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Ding YP, Liu CC, Yu KD. RNA modifications in the tumor microenvironment: insights into the cancer-immunity cycle and beyond. Exp Hematol Oncol 2025; 14:48. [PMID: 40176140 PMCID: PMC11963313 DOI: 10.1186/s40164-025-00648-1] [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: 11/19/2024] [Accepted: 03/24/2025] [Indexed: 04/04/2025] Open
Abstract
The chemical modification of biological molecules is a critical regulatory mechanism for controlling molecular functions. Although research has long focused on DNA and proteins, RNA modifications have recently attracted substantial interest with the advancement in detection technologies. In oncology, many studies have identified dysregulated RNA modifications including m6A, m1A, m5C, m7G, pseudouridylation and A to I editing, leading to disrupted downstream pathways. As the concept of the tumor microenvironment has gained prominence, studies have increasingly examined the role of RNA modifications in this context, focusing on interactions among cancer cells, immune cells, stromal cells, and other components. Here we review the RNA modifications in the tumor microenvironment through the perspective of the Cancer-Immunity Cycle. The extracellular RNA modifications including exosomes and influence of microbiome in RNA modifications are potential research questions. Additionally, RNA modifying enzymes including FTO, ALKBH5, METTL3, PUS7 are under investigation as potential biomarkers and targets for combination with immunotherapies. ADCs and mimetics of modified RNA could be potential novel drugs. This review discusses the regulatory roles of RNA modifications within the tumor microenvironment.
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Affiliation(s)
- You-Peng Ding
- Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Cui-Cui Liu
- Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Ke-Da Yu
- Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
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Sun L, Huangfu L, Li F, Yan Y, Kong R, Ji K, Li J. Identification and functional characterization of m1A-related genes in colorectal cancer: implications for prognosis, immune infiltration, and therapeutic strategies. Front Oncol 2025; 15:1532602. [PMID: 40040720 PMCID: PMC11876182 DOI: 10.3389/fonc.2025.1532602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 01/24/2025] [Indexed: 03/06/2025] Open
Abstract
Introduction Colorectal cancer (CRC), characterized by its complex genetic heterogeneity and varied responses to treatment, is a leading cause of cancer-related mortality worldwide. The role of N1-methyladenosine (m1A)-related genes in tumor biology remains underexplored. This study aimed to investigate the prognostic value of m1A-related genes in CRC, characterize their role in tumor molecular subtyping, and explore their influence on the tumor microenvironment (TME) and immune infiltration. Methods To identify prognostic markers, univariate Cox analysis was performed using multiple datasets, including TCGA and GEO, identifying 43 m1A-related genes. Four distinct molecular subtypes of CRC were defined based on the expression of these genes using non-negative matrix factorization (NMF). Immune infiltration analysis was conducted, and the TIDE algorithm was used to predict response to immune checkpoint inhibitors (ICIs). Furthermore, a prognostic model based on m1A-related genes was constructed and validated across multiple datasets. Results The results demonstrated that the four CRC molecular subtypes exhibited significant differences in survival outcomes and clinical characteristics. Stromal cells showed higher m1A scores, suggesting a regulatory role in the TME. There was a positive correlation between m1A-related gene expression and immune checkpoint genes. Moreover, the constructed prognostic model showed robust predictive performance and outperformed other recently published models. Discussion The findings suggest that m1A-related genes are not only valuable biomarkers for CRC prognosis but also have significant implications for the immune landscape and could serve as potential targets for therapeutic intervention, particularly in the context of immunotherapy. For instance, SLC12A2 was found to enhance invasion, proliferation, and migration of colorectal cancer cells while inhibiting apoptosis. Further studies are needed to understand the functional roles of m1A modifications across different cell types within the TME.
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Affiliation(s)
- Lan Sun
- Department of Pharmaceutical Engineering, Jiangsu Food and Pharmaceutical Science College, Huaian, Jiangsu, China
| | - Liwei Huangfu
- Department of Pharmaceutical Engineering, Jiangsu Food and Pharmaceutical Science College, Huaian, Jiangsu, China
| | - Fang Li
- State Key Laboratory of New-tech For Chinese Medicine Pharmaceutic Process, Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, Jiangsu, China
| | - Yuhui Yan
- Department of Pharmaceutical Engineering, Jiangsu Food and Pharmaceutical Science College, Huaian, Jiangsu, China
| | - Ruiping Kong
- Department of Pharmaceutical Engineering, Jiangsu Food and Pharmaceutical Science College, Huaian, Jiangsu, China
| | - Kun Ji
- Department of Pharmaceutical Engineering, Jiangsu Food and Pharmaceutical Science College, Huaian, Jiangsu, China
| | - Jiachun Li
- Department of Grain and Food Pharmacy, Jiangsu Vocational College of Finance and Economics, Huaian, Jiangsu, China
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Huang X, Lu J, Deng C, Tang W, Wang X, Zhou H, Zhang J, Cheng J, Li S, He J, Ruan J. Association between TRMT61B gene polymorphism and Wilms tumor susceptibility in Chinese children. BMC Cancer 2025; 25:260. [PMID: 39953499 PMCID: PMC11827147 DOI: 10.1186/s12885-025-13670-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 02/06/2025] [Indexed: 02/17/2025] Open
Abstract
BACKGROUND Wilms tumor is among the most common pediatric malignant tumors. Although m1A modification influences the structure and function of RNA and participates in tumorigenesis, the relationship between m1A methyltransferase TRMT61B gene polymorphisms and Wilms tumor susceptibility is unclear. METHODS We examined the relationship between TRMT61B gene rs4563180 G > C polymorphism (detected by TaqMan probe method) in 414 children with Wilms tumor and 1199 healthy controls. The relationship between the genotype of each sublayer and the risk of Wilms tumor was studied by stratified analysis. The GTEx database was used to analyze the influence of TRMT61B rs4563180 G > C polymorphism on mRNA expression. RESULTS The TRMT61B gene polymorphism significantly reduced the susceptibility to Wilms tumor (GC vs. GG: adjusted odds ratio [AOR] = 0.72, 95% confidence interval [CI] = 0.56-0.93, P = 0.012; GC/CC vs. GG: AOR = 0.76, 95% CI = 0.60-0.96, P = 0.021). GC/CC genotype had a protective effect in boys and children with stage III tumors compared with rs4563180 GG genotype. Additionally, the C allele was significantly associated with decreased mRNA expression of TRMT61B gene compared with rs4563180G allele in cultured fibroblasts (P = 3.3e - 80), EBV-transformed lymphocytes (P = 9.5e - 14), and whole blood (P = 6.0e - 12). CONCLUSIONS Our results confirm that TRMT61B gene is associated with the development of Wilms tumors, but its underlying mechanism requires further exploration.
