanisms. We also propose the prevention of metastasis in the early stages of cancer progression and discuss current translational studies using ncRNAs as targets for metastasis diagnosis and treatments. These studies provide insights into developing more effective strategies to target metastatic relapse.
Collapse
Affiliation(s)
- Yi Xiao
- Department of Stomatology, Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Yijun Hu
- Clinical Research Center, Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Shanrong Liu
- Department of Laboratory Diagnostics, Changhai Hospital, Naval Medical University, Shanghai 200433, China
| |
Collapse
|
|
23
|
Liu S, Jia M, Dai R. Deciphering the tumour immune microenvironment of hepatocellular carcinoma. Scand J Immunol 2023; 98:e13327. [PMID: 38441331 DOI: 10.1111/sji.13327] [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] [Revised: 08/13/2023] [Accepted: 08/28/2023] [Indexed: 03/07/2024]
Abstract
Current treatments for hepatocellular carcinoma (HCC) are less effective and prone to recurrence after surgery, so it's needed to seek new ideas for its therapy. Tumour immune microenvironment (TME) is crucial for the pathogenesis, development and metastasis of HCC. Interactions between immune cells and tumour cells significantly impact responses to immunotherapies and patient prognosis. In recent years, immunotherapies for HCC have shown promising potential, but the response rate is still unsatisfactory. Understanding their cross-talks is helpful for selecting potential therapeutic targets, predicting immunotherapy responses, determining immunotherapy efficacy, identifying prognostic markers and selecting individualized treatment options. In this paper, we reviewed the research advances on the roles of immune cells and multi-omic research associated with HCC pathogenesis and therapy, and future perspectives on TME.
Collapse
Affiliation(s)
- Sha Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
- Department of Pain, Daping Hospital, Army Medical University, Chongqing, China
| | - Man Jia
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Rongyang Dai
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| |
Collapse
|
|
24
|
Chakraborty S, Banerjee S. Understanding crosstalk of organ tropism, tumor microenvironment and noncoding RNAs in breast cancer metastasis. Mol Biol Rep 2023; 50:9601-9623. [PMID: 37792172 DOI: 10.1007/s11033-023-08852-0] [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: 06/23/2023] [Accepted: 09/26/2023] [Indexed: 10/05/2023]
Abstract
Cancer metastasis is one of the major clinical challenges worldwide due to limited existing effective treatments. Metastasis roots from the host organ of origin and gradually migrates to different regional and distant organs. In different breast cancer subtypes, different organs like bones, liver, lungs and brain are targeted by the metastatic tumor cells. Cancer renders mortality to their respective metastasizing sites like bones, brain, liver, and lungs. Metastatic breast cancers are best treated and managed if detected at an early stage. Metastasis is regulated by various molecular activators and suppressors. The conventional theory of 'seed and soil' states that metastatic tumor cells move to tumor microenvironment that has favorable conditions like blood flow for them to grow just like seeds grows when planted in fertile land. Additionally, different coding as well as non-coding RNAs play a very significant role in the process of metastasis by modulating their expression levels leading to a crosstalk of various tumorigenic cascades. Treatments for metastasis is also very critical in controlling this lethal process. Detecting breast cancer metastasis at an early stage is crucial for managing and predicting metastatic progression. In this review, we have compiled several factors that can be targeted to manage the onset and gradual stages of breast cancer metastasis.
Collapse
Affiliation(s)
- Sohini Chakraborty
- Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India
| | - Satarupa Banerjee
- Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India.
| |
Collapse
|
|
25
|
Hao L, Li S, Hu X. New insights into T-cell exhaustion in liver cancer: from mechanism to therapy. J Cancer Res Clin Oncol 2023; 149:12543-12560. [PMID: 37423958 DOI: 10.1007/s00432-023-05083-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 06/29/2023] [Indexed: 07/11/2023]
Abstract
Liver cancer is one of the most common malignancies. T-cell exhaustion is associated with immunosuppression of tumor and chronic infection. Although immunotherapies that enhance the immune response by targeting programmed cell death-1(PD-1)/programmed cell death ligand 1 (PD-L1) have been applied to malignancies, these treatments have shown limited response rates. This suggested that additional inhibitory receptors (IRs) also contributed to T-cell exhaustion and tumor prognosis. Exhausted T-cells (Tex) in the tumor immune microenvironment (TME) are usually in a dysfunctional state of exhaustion, such as impaired activity and proliferative ability, increased apoptosis rate, and reduced production of effector cytokines. Tex cells participate in the negative regulation of tumor immunity mainly through IRs on the cell surface, changes in cytokines and immunomodulatory cell types, causing tumor immune escape. However, T-cell exhaustion is not irreversible and targeted immune checkpoint inhibitors (ICIs) can effectively reverse the exhaustion of T-cells and restore the anti-tumor immune response. Therefore, the research on the mechanism of T-cell exhaustion in liver cancer, aimed at maintaining or restoring the effector function of Tex cells, might provide a new method for the treatment of liver cancer. In this review, we summarized the basic characteristics of Tex cells (such as IRs and cytokines), discussed the mechanisms associated with T-cell exhaustion, and specifically discussed how these exhaustion characteristics were acquired and shaped by key factors within TME. Then new insights into the molecular mechanism of T-cell exhaustion suggested a potential way to improve the efficacy of cancer immunotherapy, namely to restore the effector function of Tex cells. In addition, we also reviewed the research progress of T-cell exhaustion in recent years and provided suggestions for further research.
Collapse
Affiliation(s)
- Liyuan Hao
- Chengdu University of Traditional Chinese Medicine, No. 37 Shi-Er-Qiao Road, Chengdu, 610075, Sichuan Province, People's Republic of China
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Shenghao Li
- Chengdu University of Traditional Chinese Medicine, No. 37 Shi-Er-Qiao Road, Chengdu, 610075, Sichuan Province, People's Republic of China
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Xiaoyu Hu
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China.
| |
Collapse
|
|
26
|
Chen W, Ruan M, Zou M, Liu F, Liu H. Clinical Significance of Non-Coding RNA Regulation of Programmed Cell Death in Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:4187. [PMID: 37627215 PMCID: PMC10452865 DOI: 10.3390/cancers15164187] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/02/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a widely prevalent and malignantly progressive tumor. Most patients are typically diagnosed with HCC at an advanced stage, posing significant challenges in the execution of curative surgical interventions. Non-coding RNAs (ncRNAs) represent a distinct category of RNA molecules not directly involved in protein synthesis. However, they possess the remarkable ability to regulate gene expression, thereby exerting significant regulatory control over cellular processes. Notably, ncRNAs have been implicated in the modulation of programmed cell death (PCD), a crucial mechanism that various therapeutic agents target in the fight against HCC. This review summarizes the clinical significance of ncRNA regulation of PCD in HCC, including patient diagnosis, prognosis, drug resistance, and side effects. The aim of this study is to provide new insights and directions for the diagnosis and drug treatment strategies of HCC.