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Affiliation(s)
- Xiaokai Huang
- Department of Hematology, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, 109 West Xueyuan Road, Wenzhou, 325027, Zhejiang, China
- The Key Laboratory of Pediatric Hematology and oncology Diseases of Wenzhou, the Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Jinyu Lu
- Department of Hematology, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, 109 West Xueyuan Road, Wenzhou, 325027, Zhejiang, China
| | - Changmi Deng
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou, 510623, Guangdong, China
| | - Weixian Tang
- Department of Hematology, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, 109 West Xueyuan Road, Wenzhou, 325027, Zhejiang, China
| | - Xilin Wang
- Department of Hematology, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, 109 West Xueyuan Road, Wenzhou, 325027, Zhejiang, China
| | - Haixia Zhou
- Department of Hematology, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, 109 West Xueyuan Road, Wenzhou, 325027, Zhejiang, China
- The Key Laboratory of Pediatric Hematology and oncology Diseases of Wenzhou, the Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Jiao Zhang
- Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Jiwen Cheng
- Department of Pediatric Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Suhong Li
- Department of Pathology, Children Hospital and Women Health Center of Shanxi, Taiyuan, 030013, Shannxi, China
| | - Jing He
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou, 510623, Guangdong, China.
| | - Jichen Ruan
- Department of Hematology, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, 109 West Xueyuan Road, Wenzhou, 325027, Zhejiang, China.
- The Key Laboratory of Pediatric Hematology and oncology Diseases of Wenzhou, the Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.
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Kim HS, Eun JW, Jang SH, Kim JY, Jeong JY. The diverse landscape of RNA modifications in cancer development and progression. Genes Genomics 2025; 47:135-155. [PMID: 39643826 DOI: 10.1007/s13258-024-01601-y] [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: 10/25/2024] [Accepted: 11/22/2024] [Indexed: 12/09/2024]
Abstract
BACKGROUND RNA modifications, a central aspect of epitranscriptomics, add a regulatory layer to gene expression by modifying RNA function without altering nucleotide sequences. These modifications play vital roles across RNA species, influencing RNA stability, translation, and interaction dynamics, and are regulated by specific enzymes that add, remove, and interpret these chemical marks. OBJECTIVE This review examines the role of aberrant RNA modifications in cancer progression, exploring their potential as diagnostic and prognostic biomarkers and as therapeutic targets. We focus on how altered RNA modification patterns impact oncogenes, tumor suppressor genes, and overall tumor behavior. METHODS We performed an in-depth analysis of recent studies and advances in RNA modification research, highlighting key types and functions of RNA modifications and their roles in cancer biology. Studies involving preclinical models targeting RNA-modifying enzymes were reviewed to assess therapeutic efficacy and potential clinical applications. RESULTS Aberrant RNA modifications were found to significantly influence cancer initiation, growth, and metastasis. Dysregulation of RNA-modifying enzymes led to altered gene expression profiles in oncogenes and tumor suppressors, correlating with tumor aggressiveness, patient outcomes, and response to immunotherapy. Notably, inhibitors of these enzymes demonstrated potential in preclinical models by reducing tumor growth and enhancing the efficacy of existing cancer treatments. CONCLUSIONS RNA modifications present promising avenues for cancer diagnosis, prognosis, and therapy. Understanding the mechanisms of RNA modification dysregulation is essential for developing targeted treatments that improve patient outcomes. Further research will deepen insights into these pathways and support the clinical translation of RNA modification-targeted therapies.
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Affiliation(s)
- Hyung Seok Kim
- Department of Biochemistry, Kosin University College of Medicine, Seo-Gu, Busan, 49267, South Korea
| | - Jung Woo Eun
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-Ro, Yeongtong-Gu, Suwon, 16499, South Korea
| | - Se Ha Jang
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-Ro, Yeongtong-Gu, Suwon, 16499, South Korea
| | - Ji Yun Kim
- Department of Biochemistry, Kosin University College of Medicine, Seo-Gu, Busan, 49267, South Korea
| | - Jee-Yeong Jeong
- Department of Biochemistry, Kosin University College of Medicine, Seo-Gu, Busan, 49267, South Korea.
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Wu H, Chen S, Li X, Li Y, Shi H, Qing Y, Shi B, Tang Y, Yan Z, Hao Y, Wang D, Liu W. RNA modifications in cancer. MedComm (Beijing) 2025; 6:e70042. [PMID: 39802639 PMCID: PMC11718328 DOI: 10.1002/mco2.70042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 11/12/2024] [Accepted: 11/14/2024] [Indexed: 01/16/2025] Open
Abstract
RNA modifications are emerging as critical cancer regulators that influence tumorigenesis and progression. Key modifications, such as N6-methyladenosine (m6A) and 5-methylcytosine (m5C), are implicated in various cellular processes. These modifications are regulated by proteins that write, erase, and read RNA and modulate RNA stability, splicing, translation, and degradation. Recent studies have highlighted their roles in metabolic reprogramming, signaling pathways, and cell cycle control, which are essential for tumor proliferation and survival. Despite these scientific advances, the precise mechanisms by which RNA modifications affect cancer remain inadequately understood. This review comprehensively examines the role RNA modifications play in cancer proliferation, metastasis, and programmed cell death, including apoptosis, autophagy, and ferroptosis. It explores their effects on epithelial-mesenchymal transition (EMT) and the immune microenvironment, particularly in cancer metastasis. Furthermore, RNA modifications' potential in cancer therapies, including conventional treatments, immunotherapy, and targeted therapies, is discussed. By addressing these aspects, this review aims to bridge current research gaps and underscore the therapeutic potential of targeting RNA modifications to improve cancer treatment strategies and patient outcomes.