Collapse
Affiliation(s)
| | | | | | - Fuchen Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China; (W.C.); (M.R.)
| | - Hui Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China; (W.C.); (M.R.)
| |
Collapse
|
|
27
|
Zhan DT, Xian HC. Exploring the regulatory role of lncRNA in cancer immunity. Front Oncol 2023; 13:1191913. [PMID: 37637063 PMCID: PMC10448763 DOI: 10.3389/fonc.2023.1191913] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 07/24/2023] [Indexed: 08/29/2023] Open
Abstract
Imbalanced immune homeostasis in cancer microenvironment is a hallmark of cancer. Increasing evidence demonstrated that long non-coding RNAs (lncRNAs) have emerged as key regulatory molecules in directly blocking the cancer immunity cycle, apart from activating negative regulatory pathways for restraining tumor immunity. lncRNAs reshape the tumor microenvironment via the recruitment and activation of innate and adaptive lymphoid cells. In this review, we summarized the versatile mechanisms of lncRNAs implicated in cancer immunity cycle, including the inhibition of antitumor T cell activation, blockade of effector T cell recruitment, disruption of T cell homing, recruitment of immunosuppressive cells, and inducing an imbalance between antitumor effector cells (cytotoxic T lymphocytes, M1 macrophages, and T helper type 1 cells) versus immunosuppressive cells (M2 macrophages, T helper type 2 cells, myeloid derived suppressor cells, and regulatory T cells) that infiltrate in the tumor. As such, we would highlight the potential of lncRNAs as novel targets for immunotherapy.
Collapse
Affiliation(s)
- Dan-ting Zhan
- Department of Prosthodontics, Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, China
| | - Hong-chun Xian
- Department of Plastic and Maxillofacial Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
28
|
Lu S, Liu X, Wu C, Zhang J, Stalin A, Huang Z, Tan Y, Wu Z, You L, Ye P, Fu C, Zhang X, Wu J. Identification of an immune-related 6-lncRNA panel with a good performance for prognostic prediction in hepatocellular carcinoma by integrated bioinformatics analysis. Medicine (Baltimore) 2023; 102:e33990. [PMID: 37478241 PMCID: PMC10662904 DOI: 10.1097/md.0000000000033990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 05/23/2023] [Indexed: 07/23/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most malignant tumors with a poor prognosis. The long non-coding RNA (lncRNA) has been found to have great potential as a prognostic biomarker or therapeutic target for cancer patients. However, the prognostic value and tumor immune infiltration of lncRNAs in HCC has yet to be fully elucidated. To identify prognostic biomarkers of lncRNA in HCC by integrated bioinformatics analysis and explore their functions and relationship with tumor immune infiltration. The prognostic risk assessment model for HCC was constructed by comprehensively using univariate/multivariate Cox regression analysis, Kaplan-Meier survival analysis, and the least absolute shrinkage and selection operator regression analysis. Subsequently, the accuracy, independence, and sensitivity of our model were evaluated, and a nomogram for individual prediction in the clinic was constructed. Tumor immune microenvironment (TIME), immune checkpoints, and human leukocyte antigen alleles were compared in high- and low-risk patients. Finally, the functions of our lncRNA signature were examined using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and gene set enrichment analysis. A 6-lncRNA panel of HCC consisting of RHPN1-AS1, LINC01224, CTD-2510F5.4, RP1-228H13.5, LINC01011, and RP11-324I22.4 was eventually identified, and show good performance in predicting the survivals of patients with HCC and distinguishing the immunomodulation of TIME of high- and low-risk patients. Functional analysis also suggested that this 6-lncRNA panel may play an essential role in promoting tumor progression and immune regulation of TIME. In this study, 6 potential lncRNAs were identified as the prognostic biomarkers in HCC, and the regulatory mechanisms involved in HCC were initially explored.
Collapse
Affiliation(s)
- Shan Lu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xinkui Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Chao Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jingyuan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Antony Stalin
- Institute of Fundamental and Frontier Sciences, University of Electronic Science and Technology of China, Chengdu, China
| | - Zhihong Huang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yingying Tan
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zhishan Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Leiming You
- Department of Immunology and Microbiology, School of Life Science, Beijing University of Chinese Medicine, Beijing, China
| | - Peizhi Ye
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Changgeng Fu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaomeng Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| |
Collapse
|
|
29
|
Erber J, Herndler-Brandstetter D. Regulation of T cell differentiation and function by long noncoding RNAs in homeostasis and cancer. Front Immunol 2023; 14:1181499. [PMID: 37346034 PMCID: PMC10281531 DOI: 10.3389/fimmu.2023.1181499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 05/02/2023] [Indexed: 06/23/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) increase in genomes of complex organisms and represent the largest group of RNA genes transcribed in mammalian cells. Previously considered only transcriptional noise, lncRNAs comprise a heterogeneous class of transcripts that are emerging as critical regulators of T cell-mediated immunity. Here we summarize the lncRNA expression landscape of different T cell subsets and highlight recent advances in the role of lncRNAs in regulating T cell differentiation, function and exhaustion during homeostasis and cancer. We discuss the different molecular mechanisms of lncRNAs and highlight lncRNAs that can serve as novel targets to modulate T cell function or to improve the response to cancer immunotherapies by modulating the immunosuppressive tumor microenvironment.
Collapse
|
|
30
|
Yang J, Xu J, Wang W, Zhang B, Yu X, Shi S. Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2023; 8:210. [PMID: 37217462 PMCID: PMC10203321 DOI: 10.1038/s41392-023-01480-x] [Citation(s) in RCA: 138] [Impact Index Per Article: 69.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 04/17/2023] [Accepted: 04/28/2023] [Indexed: 05/24/2023] Open
Abstract
Over decades, researchers have focused on the epigenetic control of DNA-templated processes. Histone modification, DNA methylation, chromatin remodeling, RNA modification, and noncoding RNAs modulate many biological processes that are crucial to the development of cancers. Dysregulation of the epigenome drives aberrant transcriptional programs. A growing body of evidence suggests that the mechanisms of epigenetic modification are dysregulated in human cancers and might be excellent targets for tumor treatment. Epigenetics has also been shown to influence tumor immunogenicity and immune cells involved in antitumor responses. Thus, the development and application of epigenetic therapy and cancer immunotherapy and their combinations may have important implications for cancer treatment. Here, we present an up-to-date and thorough description of how epigenetic modifications in tumor cells influence immune cell responses in the tumor microenvironment (TME) and how epigenetics influence immune cells internally to modify the TME. Additionally, we highlight the therapeutic potential of targeting epigenetic regulators for cancer immunotherapy. Harnessing the complex interplay between epigenetics and cancer immunology to develop therapeutics that combine thereof is challenging but could yield significant benefits. The purpose of this review is to assist researchers in understanding how epigenetics impact immune responses in the TME, so that better cancer immunotherapies can be developed.
Collapse
Affiliation(s)
- Jing Yang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| |
Collapse
|
|
31
|
Zhang Y, Zhan L, Li J, Jiang X, Yin L. Insights into N6-methyladenosine (m6A) modification of noncoding RNA in tumor microenvironment. Aging (Albany NY) 2023; 15:3857-3889. [PMID: 37178254 PMCID: PMC10449301 DOI: 10.18632/aging.204679] [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: 08/25/2022] [Accepted: 04/15/2023] [Indexed: 05/15/2023]
Abstract
N6-methyladenosine (m6A) is the most abundant RNA modification in eukaryotes, and it participates in the regulation of pathophysiological processes in various diseases, including malignant tumors, by regulating the expression and function of both coding and non-coding RNAs (ncRNAs). More and more studies demonstrated that m6A modification regulates the production, stability, and degradation of ncRNAs and that ncRNAs also regulate the expression of m6A-related proteins. Tumor microenvironment (TME) refers to the internal and external environment of tumor cells, which is composed of numerous tumor stromal cells, immune cells, immune factors, and inflammatory factors that are closely related to tumors occurrence and development. Recent studies have suggested that crosstalk between m6A modifications and ncRNAs plays an important role in the biological regulation of TME. In this review, we summarized and analyzed the effects of m6A modification-associated ncRNAs on TME from various perspectives, including tumor proliferation, angiogenesis, invasion and metastasis, and immune escape. Herein, we showed that m6A-related ncRNAs can not only be expected to become detection markers of tumor tissue samples, but can also be wrapped into exosomes and secreted into body fluids, thus exhibiting potential as markers for liquid biopsy. This review provides a deeper understanding of the relationship between m6A-related ncRNAs and TME, which is of great significance to the development of a new strategy for precise tumor therapy.
Collapse
Affiliation(s)
- YanJun Zhang
- College of Pharmacy and Traditional Chinese Medicine, Jiangsu College of Nursing, Huaian, Jiangsu 223005, China
| | - Lijuan Zhan
- College of Pharmacy and Traditional Chinese Medicine, Jiangsu College of Nursing, Huaian, Jiangsu 223005, China
| | - Jing Li
- College of Pharmacy and Traditional Chinese Medicine, Jiangsu College of Nursing, Huaian, Jiangsu 223005, China
| | - Xue Jiang
- College of Pharmacy and Traditional Chinese Medicine, Jiangsu College of Nursing, Huaian, Jiangsu 223005, China
| | - Li Yin
- Department of Biopharmaceutics, Yulin Normal University, Guangxi, Yulin 537000, China
- Bioengineering and Technology Center for Native Medicinal Resources Development, Yulin Normal University, Yulin 537000, China
| |
Collapse
|
|
32
|
Han B, He J, Chen Q, Yuan M, Zeng X, Li Y, Zeng Y, He M, Zhou Q, Feng D, Ma D. ELFN1-AS1 promotes GDF15-mediated immune escape of colorectal cancer from NK cells by facilitating GCN5 and SND1 association. Discov Oncol 2023; 14:56. [PMID: 37147528 PMCID: PMC10163203 DOI: 10.1007/s12672-023-00675-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 04/27/2023] [Indexed: 05/07/2023] Open
Abstract
The ability of colorectal cancer (CRC) cells to escape from natural killer (NK) cell immune surveillance leads to anti-tumor treatment failure. The long non-coding RNA (lncRNA) ELFN1-AS1 is aberrantly expressed in multiple tumors suggesting a role as an oncogene in cancer development. However, whether ELFN1-AS1 regulates immune surveillance in CRC is unclear. Here, we determined that ELFN1-AS1 enhanced the ability of CRC cells to escape from NK cell surveillance in vitro and in vivo. In addition, we confirmed that ELFN1-AS1 in CRC cells attenuated the activity of NK cell by down-regulating NKG2D and GZMB via the GDF15/JNK pathway. Furthermore, mechanistic investigations demonstrated that ELFN1-AS1 enhanced the interaction between the GCN5 and SND1 protein and this influenced H3k9ac enrichment at the GDF15 promotor to stimulate GDF15 production in CRC cells. Taken together, our findings indicate that ELFN1-AS1 in CRC cells suppresses NK cell cytotoxicity and ELFN1-AS1 is a potential therapeutic target for CRC.