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Affiliation(s)
- Han Wu
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
| | - Shi Chen
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
| | - Xiang Li
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
| | - Yuyang Li
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
| | - He Shi
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
| | - Yiwen Qing
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
| | - Bohe Shi
- Laboratory Animal CenterCollege of Animal ScienceJilin University, ChangchunJilin provinceChina
| | - Yifei Tang
- Laboratory Animal CenterCollege of Animal ScienceJilin University, ChangchunJilin provinceChina
| | - Zhuoyi Yan
- Laboratory Animal CenterCollege of Animal ScienceJilin University, ChangchunJilin provinceChina
| | - Yang Hao
- Laboratory Animal CenterCollege of Animal ScienceJilin University, ChangchunJilin provinceChina
| | - Dongxu Wang
- Laboratory Animal CenterCollege of Animal ScienceJilin University, ChangchunJilin provinceChina
| | - Weiwei Liu
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
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Wang X, Ma X, Chen S, Fan M, Jin C, Chen Y, Wang S, Wang Z, Meng F, Zhang C, Yang L. Harnessing m1A modification: a new frontier in cancer immunotherapy. Front Immunol 2024; 15:1517604. [PMID: 39687616 PMCID: PMC11647001 DOI: 10.3389/fimmu.2024.1517604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Accepted: 11/18/2024] [Indexed: 12/18/2024] Open
Abstract
N1-methyladenosine (m1A) modification is an epigenetic change that occurs on RNA molecules, regulated by a suite of enzymes including methyltransferases (writers), demethylases (erasers), and m1A-recognizing proteins (readers). This modification significantly impacts the function of RNA and various biological processes by affecting the structure, stability, translation, metabolism, and gene expression of RNA. Thereby, m1A modification is closely associated with the occurrence and progression of cancer. This review aims to explore the role of m1A modification in tumor immunity. m1A affects tumor immune responses by directly regulating immune cells and indirectly modulating tumor microenvironment. Besides, we also discuss the implications of m1A-mediated metabolic reprogramming and its nexus with immune checkpoint inhibitors, unveiling promising avenues for immunotherapeutic intervention. Additionally, the m1AScore, established based on the expression patterns of m1A modification, can be used to predict tumor prognosis and guide personalized therapy. Our review underscores the significance of m1A modification as a burgeoning frontier in cancer biology and immuno-oncology, with the potential to revolutionize cancer treatment strategies.
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Affiliation(s)
- Xinru Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Xiaoqing Ma
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Siyu Chen
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Minyan Fan
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Chenying Jin
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Yushi Chen
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Shaodong Wang
- Affiliated Nanjing Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, China
| | - Zhiying Wang
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, Shandong, China
| | - Fei Meng
- Department of Clinical Laboratory, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Chengwan Zhang
- Department of Central Laboratory, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai’an, Jiangsu, China
| | - Lin Yang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
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Tan Q, Zhou D, Guo Y, Chen H, Xie P. Identification of the m6A/m5C/m1A methylation modification genes in Alzheimer's disease based on bioinformatic analysis. Aging (Albany NY) 2024; 16:13340-13355. [PMID: 39485681 PMCID: PMC11719101 DOI: 10.18632/aging.206146] [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: 04/22/2024] [Accepted: 10/01/2024] [Indexed: 11/03/2024]
Abstract
BACKGROUND As a progressive neurodegenerative disease, the comprehensive understanding of the pathogenesis of Alzheimer's disease (AD) is yet to be clarified. Modifications in RNA, including m6A/m5C/m1A, affect the onset and progression of many diseases. Consequently, this study focuses on the role of methylation modification in the pathogenesis of AD. MATERIALS AND METHODS Three AD-related datasets, namely GSE33000, GSE122063, and GSE44770, were acquired from GEO. Differential analysis of m6A/m5C/m1A regulator genes was conducted. Applying a consensus clustering approach, distinct subtypes within AD were identified as per the expression patterns of relevant differentially expressed genes. Machine learning models were constructed to identify five significant genes from the best model. The analysis of hub gene-based drug regulatory networks and ceRNA regulatory networks was conducted by Cytoscape. RESULTS In comparison to non-AD patients, 24 genes were identified as dysregulated in AD patients, and these genes were associated with various immunological characteristics. Two distinct clusters were successfully identified through consensus clustering, with cluster 2 demonstrating higher immune characteristics compared to cluster 1. The performance of four machine learning models was determined by conducting a receiver operating characteristic (ROC) analysis. The analysis revealed that the SVM model achieved the highest AUC value of 0.947. Five genes (YTHDF1, METTL3, DNMT1, DNMT3A, ALKBH1) were selected as the predicted genes. Finally, a hub gene-based Gene-Drug regulatory network and a ceRNA regulatory network were successfully developed. CONCLUSIONS The findings offered fresh perspectives on the molecular patterns and immune mechanisms underlying AD, contributing valuable insights into our understanding of this complex neurodegenerative disorder.
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Affiliation(s)
- Qifa Tan
- Ganzhou City Key Laboratory of Mental Health, The Third People’s Hospital of Ganzhou City, Ganzhou 341000, Jiangxi, China
| | - Desheng Zhou
- Guangzhou Medical University, Guangzhou 510182, Guangdong, China
| | - Yuan Guo
- Ganzhou City Key Laboratory of Mental Health, The Third People’s Hospital of Ganzhou City, Ganzhou 341000, Jiangxi, China
| | - Haijun Chen
- Department of Medical Genetics, Ganzhou Maternal and Child Health Hospital, Ganzhou 341000, China
| | - Peng Xie
- Ganzhou City Key Laboratory of Mental Health, The Third People’s Hospital of Ganzhou City, Ganzhou 341000, Jiangxi, China
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Kvolik Pavić A, Čonkaš J, Mumlek I, Zubčić V, Ozretić P. Clinician's Guide to Epitranscriptomics: An Example of N 1-Methyladenosine (m 1A) RNA Modification and Cancer. Life (Basel) 2024; 14:1230. [PMID: 39459530 PMCID: PMC11508930 DOI: 10.3390/life14101230] [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: 05/22/2024] [Revised: 09/09/2024] [Accepted: 09/24/2024] [Indexed: 09/28/2024] Open
Abstract
Epitranscriptomics is the study of modifications of RNA molecules by small molecular residues, such as the methyl (-CH3) group. These modifications are inheritable and reversible. A specific group of enzymes called "writers" introduces the change to the RNA; "erasers" delete it, while "readers" stimulate a downstream effect. Epitranscriptomic changes are present in every type of organism from single-celled ones to plants and animals and are a key to normal development as well as pathologic processes. Oncology is a fast-paced field, where a better understanding of tumor biology and (epi)genetics is necessary to provide new therapeutic targets and better clinical outcomes. Recently, changes to the epitranscriptome have been shown to be drivers of tumorigenesis, biomarkers, and means of predicting outcomes, as well as potential therapeutic targets. In this review, we aimed to give a concise overview of epitranscriptomics in the context of neoplastic disease with a focus on N1-methyladenosine (m1A) modification, in layman's terms, to bring closer this omics to clinicians and their future clinical practice.
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Affiliation(s)
- Ana Kvolik Pavić
- Department of Maxillofacial and Oral Surgery, University Hospital Osijek, Josipa Huttlera 4, 31000 Osijek, Croatia; (A.K.P.); (V.Z.)