Collapse
Affiliation(s)
- Bin Han
- GCP Center/Institute of Drug Clinical Trials, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Institute of Pharmacy, North Sichuan Medical College, Nanchong, China
| | - Jinsong He
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Qing Chen
- GCP Center/Institute of Drug Clinical Trials, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Institute of Pharmacy, North Sichuan Medical College, Nanchong, China
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Min Yuan
- GCP Center/Institute of Drug Clinical Trials, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Institute of Pharmacy, North Sichuan Medical College, Nanchong, China
| | - Xi Zeng
- GCP Center/Institute of Drug Clinical Trials, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Institute of Pharmacy, North Sichuan Medical College, Nanchong, China
| | - Yuanting Li
- GCP Center/Institute of Drug Clinical Trials, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Institute of Pharmacy, North Sichuan Medical College, Nanchong, China
| | - Yan Zeng
- GCP Center/Institute of Drug Clinical Trials, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Meibo He
- GCP Center/Institute of Drug Clinical Trials, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Institute of Pharmacy, North Sichuan Medical College, Nanchong, China
| | - Qilin Zhou
- GCP Center/Institute of Drug Clinical Trials, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Dan Feng
- GCP Center/Institute of Drug Clinical Trials, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Institute of Pharmacy, North Sichuan Medical College, Nanchong, China
| | - Daiyuan Ma
- GCP Center/Institute of Drug Clinical Trials, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| |
Collapse
|
|
33
|
Wang D, Han Y, Peng L, Huang T, He X, Wang J, Ou C. Crosstalk between N6-methyladenosine (m6A) modification and noncoding RNA in tumor microenvironment. Int J Biol Sci 2023; 19:2198-2219. [PMID: 37151887 PMCID: PMC10158024 DOI: 10.7150/ijbs.79651] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 04/05/2023] [Indexed: 05/09/2023] Open
Abstract
N6-methyladenosine (m6A) is the most abundant RNA modification in eukaryotes, and it participates in the regulation of pathophysiological processes in various diseases, including malignant tumors, by regulating the expression and function of both coding and non-coding RNAs (ncRNAs). More and more studies demonstrated that m6A modification regulates the production, stability, and degradation of ncRNAs and that ncRNAs also regulate the expression of m6A-related proteins. Tumor microenvironment (TME) refers to the internal and external environment of tumor cells, which is composed of numerous tumor stromal cells, immune cells, immune factors, and inflammatory factors that are closely related to tumors occurrence and development. Recent studies have suggested that crosstalk between m6A modifications and ncRNAs plays an important role in the biological regulation of TME. In this review, we summarized and analyzed the effects of m6A modification-associated ncRNAs on TME from various perspectives, including tumor proliferation, angiogenesis, invasion and metastasis, and immune escape. Herein, we showed that m6A-related ncRNAs can not only be expected to become detection markers of tumor tissue samples, but can also be wrapped into exosomes and secreted into body fluids, thus exhibiting potential as markers for liquid biopsy. This review provides a deeper understanding of the relationship between m6A-related ncRNAs and TME, which is of great significance to the development of a new strategy for precise tumor therapy.
Collapse
Affiliation(s)
- Dan Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Yingying Han
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Lushan Peng
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Tao Huang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Xiaoyun He
- Departments of Ultrasound Imaging, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Junpu Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
- Department of Pathology, School of Basic Medicine, Central South University, Changsha 410031, Hunan, China
- Key Laboratory of Hunan Province in Neurodegenerative Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| |
Collapse
|
|
34
|
Khadela A, Chavda VP, Postwala H, Ephraim R, Apostolopoulos V, Shah Y. Configuring Therapeutic Aspects of Immune Checkpoints in Lung Cancer. Cancers (Basel) 2023; 15:543. [PMID: 36672492 PMCID: PMC9856297 DOI: 10.3390/cancers15020543] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/25/2022] [Accepted: 01/13/2023] [Indexed: 01/18/2023] Open
Abstract
Immune checkpoints are unique components of the body's defense mechanism that safeguard the body from immune responses that are potent enough to harm healthy body cells. When proteins present on the surface of T cells recognize and bind to the proteins present on other tumor cells, immune checkpoints are triggered. These proteins are called immunological checkpoints. The T cells receive an on/off signal when the checkpoints interact with companion proteins. This might avert the host's immune system from eliminating cancer cells. The standard care plan for the treatment of non-small cell lung cancer (NSCLC) has been revolutionized with the use of drugs targeting immune checkpoints, in particular programmed cell death protein 1. These drugs are now extended for their potential to manage SCLC. However, it is acknowledged that these drugs have specific immune related adverse effects. Herein, we discuss the use of immune checkpoint inhibitors in patients with NSCLC and SCLC, their outcomes, and future perspectives.
Collapse
Affiliation(s)
- Avinash Khadela
- Department of Pharmacology, L. M. College of Pharmacy, Navrangpura, Ahmedabad 380009, Gujarat, India
| | - Vivek P. Chavda
- Department of Pharmaceutics and Pharmaceutical Technology, L. M. College of Pharmacy, Navrangpura, Ahmedabad 380009, Gujarat, India
| | - Humzah Postwala
- Pharm. D Section, L. M. College of Pharmacy, Navrangpura, Ahmedabad 380009, Gujarat, India
| | - Ramya Ephraim
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia
| | - Vasso Apostolopoulos
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia
- Australian Institute for Musculoskeletal Science, Melbourne, VIC 3021, Australia
| | - Yesha Shah
- Pharm. D Section, L. M. College of Pharmacy, Navrangpura, Ahmedabad 380009, Gujarat, India
| |
Collapse
|
|
35
|
Luaibi AR, Al-Saffar M, Jalil AT, Rasol MA, Fedorovich EV, Saleh MM, Ahmed OS. Long non-coding RNAs: The modulators of innate and adaptive immune cells. Pathol Res Pract 2023; 241:154295. [PMID: 36608622 DOI: 10.1016/j.prp.2022.154295] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/27/2022] [Accepted: 12/27/2022] [Indexed: 12/31/2022]
Abstract
Before very sensitive current genomics platforms were discovered, long non-coding RNAs (lncRNAs) as controllers of gene expression, were thought to be accumulated genetic garbage. The past few years have seen a lot of interest in a large classification of non-coding transcripts with an indeterminate length of more than 200 nucleotides [1]. lncRNAs' association with immunity and disease progression has been revealed by a growing body of experimental research. Only a limited subset of lncRNAs, however, has solid proof of their role. It is also clear that various immune cells express lncRNAs differently. In this review, we concentrated on the role of lncRNA expression in the regulation of immune cell function and response to pathological conditions in macrophages, dendritic cells, natural killer (NK) cells, neutrophils, Myeloid-derived suppressor cells (MDSCs), T cells, and B cells. The innate and adaptive immune response systems may be significantly regulated by lncRNAs, according to emerging research. To discover possible therapeutic targets for the therapy of different diseases, it may be helpful to have a better realization of the molecular mechanisms beyond the role of lncRNAs in the immune response. Therefore, it is crucial to investigate lncRNA expression and comprehend its significance for the immune system.
Collapse
Affiliation(s)
- Aseel Riyadh Luaibi
- Utbah bin Ghazwan High School for Girls, Al_Karkh first Directorate of Education, Ministry of Education, Baghdad, Iraq
| | - Montaha Al-Saffar
- Community Health Department, Institute of Medical Technology /Baghdad, Middle Technical University, Baghdad, Iraq
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq.
| | - Mustafa Asaad Rasol
- College of Dentistry, National University of Science and Technology, Dhi Qar, Iraq
| | - Eremin Vladimir Fedorovich
- Republican Scientific and Practical Center for Transfusiology and Medical, Biotechnologies, Minsk, Belarus
| | - Marwan Mahmood Saleh
- Department of Biophysics, College of Applied Sciences, University of Anbar, Ramadi, Iraq; Department of Medical Laboratory Technology, College of Medical Technology, The Islamic University, Najaf, Iraq
| | | |
Collapse
|
|
36
|
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.
Collapse
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.)
| |
Collapse
|
|
37
|
Zhang W, Ji K, Min C, Zhang C, Yang L, Zhang Q, Tian Z, Zhang M, Wang X, Li X. Oncogenic LINC00857 recruits TFAP2C to elevate FAT1 expression in gastric cancer. Cancer Sci 2022; 114:63-74. [PMID: 35524544 PMCID: PMC9807510 DOI: 10.1111/cas.15394] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 03/30/2022] [Accepted: 04/29/2022] [Indexed: 01/07/2023] Open
Abstract
FAT atypical cadherin 1 (FAT1) is a mutant gene frequently found in human cancers and mainly accumulates at the plasma membrane of cancer cells. Emerging evidence has implicated FAT1 in the progression of gastric cancer (GC). This study intended to identify a regulatory network related to FAT1 in GC development. Upregulated expression of FAT1 was confirmed in GC tissues, and silencing FAT1 was observed to result in suppression of GC cell oncogenic phenotypes. Mechanistic investigation results demonstrated that FAT1 upregulated AP-1 expression by phosphorylating c-JUN and c-FOS, whereas LINC00857 elevated the expression of FAT1 by recruiting a transcription factor TFAP2C. Functional experiments further suggested that LINC00857 enhanced the malignant biological characteristics of GC cells through TFAP2C-mediated promotion of FAT1. More importantly, LINC00857 silencing delayed the tumor growth and blocked epithelial-mesenchymal transition in tumor-bearing mice, which was associated with downregulated expression of TFAP2C/FAT1. To conclude, LINC00857 plays an oncogenic role in GC through regulating the TFAP2C/FAT1/AP-1 axis. Therefore, this study contributes to extended the understanding of gastric carcinogenesis and LINC00857 may serve as a therapeutic target for GC.
Collapse
Affiliation(s)
- Wenqing Zhang
- Department of GastroenterologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Kaiyue Ji
- Department of GastroenterologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | | | - Cuiping Zhang
- Department of GastroenterologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Lin Yang
- Department of GastroenterologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Qi Zhang
- Department of GastroenterologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Zibin Tian
- Department of GastroenterologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Mengyuan Zhang
- Department of GastroenterologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Xinyu Wang
- Department of GastroenterologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Xiaoyu Li
- Department of GastroenterologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| |
Collapse
|
|
38
|
Li R, Jin C, Zhao W, Liang R, Xiong H. Development of a novel immune-related lncRNA prognostic signature for patients with hepatocellular carcinoma. BMC Gastroenterol 2022; 22:450. [PMID: 36344926 PMCID: PMC9639314 DOI: 10.1186/s12876-022-02540-2] [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: 06/06/2022] [Accepted: 10/14/2022] [Indexed: 11/09/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common neoplasm and the major cause of cancer-associated death worldwide. The high mortality rate of HCC is mainly attributed to its widespread prevalence and the lack of effective treatment. Immunotherapy as a promising, innovative approach has revolutionised the treatment of solid tumours. However, owing to the heterogeneity and complex tumour microenvironment of HCC, an efficient biomarker for immunotherapy has yet to be identified. We investigated the role of immune-related long non-coding RNAs (lncRNAs) as prognostic biomarkers in patients with HCC from The Cancer Genome Atlas (TCGA) database. Spearman correlation, univariate and multivariate Cox, and lasso regression analyses were utilised to screen lncRNAs associated with prognosis. Four lncRNAs were filtered out to develop an immune-associated lncRNA prognostic signature in TCGA training as well as validation cohorts. Patients with HCC were then categorised into low- and high-risk groups according to the median value of the risk scores to evaluate the ability of the prognostic model between training and validation cohorts. A nomogram (based on risk score and stage) was constructed to appraise the general overall survival (OS) of patients with HCC. Differences in immune cell infiltration, immune checkpoint inhibitor (ICI) treatment response, gene mutation, and drug sensitivity were observed between the two groups. Thus, the lncRNA prognostic signature can serve as a sensitive prognostic biomarker with potential in individualised immunotherapy for HCC patients.
Collapse
Affiliation(s)
- Rui Li
- grid.33199.310000 0004 0368 7223Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei China
| | - Chen Jin
- grid.268099.c0000 0001 0348 3990Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang China
| | - Weiheng Zhao
- grid.33199.310000 0004 0368 7223Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei China
| | - Rui Liang
- grid.190737.b0000 0001 0154 0904Biological Engineering Academy, Chongqing University, Chongqing, China
| | - Huihua Xiong
- grid.33199.310000 0004 0368 7223Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei China
| |
Collapse
|
|
39
|
Harkus U, Wankell M, Palamuthusingam P, McFarlane C, Hebbard L. Immune checkpoint inhibitors in HCC: Cellular, molecular and systemic data. Semin Cancer Biol 2022; 86:799-815. [PMID: 35065242 DOI: 10.1016/j.semcancer.2022.01.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/12/2022] [Accepted: 01/17/2022] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related deaths in the world, and for patients with advanced disease there are few therapeutic options available. The complex immunological microenvironment of HCC and the success of immunotherapy in several types of tumours, has raised the prospect of potential benefit for immune based therapies, such as immune checkpoint inhibitors (ICIs), in HCC. This has led to significant breakthrough research, numerous clinical trials and the rapid approval of multiple systemic drugs for HCC by regulatory bodies worldwide. Although some patients responded well to ICIs, many have failed to achieve significant benefit, while others showed unexpected and paradoxical deterioration. The aim of this review is to discuss the pathophysiology of HCC, the tumour microenvironment, key clinical trials evaluating ICIs in HCC, various resistance mechanisms to ICIs, and possible ways to overcome these impediments to improve patient outcomes.