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, Josipa Huttlera 4, 31000 Osijek, Croatia;
| | - Josipa Čonkaš
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička Cesta 54, 10000 Zagreb, Croatia;
| | - Ivan Mumlek
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, Josipa Huttlera 4, 31000 Osijek, Croatia;
| | - Vedran Zubčić
- Department of Maxillofacial and Oral Surgery, University Hospital Osijek, Josipa Huttlera 4, 31000 Osijek, Croatia; (A.K.P.); (V.Z.)
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, Josipa Huttlera 4, 31000 Osijek, Croatia;
| | - Petar Ozretić
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička Cesta 54, 10000 Zagreb, Croatia;
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Qin X, Liu H, Zhang Q, Che Y, Lei T, Tang F, Hu Q. RNA modifications in cancer immune therapy: regulators of immune cells and immune checkpoints. Front Immunol 2024; 15:1463847. [PMID: 39372415 PMCID: PMC11449722 DOI: 10.3389/fimmu.2024.1463847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 09/02/2024] [Indexed: 10/08/2024] Open
Abstract
RNA modifications are epigenetic changes that alter the structure and function of RNA molecules, playing a crucial role in the onset, progression, and treatment of cancer. Immune checkpoint inhibitor (ICI) therapies, particularly PD-1 blockade and anti-CTLA-4 treatments, have changed the treatment landscape of virous cancers, showing great potential in the treatment of different cancer patients, but sensitivity to these therapies is limited to certain individuals. This review offers a comprehensive survey of the functions and therapeutic implications of the four principal RNA modifications, particularly highlighting the significance of m6A in the realms of immune cells in tumor and immunotherapy. This review starts by providing a foundational summary of the roles RNA modifications assume within the immune cell community, focusing on T cells, NK cells, macrophages, and dendritic cells. We then discuss how RNA modifications influence the intricate regulatory mechanisms governing immune checkpoint expression, modulation of ICI efficacy, and prediction of ICI treatment outcomes, and review drug therapies targeting genes regulated by RNA modifications. Finally, we explore the role of RNA modifications in gene editing, cancer vaccines, and adoptive T cell therapies, offering valuable insights into the use of RNA modifications in cancer immunotherapy.
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Affiliation(s)
- Xiangyu Qin
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China
- Renmin Hospital of Wuhan Economic and Technological Development Zone (Hannan), Wuhan, China
- Wuhan University Heavy Ion Medicine Center, Wuhan, China
| | - Huali Liu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qixuan Zhang
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yuhang Che
- Renmin Hospital of Wuhan Economic and Technological Development Zone (Hannan), Wuhan, China
- Wuhan University Heavy Ion Medicine Center, Wuhan, China
| | - Tianyu Lei
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China
- Renmin Hospital of Wuhan Economic and Technological Development Zone (Hannan), Wuhan, China
- Wuhan University Heavy Ion Medicine Center, Wuhan, China
| | - Fang Tang
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qinyong Hu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China
- Renmin Hospital of Wuhan Economic and Technological Development Zone (Hannan), Wuhan, China
- Wuhan University Heavy Ion Medicine Center, Wuhan, China
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Deng Y, Zhou J, Li HB. The physiological and pathological roles of RNA modifications in T cells. Cell Chem Biol 2024; 31:1578-1592. [PMID: 38986618 DOI: 10.1016/j.chembiol.2024.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 04/20/2024] [Accepted: 06/12/2024] [Indexed: 07/12/2024]
Abstract
RNA molecules undergo dynamic chemical modifications in response to various external or cellular stimuli. Some of those modifications have been demonstrated to post-transcriptionally modulate the RNA transcription, localization, stability, translation, and degradation, ultimately tuning the fate decisions and function of mammalian cells, particularly T cells. As a crucial part of adaptive immunity, T cells play fundamental roles in defending against infections and tumor cells. Recent findings have illuminated the importance of RNA modifications in modulating T cell survival, proliferation, differentiation, and functional activities. Therefore, understanding the epi-transcriptomic control of T cell biology enables a potential avenue for manipulating T cell immunity. This review aims to elucidate the physiological and pathological roles of internal RNA modifications in T cell development, differentiation, and functionality drawn from current literature, with the goal of inspiring new insights for future investigations and providing novel prospects for T cell-based immunotherapy.
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Affiliation(s)
- Yu Deng
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jing Zhou
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hua-Bing Li
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Geriatrics, Medical Center on Aging of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Chongqing International Institute for Immunology, Chongqing 401320, China.
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11
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Nian Z, Deng M, Ye L, Tong X, Xu Y, Xu Y, Chen R, Wang Y, Mao F, Xu C, Lu R, Mao Y, Xu H, Shen X, Xue X, Guo G. RNA epigenetic modifications in digestive tract cancers: Friends or foes. Pharmacol Res 2024; 206:107280. [PMID: 38914382 DOI: 10.1016/j.phrs.2024.107280] [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: 04/24/2024] [Revised: 06/19/2024] [Accepted: 06/20/2024] [Indexed: 06/26/2024]
Abstract
Digestive tract cancers are among the most common malignancies worldwide and have high incidence and mortality rates. Thus, the discovery of more effective diagnostic and therapeutic targets is urgently required. The development of technologies to accurately detect RNA modification has led to the identification of numerous RNA chemical modifications in humans (epitranscriptomics) that are involved in the occurrence and development of digestive tract cancers. RNA modifications can cooperatively regulate gene expression to facilitate normal physiological functions of the digestive system. However, the dysfunction of relevant RNA-modifying enzymes ("writers," "erasers," and "readers") can lead to the development of digestive tract cancers. Consequently, targeting dysregulated enzyme activity could represent a potent therapeutic strategy for the treatment of digestive tract cancers. In this review, we summarize the most widely studied roles and mechanisms of RNA modifications (m6A, m1A, m5C, m7G, A-to-I editing, pseudouridine [Ψ]) in relation to digestive tract cancers, highlight the crosstalk between RNA modifications, and discuss their roles in the interactions between the digestive system and microbiota during carcinogenesis. The clinical significance of novel therapeutic methods based on RNA-modifying enzymes is also discussed. This review will help guide future research into digestive tract cancers that are resistant to current therapeutics.