Collapse
Affiliation(s)
- Uasim Harkus
- Townsville University Hospital, Townsville, Queensland 4811, Australia
| | - Miriam Wankell
- Department of Molecular and Cell Biology, College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Medicine and Health, James Cook University, Townsville, Queensland 4811, Australia
| | - Pranavan Palamuthusingam
- College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia; Townsville University Hospital, Townsville, Queensland 4811, Australia; Mater Hospital, Townsville, Queensland 4811, Australia
| | - Craig McFarlane
- Department of Molecular and Cell Biology, College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Medicine and Health, James Cook University, Townsville, Queensland 4811, Australia
| | - Lionel Hebbard
- Department of Molecular and Cell Biology, College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Medicine and Health, James Cook University, Townsville, Queensland 4811, Australia; Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales 2145, Australia.
| |
Collapse
|
|
40
|
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.
Collapse
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,
| |
Collapse
|
|
41
|
Li K, Wang Z. Non-coding RNAs: Key players in T cell exhaustion. Front Immunol 2022; 13:959729. [PMID: 36268018 PMCID: PMC9577297 DOI: 10.3389/fimmu.2022.959729] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 09/16/2022] [Indexed: 11/13/2022] Open
Abstract
T cell exhaustion caused by continuous antigen stimulation in chronic viral infections and the tumor microenvironment is a major barrier to successful elimination of viruses and tumor cells. Although immune checkpoint inhibitors should reverse T cell exhaustion, shortcomings, such as off-target effects and single targets, limit their application. Therefore, it is important to identify molecular targets in effector T cells that simultaneously regulate the expression of multiple immune checkpoints. Over the past few years, non-coding RNAs, including microRNAs and long non-coding RNAs, have been shown to participate in the immune response against viral infections and tumors. In this review, we focus on the roles and underlying mechanisms of microRNAs and long non-coding RNAs in the regulation of T cell exhaustion during chronic viral infections and tumorigenesis. We hope that this review will stimulate research to provide more precise and effective immunotherapies against viral infections and tumors.
Collapse
Affiliation(s)
- Kun Li
- Department of Nuclear Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Ziqiang Wang
- Department of Nuclear Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
- *Correspondence: Ziqiang Wang,
| |
Collapse
|
|
42
|
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: 17] [Impact Index Per Article: 5.7] [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.
Collapse
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.)
| |
Collapse
|
|
43
|
Xie X, Liang H, Ruan Q, Ma X, Xie C, Luo Z, Tang L, Cheng L, Wang T. Comprehensive analysis of N6-methyladenosine-related lncRNAs reveals distinct hepatocellular carcinoma subtypes with immunotherapeutic implications. Am J Transl Res 2022; 14:6504-6520. [PMID: 36247272 PMCID: PMC9556473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 08/02/2022] [Indexed: 06/16/2023]
Abstract
Accumulating studies have demonstrated critical roles of N6-methyladenosine (m6A) modification and long noncoding RNAs (lncRNAs) in the biological processes leading to occurrence, development and chemoresistance of cancers. However, the specific identities and functional roles of lncRNAs associated with m6A modification in hepatocellular carcinoma (HCC) remain elusive. In this study, eighty-two prognostic m6A-related lncRNAs (m6A-LncRNAs) were identified in HCC datasets. Patients with HCC were classified into three subtypes (C1, C2 and C3) based on the expression of the m6A-LncRNAs. The three subtypes showed significant differences in clinical features, immune and stromal infiltration signatures, and immunotherapy sensitivity. Subclass C1 was notable for high immune and stromal cell infiltration and active immune responses, low serum α-fetoprotein (AFP) levels and high sensitivity to immune checkpoint inhibitors (ICIs). Subclass C2 showed high metabolic activities and absence of immune infiltration with favorable prognosis. Subclass C3 was associated with an exhausted immune environment, high serum AFP and poor prognosis. Notably, subclass C3 displayed high expression of immune checkpoints but failed to respond to ICIs. Finally, 12 m6A-LncRNA signatures were identified for HCC classification and validated in an external dataset. This integrated analysis indicated that the interactions between m6A methylation and lncRNAs are involved in immune and stromal cell infiltration in HCC, and may provide novel insights into precision diagnostics as well as therapeutics for HCC patients.
Collapse
Affiliation(s)
- Xiaodong Xie
- Department of General Surgery, The General Hospital of Western Theater Command (Chengdu Military General Hospital)Chengdu 610083, Sichuan Province, China
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital)Chengdu 610083, Sichuan Province, China
| | - Hongyin Liang
- Department of General Surgery, The General Hospital of Western Theater Command (Chengdu Military General Hospital)Chengdu 610083, Sichuan Province, China
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital)Chengdu 610083, Sichuan Province, China
| | - Qing Ruan
- Department of General Surgery, The General Hospital of Western Theater Command (Chengdu Military General Hospital)Chengdu 610083, Sichuan Province, China
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital)Chengdu 610083, Sichuan Province, China
| | - Xiao Ma
- Department of General Surgery, The General Hospital of Western Theater Command (Chengdu Military General Hospital)Chengdu 610083, Sichuan Province, China
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital)Chengdu 610083, Sichuan Province, China
| | - Chuan Xie
- Department of General Surgery, The General Hospital of Western Theater Command (Chengdu Military General Hospital)Chengdu 610083, Sichuan Province, China
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital)Chengdu 610083, Sichuan Province, China
| | - Zhulin Luo
- Department of General Surgery, The General Hospital of Western Theater Command (Chengdu Military General Hospital)Chengdu 610083, Sichuan Province, China
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital)Chengdu 610083, Sichuan Province, China
| | - Lijun Tang
- Department of General Surgery, The General Hospital of Western Theater Command (Chengdu Military General Hospital)Chengdu 610083, Sichuan Province, China
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital)Chengdu 610083, Sichuan Province, China
| | - Long Cheng
- Department of General Surgery, The General Hospital of Western Theater Command (Chengdu Military General Hospital)Chengdu 610083, Sichuan Province, China
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital)Chengdu 610083, Sichuan Province, China
| | - Tao Wang
- Department of General Surgery, The General Hospital of Western Theater Command (Chengdu Military General Hospital)Chengdu 610083, Sichuan Province, China
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital)Chengdu 610083, Sichuan Province, China
| |
Collapse
|
|
44
|
Zhong Y, Ashley CL, Steain M, Ataide SF. Assessing the suitability of long non-coding RNAs as therapeutic targets and biomarkers in SARS-CoV-2 infection. Front Mol Biosci 2022; 9:975322. [PMID: 36052163 PMCID: PMC9424846 DOI: 10.3389/fmolb.2022.975322] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 07/20/2022] [Indexed: 11/13/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) are RNA transcripts that are over 200 nucleotides and rarely encode proteins or peptides. They regulate gene expression and protein activities and are heavily involved in many cellular processes such as cytokine secretion in respond to viral infection. In severe COVID-19 cases, hyperactivation of the immune system may cause an abnormally sharp increase in pro-inflammatory cytokines, known as cytokine release syndrome (CRS), which leads to severe tissue damage or even organ failure, raising COVID-19 mortality rate. In this review, we assessed the correlation between lncRNAs expression and cytokine release syndrome by comparing lncRNA profiles between COVID-19 patients and health controls, as well as between severe and non-severe cases. We also discussed the role of lncRNAs in CRS contributors and showed that the lncRNA profiles display consistency with patients’ clinic symptoms, thus suggesting the potential of lncRNAs as drug targets or biomarkers in COVID-19 treatment.