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Affiliation(s)
- Zekai Nian
- Second Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Ming Deng
- School of Public Health, Wenzhou Medical University, Wenzhou, China
| | - Lele Ye
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xinya Tong
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yixi Xu
- School of public administration, Hangzhou Normal University, Hangzhou, China
| | - Yiliu Xu
- Research Center of Fluid Machinery Engineering & Technology, Jiangsu University, Zhenjiang, China
| | - Ruoyao Chen
- Second Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Yulin Wang
- School of Public Health, Wenzhou Medical University, Wenzhou, China
| | - Feiyang Mao
- Second Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Chenyv Xu
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ruonan Lu
- First Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Yicheng Mao
- Ophthalmology College, Wenzhou Medical University, Wenzhou, China
| | - Hanlu Xu
- Ophthalmology College, Wenzhou Medical University, Wenzhou, China
| | - Xian Shen
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Xiangyang Xue
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
| | - Gangqiang Guo
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
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12
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Gao Y, Chen S, Wang H, Wu C, An R, Li G, Yang M, Zhou Y, Zhou Y, Xie X, Yu H, Zhang J. Liver metastases across cancer types sharing tumor environment immunotolerance can impede immune response therapy and immune monitoring. J Adv Res 2024; 61:151-164. [PMID: 37619932 PMCID: PMC11258657 DOI: 10.1016/j.jare.2023.08.011] [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: 10/27/2022] [Revised: 07/16/2023] [Accepted: 08/19/2023] [Indexed: 08/26/2023] Open
Abstract
BACKGROUND Hepatic immune tolerance might contribute to the development of therapeutic resistance to immunotherapy. However, addressing this issue is challenging since the efficacy of immunotherapy in the context of liver metastasis (LM) remains poorly studied. Here, we aimed to establish an LM common immune feature (LMCIF) score to quantify the characteristics of LM immunotolerance across cancer types for assisting clinical disease management. METHODS Large-scale clinical data were collected to identify the prognosis of LM. Multi-omics datasets of metastatic cancers with LM special immune-related pathways (LMSIPs) from the Molecular Signatures Database (MSigDB)were used to obtain an LMCIF cluster. Based on differential expression genes (DEGs), a novel LMCIF score for the LMCIF cluster was constructed. In addition, multi-omics, and immunohistochemistry (IHC) data from the public and in-house cohorts were used to explore the features of LM, and LMCIF score. RESULTS Patients with LM had a worse prognosis and significantly lower infiltration of immune cells than patients with metastasis to other organs when analyzed with combined clinical and RNA sequencing data. After extracting the LMCIF cluster from 373 samples by utilizing 29 LMSIPs and validating them in a microarray cohort, an LMCIF score was established to confirm the role of the immunosuppressive environment as a contributor to the poor prognosis of LM across cancer types. Moreover, this LMCIF score could be used to predict the immune response of cancer patients undergoing immunotherapy. Finally, we identified that the majority of the 31 LMCIF genes exhibited a negative correlation with TME cells in LM patients, one of them, KRT19, which possessed the strongest positive correlation with LMCIF score, was confirmed to have an immunosuppressive effect through IHC analysis. CONCLUSIONS Our results suggest that LM across cancer types share similar immunological profiles that induce immunotolerance and escape from immune monitoring. The novel LMCIF score represents a common liver metastasis immune cluster for predicting immunotherapy response, the results of which might benefit clinical disease management.
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Affiliation(s)
- Yuzhen Gao
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Shipeng Chen
- Department of Laboratory Medicine, Xiamen Key Laboratory of Genetic Testing, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China; School of Clinical Medicine, Fujian Medical University, Fuzhou, China
| | - Hao Wang
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chenghao Wu
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Rui An
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Guoli Li
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Min Yang
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Ying Zhou
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou, China
| | - Yundong Zhou
- Shanghai Medical Innovation Fusion Biomedical Research Center, Shanghai, China
| | - Xinyou Xie
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Hong Yu
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| | - Jun Zhang
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, China.
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13
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Li Y, Jin H, Li Q, Shi L, Mao Y, Zhao L. The role of RNA methylation in tumor immunity and its potential in immunotherapy. Mol Cancer 2024; 23:130. [PMID: 38902779 PMCID: PMC11188252 DOI: 10.1186/s12943-024-02041-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Accepted: 06/10/2024] [Indexed: 06/22/2024] Open
Abstract
RNA methylation, a prevalent post-transcriptional modification, has garnered considerable attention in research circles. It exerts regulatory control over diverse biological functions by modulating RNA splicing, translation, transport, and stability. Notably, studies have illuminated the substantial impact of RNA methylation on tumor immunity. The primary types of RNA methylation encompass N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G), and 3-methylcytidine (m3C). Compelling evidence underscores the involvement of RNA methylation in regulating the tumor microenvironment (TME). By affecting RNA translation and stability through the "writers", "erasers" and "readers", RNA methylation exerts influence over the dysregulation of immune cells and immune factors. Consequently, RNA methylation plays a pivotal role in modulating tumor immunity and mediating various biological behaviors, encompassing proliferation, invasion, metastasis, etc. In this review, we discussed the mechanisms and functions of several RNA methylations, providing a comprehensive overview of their biological roles and underlying mechanisms within the tumor microenvironment and among immunocytes. By exploring how these RNA modifications mediate tumor immune evasion, we also examine their potential applications in immunotherapy. This review aims to provide novel insights and strategies for identifying novel targets in RNA methylation and advancing cancer immunotherapy efficacy.
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Affiliation(s)
- Yan Li
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Pathology, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Haoer Jin
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Pathology, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Qingling Li
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Pathology, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Liangrong Shi
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yitao Mao
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Luqing Zhao
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Department of Pathology, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Jiang J, Duan M, Wang Z, Lai Y, Zhang C, Duan C. RNA epigenetics in pulmonary diseases: Insights into methylation modification of lncRNAs in lung cancer. Biomed Pharmacother 2024; 175:116704. [PMID: 38749181 DOI: 10.1016/j.biopha.2024.116704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/26/2024] [Accepted: 05/02/2024] [Indexed: 06/03/2024] Open
Abstract
Long non-coding RNAs (lncRNAs) are pivotal controllers of gene expression through epigenetic mechanisms, Methylation, a prominent area of study in epigenetics, significantly impacts cellular processes. Various RNA base methylations, including m6A, m5C, m1A, and 2'-O-methylation, profoundly influence lncRNA folding, interactions, and stability, thereby shaping their functionality. LncRNAs and methylation significantly contribute to tumor development, especially in lung cancer. Their roles encompass cell differentiation, proliferation, the generation of cancer stem cells, and modulation of immune responses. Recent studies have suggested that dysregulation of lncRNA methylation can contribute to lung cancer development. Furthermore, methylation modifications of lncRNAs hold potential for clinical application in lung cancer. Dysregulated lncRNA methylation can promote lung cancer progression and may offer insights into potential biomarker or therapeutic target. This review summarizes the current knowledge of lncRNA methylation in lung cancer and its implications for RNA epigenetics and pulmonary diseases.
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Affiliation(s)
- Junjie Jiang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China; Hunan Engineering Research Center for Pulmonary Nodules Precise Diagnosis & Treatment, Changsha, 410008, Hunan, People's Republic of China
| | - Minghao Duan
- Department of Public Health Laboratory Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, 412017, Hunan, People's Republic of China
| | - Zheng Wang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China; Hunan Engineering Research Center for Pulmonary Nodules Precise Diagnosis & Treatment, Changsha, 410008, Hunan, People's Republic of China
| | - Yuwei Lai
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China; Hunan Engineering Research Center for Pulmonary Nodules Precise Diagnosis & Treatment, Changsha, 410008, Hunan, People's Republic of China
| | - Chunfang Zhang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China; Hunan Engineering Research Center for Pulmonary Nodules Precise Diagnosis & Treatment, Changsha, 410008, Hunan, People's Republic of China; Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China
| | - Chaojun Duan
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China; Hunan Engineering Research Center for Pulmonary Nodules Precise Diagnosis & Treatment, Changsha, 410008, Hunan, People's Republic of China; Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China; Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China; National Clinical Research Center for Geriatric Disorders, Changsha 410008, Hunan, People's Republic of China.
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15
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Li G, Yao Q, Liu P, Zhang H, Liu Y, Li S, Shi Y, Li Z, Zhu W. Critical roles and clinical perspectives of RNA methylation in cancer. MedComm (Beijing) 2024; 5:e559. [PMID: 38721006 PMCID: PMC11077291 DOI: 10.1002/mco2.559] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 04/02/2024] [Accepted: 04/11/2024] [Indexed: 01/06/2025] Open
Abstract
RNA modification, especially RNA methylation, is a critical posttranscriptional process influencing cellular functions and disease progression, accounting for over 60% of all RNA modifications. It plays a significant role in RNA metabolism, affecting RNA processing, stability, and translation, thereby modulating gene expression and cell functions essential for proliferation, survival, and metastasis. Increasing studies have revealed the disruption in RNA metabolism mediated by RNA methylation has been implicated in various aspects of cancer progression, particularly in metabolic reprogramming and immunity. This disruption of RNA methylation has profound implications for tumor growth, metastasis, and therapy response. Herein, we elucidate the fundamental characteristics of RNA methylation and their impact on RNA metabolism and gene expression. We highlight the intricate relationship between RNA methylation, cancer metabolic reprogramming, and immunity, using the well-characterized phenomenon of cancer metabolic reprogramming as a framework to discuss RNA methylation's specific roles and mechanisms in cancer progression. Furthermore, we explore the potential of targeting RNA methylation regulators as a novel approach for cancer therapy. By underscoring the complex mechanisms by which RNA methylation contributes to cancer progression, this review provides a foundation for developing new prognostic markers and therapeutic strategies aimed at modulating RNA methylation in cancer treatment.
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Affiliation(s)
- Ganglei Li
- Department of NeurosurgeryHuashan Hospital, Fudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Qinfan Yao
- Kidney Disease CenterThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Peixi Liu
- Department of NeurosurgeryHuashan Hospital, Fudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Hongfei Zhang
- Department of NeurosurgeryHuashan Hospital, Fudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Yingjun Liu
- Department of NeurosurgeryHuashan Hospital, Fudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Sichen Li
- Department of NeurosurgeryHuashan Hospital, Fudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Yuan Shi
- Department of NeurosurgeryHuashan Hospital, Fudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Zongze Li
- Department of NeurosurgeryHuashan Hospital, Fudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Wei Zhu
- Department of NeurosurgeryHuashan Hospital, Fudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
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16
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Tian X, Hu D, Wang N, Zhang L, Wang X. LINC01614 is a promising diagnostic and prognostic marker in HNSC linked to the tumor microenvironment and oncogenic function. Front Genet 2024; 15:1337525. [PMID: 38655053 PMCID: PMC11035733 DOI: 10.3389/fgene.2024.1337525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 03/25/2024] [Indexed: 04/26/2024] Open
Abstract
Background Tumor initiation and metastasis influence tumor immune exclusion and immunosuppression. Long non-coding RNA (lncRNA) LINC01614 is associated with the prognosis and metastasis of several cancers. However, the relationship between LINC01614 and cancer immune infiltration and the biofunction of LINC01614 in head and neck squamous cell carcinoma (HNSC) remain unclear. Methods The Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets were used to analyze the expression difference and diagnostic value of LINC01614 in normal and tumor tissues. The correlation of pan-cancer prognosis and tumor stage of LINC01614 was analyzed based on the TCGA database. The pan-cancer association of LINC01614 expression with the tumor microenvironment (TME) including immune infiltration, expression of immune-related genes, and genomic instability parameters, was analyzed using the Spearman correlation method. The correlation between LINC01614 and tumor stemness evaluation indicators, RNA methylation-related genes, and drug resistance was also analyzed. The functional analysis of LINC01614 was performed using the clusterProfiler R package. The protein-protein interaction (PPI) network and ceRNA network of LINC01614 co-expressed genes and miRNA were constructed and visualized by STRING and Cytoscape, respectively. Finally, the cell location and influence of LINC01614 on cell proliferation and metastasis of HNSC cell lines were evaluated using FISH, CCK-8, wound-healing assay, and transwell assay. Results LINC01614 was found to be overexpressed in 23 cancers and showed a highly sensitive prediction value in nine cancers (AUC >0.85). LINC01614 dysregulation was associated with tumor stage in 12 cancers and significantly influenced the survival outcomes of 26 cancer types, with only Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (DLBC), uterine corpus endometrial carcinoma (UCEC), and bladder urothelial carcinoma (BLCA) showing a benign influence. LINC01614 was also associated with immune cell infiltration, tumor heterogeneity, cancer stemness, RNA methylation modification, and drug resistance. The potential biological function of LINC01614 was verified in HNSC, and it was found to play important roles in proliferation, immune infiltration, immunotherapy response, and metastasis of HNSC. Conclusion LINC01614 may serve as a cancer diagnosis and prognosis biomarker and an immunotherapy target for specific cancers.