Collapse
Affiliation(s)
- Yichen Zhong
- School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, Australia
| | - Caroline L. Ashley
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Megan Steain
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Sandro Fernandes Ataide
- School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, Australia
- *Correspondence: Sandro Fernandes Ataide,
| |
Collapse
|
|
45
|
He Q, Guo P, Bo Z, Yu H, Yang J, Wang Y, Chen G. Noncoding RNA-mediated molecular bases of chemotherapy resistance in hepatocellular carcinoma. Cancer Cell Int 2022; 22:249. [PMID: 35945536 PMCID: PMC9361533 DOI: 10.1186/s12935-022-02643-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 06/27/2022] [Indexed: 11/10/2022] Open
Abstract
Despite the significant progress in decreasing the occurrence and mortality of hepatocellular carcinoma (HCC), it remains a public health issue worldwide on the basis of its late presentation and tumor recurrence. To date, apart from surgical interventions, such as surgical resection, liver transplantation and locoregional ablation, current standard antitumor protocols include conventional cytotoxic chemotherapy. However, due to the high chemoresistance nature, most current therapeutic agents show dismal outcomes for this refractory malignancy, leading to disease relapse. Nevertheless, the molecular mechanisms involved in chemotherapy resistance remain systematically ambiguous. Herein, HCC is hierarchically characterized by the formation of primitive cancer stem cells (CSCs), progression of epithelial-mesenchymal transition (EMT), unbalanced autophagy, delivery of extracellular vesicles (EVs), escape of immune surveillance, disruption of ferroptosis, alteration of the tumor microenvironment and multidrug resistance-related signaling pathways that mediate the multiplicity and complexity of chemoresistance. Of note, anecdotal evidence has corroborated that noncoding RNAs (ncRNAs) extensively participate in the critical physiological processes mentioned above. Therefore, understanding the detailed regulatory bases that underlie ncRNA-mediated chemoresistance is expected to yield novel insights into HCC treatment. In the present review, a comprehensive summary of the latest progress in the investigation of chemotherapy resistance concerning ncRNAs will be elucidated to promote tailored individual treatment for HCC patients.
Collapse
Affiliation(s)
- Qikuan He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Pengyi Guo
- Department of Cardiothoracic Surgery, Ningbo Yinzhou No. 2 Hospital, Ningbo, 315199, Zhejiang, China
| | - Zhiyuan Bo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Haitao Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Jinhuan Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Yi Wang
- Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Gang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
| |
Collapse
|
|
46
|
Comprehensive Analysis of LINC01615 in Head and Neck Squamous Cell Carcinoma: A Hub Biomarker Identified by Machine Learning and Experimental Validation. JOURNAL OF ONCOLOGY 2022; 2022:5039962. [PMID: 35794984 PMCID: PMC9252709 DOI: 10.1155/2022/5039962] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 05/27/2022] [Accepted: 05/28/2022] [Indexed: 11/17/2022]
Abstract
Background Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers, but in clinical practice, the lack of precise biomarkers often results in an advanced diagnosis. Hence, it is crucial to explore novel biomarkers to improve the clinical outcome of HNSCC patients. Methods We downloaded RNA-seq data consisting of 502 HNSCC tissues and 44 normal tissues from the TCGA database, and lncRNA genomic sequence information was downloaded from the GENECODE database for annotating lncRNA expression profiles. We used Cox regression analysis to screen prognostic lncRNAs, the threshold as HR >1 and p value <0.05. Subsequently, three survival outcomes (overall survival, progress-free interval, and disease-specific survival)-related lncRNAs overlapped to get the common lncRNAs. The hub biomarker was identified using LASSO and random forest models. Subsequently, we used a variety of statistical methods to validate the prognostic ability of the hub marker. In addition, Spearman correlation analysis between the hub marker expression and genomic heterogeneity was conducted, such as instability (MSI), homologous recombination deficiency (HRD), and tumor mutational burden (TMB). Finally, we used enrichment analysis, ssGSEA, and ESTIMATE algorithms to explore the changes in the underlying immune-related pathway and function. Finally, the MTT assay and transwell assay were performed to determine the effect of LINC01615 silencing on tumor cell proliferation, invasion, and migration. Results Cox regression analysis revealed 133 lncRNAs with multiple prognostic significance. The machine learning algorithm screened out the hub lncRNA with the highest importance in the RF model: LINC01615. Clinical correlation analysis revealed that the LINC01615 increased with increasing the T stage, N stage, pathology grade, and clinical stage. LINC01615 could be used as a predictor of HNSCC prognosis validating by a variety of statistical methods. Subsequently, when clinical indicators were combined with the LINC01615 expression, the visualization model (nomogram) was more applicable to clinical practice. Finally, immune algorithms indicated that LINC01615 may be involved in the regulation of lymphocyte recruitment and immunological infiltration in HNSCC, and the LINC01615 expression represented genomic heterogeneity in pan-cancer. Functionally, silencing of LINC01615 suppresses cell proliferation, invasion, and migration in HEP-2 and TU212 cells. Conclusion LINC01615 may play an important role in the prostromal cell enrichment and immunosuppressive state and serve as a prognostic biomarker in HNSCC.