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Affiliation(s)
- Xiong Tian
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai, China
- Department of Public Research Platform, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Dali Hu
- Department of Plastic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Na Wang
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai, China
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Lele Zhang
- Department of Radiation Oncology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Xuequan Wang
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai, China
- Department of Radiation Oncology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
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Ma C, Gu Z, Yang Y. Development of m6A/m5C/m1A regulated lncRNA signature for prognostic prediction, personalized immune intervention and drug selection in LUAD. J Cell Mol Med 2024; 28:e18282. [PMID: 38647237 PMCID: PMC11034373 DOI: 10.1111/jcmm.18282] [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: 11/03/2023] [Revised: 03/14/2024] [Accepted: 03/18/2024] [Indexed: 04/25/2024] Open
Abstract
Research indicates that there are links between m6A, m5C and m1A modifications and the development of different types of tumours. However, it is not yet clear if these modifications are involved in the prognosis of LUAD. The TCGA-LUAD dataset was used as for signature training, while the validation cohort was created by amalgamating publicly accessible GEO datasets including GSE29013, GSE30219, GSE31210, GSE37745 and GSE50081. The study focused on 33 genes that are regulated by m6A, m5C or m1A (mRG), which were used to form mRGs clusters and clusters of mRG differentially expressed genes clusters (mRG-DEG clusters). Our subsequent LASSO regression analysis trained the signature of m6A/m5C/m1A-related lncRNA (mRLncSig) using lncRNAs that exhibited differential expression among mRG-DEG clusters and had prognostic value. The model's accuracy underwent validation via Kaplan-Meier analysis, Cox regression, ROC analysis, tAUC evaluation, PCA examination and nomogram predictor validation. In evaluating the immunotherapeutic potential of the signature, we employed multiple bioinformatics algorithms and concepts through various analyses. These included seven newly developed immunoinformatic algorithms, as well as evaluations of TMB, TIDE and immune checkpoints. Additionally, we identified and validated promising agents that target the high-risk mRLncSig in LUAD. To validate the real-world expression pattern of mRLncSig, real-time PCR was carried out on human LUAD tissues. The signature's ability to perform in pan-cancer settings was also evaluated. The study created a 10-lncRNA signature, mRLncSig, which was validated to have prognostic power in the validation cohort. Real-time PCR was applied to verify the actual manifestation of each gene in the signature in the real world. Our immunotherapy analysis revealed an association between mRLncSig and immune status. mRLncSig was found to be closely linked to several checkpoints, such as IL10, IL2, CD40LG, SELP, BTLA and CD28, which could be appropriate immunotherapy targets for LUAD. Among the high-risk patients, our study identified 12 candidate drugs and verified gemcitabine as the most significant one that could target our signature and be effective in treating LUAD. Additionally, we discovered that some of the lncRNAs in mRLncSig could play a crucial role in certain cancer types, and thus, may require further attention in future studies. According to the findings of this study, the use of mRLncSig has the potential to aid in forecasting the prognosis of LUAD and could serve as a potential target for immunotherapy. Moreover, our signature may assist in identifying targets and therapeutic agents more effectively.
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Affiliation(s)
- Chao Ma
- Department of Thoracic SurgeryFirst Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Zhuoyu Gu
- Department of Thoracic SurgeryFirst Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Yang Yang
- Department of Thoracic SurgeryFirst Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
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Lei K, Sheng Y, Luo M, Liu J, Gong C, Lv S, Tu W, Ye M, Wu M, xiao B, Fang H, Luo H, Liu X, Long X, Zhu X, Huang K, Li J. Comprehensive analyses of m1A regulator-mediated modification patterns determining prognosis in lower-grade glioma (running title: m1A in LGG). Heliyon 2024; 10:e27510. [PMID: 38510043 PMCID: PMC10950614 DOI: 10.1016/j.heliyon.2024.e27510] [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: 10/11/2023] [Revised: 02/29/2024] [Accepted: 02/29/2024] [Indexed: 03/22/2024] Open
Abstract
N1-methyladenosine (m1A) modification is a crucial post-transcriptional regulatory mechanism of messenger RNA (mRNA) in living organisms. Few studies have focused on analysis of m1A regulators in lower-grade gliomas (LGG). We employed the Nonnegative Matrix Factorization (NMF) technique on The Cancer Genome Atlas (TCGA) dataset to categorize LGG patients into 2 groups. These groups exhibited substantial disparities in terms of both overall survival (OS) and levels of infiltrating immune cells. We collected the significantly differentially expressed immune-related genes between the 2 clusters, and performed LASSO regression analysis to obtain m1AScores, and established an m1A-related immune-related gene signature (m1A-RIGS). Next, we categorized all patients with LGG into high- and low-risk subgroups, predictive significance of m1AScore was confirmed by conducting univariate/multivariate Cox regression analyses. Additionally, we confirmed variations in immune-related cells and ssGSEA and among the high-/low-risk subcategories in the TCGA dataset. Finally, our study characterized the effects of MSR1 and BIRC5 on LGG cells utilizing Edu assay and flow cytometry to explore the effects of modulation of these genes on glioma. The results of this study suggested that m1A-RIGS may be an excellent prognostic indicator for patients with LGG, and could also promote development of novel immune-based treatment strategies for LGG. Additionally, BIRC5 and MSR1 may be potential therapeutic targets for LGG.
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Affiliation(s)
- Kunjian Lei
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
- Jiangxi Provincial Key Laboratory of Nervous System Tumors and Cerebrovascular Diseases, Nanchang University, Nanchang, Jiangxi, China
- JXHC Key Laboratory of Neurological Medicine, Nanchang University, Nanchang, Jiangxi, China
| | - Yilei Sheng
- Jiangxi Provincial Key Laboratory of Nervous System Tumors and Cerebrovascular Diseases, Nanchang University, Nanchang, Jiangxi, China
- JXHC Key Laboratory of Neurological Medicine, Nanchang University, Nanchang, Jiangxi, China
- Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Min Luo
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
- Institute of Neuroscience, Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Junzhe Liu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
- Institute of Neuroscience, Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Chuandong Gong
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
- Institute of Neuroscience, Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Shigang Lv
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Wei Tu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Minhua Ye
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Miaojing Wu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Bing xiao
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Hua Fang
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Haitao Luo
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Xinjun Liu
- People's Hospital of Yingtan City, Jiangxi Province, Yingtan, Jiangxi, 335099, China
| | - Xiaoyan Long
- East China Institute of Digital Medical Engineering, Shangrao, Jiangxi, 334000, China
| | - Xingen Zhu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
- Jiangxi Provincial Key Laboratory of Nervous System Tumors and Cerebrovascular Diseases, Nanchang University, Nanchang, Jiangxi, China
- JXHC Key Laboratory of Neurological Medicine, Nanchang University, Nanchang, Jiangxi, China
| | - Kai Huang
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
- Jiangxi Provincial Key Laboratory of Nervous System Tumors and Cerebrovascular Diseases, Nanchang University, Nanchang, Jiangxi, China
- JXHC Key Laboratory of Neurological Medicine, Nanchang University, Nanchang, Jiangxi, China
| | - Jingying Li
- Department of Comprehensive Intensive Care Unit, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
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Chang X, Zhu J, Hua RX, Deng C, Zhang J, Cheng J, Li S, Zhou H, He J, Wang H. TRMT6 gene rs236110 C > A polymorphism increases the risk of Wilms tumor. Gene 2023; 882:147646. [PMID: 37473973 DOI: 10.1016/j.gene.2023.147646] [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] [Revised: 07/13/2023] [Accepted: 07/17/2023] [Indexed: 07/22/2023]
Abstract
tRNA methyltransferase 6 (TRMT6)is an enzyme catalyzing N1-methyladenosine, a reversible modification in RNA, including tRNA, mRNA, rRNA, and lncRNA. Increasing evidence has shown the implications of this post-transcriptional modification and its regulators in carcinogenesis. However, its roles in Wilms tumor haven't been reported. In this study, four TRMT6 gene polymorphisms (rs236170 A > G, rs451571 T > C, rs236188 G > A, and rs236110 C > A) were tested for association with susceptibility to Wilms tumor, the most frequently diagnosed pediatric renal tumor. TaqMan method was adopted to analyze the genotypes of these polymorphisms in 414 cases and 1199 controls. Among the four TRMT6 gene polymorphisms, only the rs236110 C > A displayed a significant association with the risk of Wilms tumor [AA vs. CC, adjusted odds ratio (OR) = 1.93, 95 % confidence interval (CI) = 1.14-3.27, P = 0.015]. This association was confirmed under the recessive models (AA vs. CC/CA, OR = 1.92, 95 % CI = 1.14-3.23, P = 0.015). Furthermore, after stratifying by age, gender, and clinical stage, we mainly detected significant associations for the rs236110 C > A in children older than 18 months, boys, and those with stage IV or III + IV diseases. The rs236110 A allele was significantly associated with decreased expression of MCM8. In conclusion, we identified the rs236110 C > A in the TRMT6 gene as a Wilms tumor susceptibility locus, and this polymorphism warrants more validation studies to be translated into individualized risk prediction strategies for children.