Collapse
|
|
47
|
Liang YL, Zhang Y, Tan XR, Qiao H, Liu SR, Tang LL, Mao YP, Chen L, Li WF, Zhou GQ, Zhao Y, Li JY, Li Q, Huang SY, Gong S, Zheng ZQ, Li ZX, Sun Y, Jiang W, Ma J, Li YQ, Liu N. A lncRNA signature associated with tumor immune heterogeneity predicts distant metastasis in locoregionally advanced nasopharyngeal carcinoma. Nat Commun 2022; 13:2996. [PMID: 35637194 PMCID: PMC9151760 DOI: 10.1038/s41467-022-30709-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 05/12/2022] [Indexed: 12/24/2022] Open
Abstract
Increasing evidence has revealed the roles of long noncoding RNAs (lncRNAs) as tumor biomarkers. Here, we introduce an immune-associated nine-lncRNA signature for predicting distant metastasis in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). The nine lncRNAs are identified through microarray profiling, followed by RT-qPCR validation and selection using a machine learning method in the training cohort (n = 177). This nine-lncRNA signature classifies patients into high and low risk groups, which have significantly different distant metastasis-free survival. Validations in the Guangzhou internal (n = 177) and Guilin external (n = 150) cohorts yield similar results, confirming that the signature is an independent risk factor for distant metastasis and outperforms anatomy-based metrics in identifying patients with high metastatic risk. Integrative analyses show that this nine-lncRNA signature correlates with immune activity and lymphocyte infiltration, which is validated by digital pathology. Our results suggest that the immune-associated nine-lncRNA signature can serve as a promising biomarker for metastasis prediction in LA-NPC.
Collapse
Affiliation(s)
- Ye-Lin Liang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| | - Yuan Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| | - Xi-Rong Tan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Han Qiao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Song-Ran Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ling-Long Tang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| | - Yan-Ping Mao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| | - Lei Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| | - Wen-Fei Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| | - Guan-Qun Zhou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| | - Yin Zhao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jun-Yan Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| | - Qian Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| | - Sheng-Yan Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Sha Gong
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zi-Qi Zheng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| | - Zhi-Xuan Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| | - Ying Sun
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| | - Wei Jiang
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, Guilin, China.
| | - Jun Ma
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China.
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China.
| | - Ying-Qin Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China.
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China.
| | - Na Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China.
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China.
| |
Collapse
|
|
48
|
Xue C, Gu X, Bao Z, Su Y, Lu J, Li L. The Mechanism Underlying the ncRNA Dysregulation Pattern in Hepatocellular Carcinoma and Its Tumor Microenvironment. Front Immunol 2022; 13:847728. [PMID: 35281015 PMCID: PMC8904560 DOI: 10.3389/fimmu.2022.847728] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/04/2022] [Indexed: 12/16/2022] Open
Abstract
HCC is one of the most common malignant tumors and has an extremely poor prognosis. Accumulating studies have shown that noncoding RNA (ncRNA) plays an important role in hepatocellular carcinoma (HCC) development. However, the details of the related mechanisms remain unclear. The heterogeneity of the tumor microenvironment (TME) calls for ample research with deep molecular characterization, with the hope of developing novel biomarkers to improve prognosis, diagnosis and treatment. ncRNAs, particularly microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), have been found to be correlated with HCC neogenesis and progression. In this review, we summarized the aberrant epigenetic and genetic alterations caused by dysregulated ncRNAs and the functional mechanism of classical ncRNAs in the regulation of gene expression. In addition, we focused on the role of ncRNAs in the TME in the regulation of tumor cell proliferation, invasion, migration, immune cell infiltration and functional activation. This may provide a foundation for the development of promising potential prognostic/predictive biomarkers and novel therapies for HCC patients.
Collapse
Affiliation(s)
- Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xinyu Gu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhengyi Bao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yuanshuai Su
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| |
Collapse
|
|
49
|
Noncoding RNAs as novel immunotherapeutic tools against cancer. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2022; 129:135-161. [PMID: 35305717 DOI: 10.1016/bs.apcsb.2021.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Immunotherapy is implemented as an important treatment strategy in various malignancies. In cancer, immunotherapy is employed for successful killing of tumor cells with high specificity and greater efficacy, with minimum side effects. Despite various available strategies, cellular immunotherapy including innate (NK cells, macrophages, dendritic cells) and adaptive (B cells and T cells) immune cells plays a critical role in tumor microenvironment. Since past few years, many drugs targeting immune checkpoint proteins including CTLA-4 and PD-1/PD-L1 have been investigated as immunotherapy approach against cancer but complete effectiveness still remains a question, as diverse mechanisms involved in tumorigenesis may result in the development of cancer cell resistance. Number of evidences have highlighted the significant role of non-coding RNAs (ncRNAs) in regulating multiple stages of cancer initiation, progression & immunity. ncRNAs comprises 98% human transcriptome and are basically considered as dark genome. Among ncRNAs, miRNAs and lncRNAs have been extensively studied in regulating diverse processes of cancer tumorigenesis. Upregulation of oncogenic and downregulation of tumor suppressive miRNAs/lncRNAs has been reported to facilitate the cancer progression and invasiveness. This chapter summarizes how an interplay between ncRNAs and immune cells in cancer pathogenesis can be therapeutically targeted to improve current treatment regimen. Strategies should be employed to improve the efficacy and reduce off-target effects of ncRNA based immunotherapy. Henceforth, combination of ncRNAs and available immunotherapy can be argued to enhance the efficacy of existing immunotherapeutic approaches against cancer to improve patient's survival.
Collapse
|
|
50
|
Xiao X, Cheng W, Zhang G, Wang C, Sun B, Zha C, Kong F, Jia Y. Long Noncoding RNA: Shining Stars in the Immune Microenvironment of Gastric Cancer. Front Oncol 2022; 12:862337. [PMID: 35402261 PMCID: PMC8989925 DOI: 10.3389/fonc.2022.862337] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 03/03/2022] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is a kind of malignant tumor disease that poses a serious threat to human health. The GC immune microenvironment (TIME) is a very complex tumor microenvironment, mainly composed of infiltrating immune cells, extracellular matrix, tumor-associated fibroblasts, cytokines and chemokines, all of which play a key role in inhibiting or promoting tumor development and affecting tumor prognosis. Long non-coding RNA (lncRNA) is a non-coding RNA with a transcript length is more than 200 nucleotides. LncRNAs are expressed in various infiltrating immune cells in TIME and are involved in innate and adaptive immune regulation, which is closely related to immune escape, migration and invasion of tumor cells. LncRNA-targeted therapeutic effect prediction for GC immunotherapy provides a new approach for clinical research on the disease.
Collapse
Affiliation(s)
- Xian Xiao
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.,Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wen Cheng
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.,Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Guixing Zhang
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.,Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Chaoran Wang
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.,Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Binxu Sun
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Chunyuan Zha
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.,Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Fanming Kong
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yingjie Jia
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| |
Collapse
|