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Affiliation(s)
- Xiaofeng Chang
- Department of Surgical Oncology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China
| | - Jinhong Zhu
- Department of Clinical Laboratory, Biobank, Harbin Medical University Cancer Hospital, Harbin 150040, Heilongjiang, China
| | - Rui-Xi Hua
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, Guangdong, China
| | - Changmi Deng
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, Guangdong, China
| | - Jiao Zhang
- Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Jiwen Cheng
- Department of Pediatric Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi, China
| | - Suhong Li
- Department of Pathology, Children Hospital and Women Health Center of Shanxi, Taiyuan 030013, Shannxi, China
| | - Haixia Zhou
- Department of Hematology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Jing He
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, Guangdong, China.
| | - Huanmin Wang
- Department of Surgical Oncology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China; MOE Key Laboratory of Major Diseases in Children, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.
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20
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Ma E, Li J, Shen C, Gu Y, Zhang X, Li L, Zhao J, Wang Z. The m 6A-related gene signature stratifies poor prognosis patients and characterizes immunosuppressive microenvironment in hepatocellular carcinoma. Front Immunol 2023; 14:1227593. [PMID: 37691948 PMCID: PMC10485364 DOI: 10.3389/fimmu.2023.1227593] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/04/2023] [Indexed: 09/12/2023] Open
Abstract
Background N6-methyladenosine (m6A) is the most abundant epitranscriptomic modification of RNA, which can affect RNA metabolism and protein translation. The m6A modification plays a critical role in cancer development, including hepatocellular carcinoma (HCC). Despite several m6A-related signatures in HCC, most of them lack the necessary validation and the reliability is still elusive. Methods Differentially expressed genes (DEGs) in the Cancer Genome Atlas were comprehensively analyzed to identify m6A signature associated with HCC prognosis. Gene set enrichment analysis, tumor mutation burden (TMB), immune infiltration, and therapeutic response were evaluated. Importantly, mass spectrometry proteomics and multiplex immunofluorescence assays were performed for validation. Results The m6A-related protein-coding gene signature was established, which can divide HCC into high-/low-risk subgroups with markedly different overall survival (OS) and clinical stages. Furthermore, we validated its reliability and robustness in our 101 independent HCC specimens using proteomic detection and confirmed that our signature readily identified high-risk HCC patients with 3-year survival rates of 44.1% vs. 71.8% in the low-risk group. Functional analysis indicated that the high-risk group might stimulate the cell cycle and activate oncogenic pathways such as MAPK, mTOR, and VEGF, whereas the low-risk group mainly regulated amino acid, fatty acid, and drug metabolism. Additionally, the high-risk group had more TMB, upregulated immune checkpoint molecule expression, including PD-1, CTLA4, TIM3, and LAG3, and preferentially formed an immunosuppressive microenvironment. Accordingly, potential therapeutic responses showed that high-risk patients were potentially sensitive to inhibitors targeting the cell cycle and MAPK signaling, with patients possibly benefiting from immunotherapy. Moreover, multiplex immunofluorescence assays indicated that high-risk HCC samples displayed distinct immunosuppressive features, with abundant M2-polarized macrophages and T-regulatory cell infiltration. Conclusion The m6A signature had a prominent capacity to evaluate OS and characterize the tumor immune microenvironment of HCC, which may serve as a useful approach for risk stratification management and provide a valuable clue to choosing rational therapeutic strategies.
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Affiliation(s)
- Ensi Ma
- Liver Transplantation Center, General Surgery, Huashan Hospital, Fudan University, Shanghai, China
- Institute of Organ Transplantation, Fudan University, Shanghai, China
| | - Jianhua Li
- Liver Transplantation Center, General Surgery, Huashan Hospital, Fudan University, Shanghai, China
- Institute of Organ Transplantation, Fudan University, Shanghai, China
| | - Conghuan Shen
- Liver Transplantation Center, General Surgery, Huashan Hospital, Fudan University, Shanghai, China
- Institute of Organ Transplantation, Fudan University, Shanghai, China
| | - Yange Gu
- Liver Transplantation Center, General Surgery, Huashan Hospital, Fudan University, Shanghai, China
- Institute of Organ Transplantation, Fudan University, Shanghai, China
| | - Xinju Zhang
- Central Laboratory, Huashan Hospital, Fudan University, Shanghai, China
| | - Li Li
- Liver Transplantation Center, General Surgery, Huashan Hospital, Fudan University, Shanghai, China
- Institute of Organ Transplantation, Fudan University, Shanghai, China
| | - Jing Zhao
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Zhengxin Wang
- Liver Transplantation Center, General Surgery, Huashan Hospital, Fudan University, Shanghai, China
- Institute of Organ Transplantation, Fudan University, Shanghai, China
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21
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Zhang Y, Chen Y, Wen W. Four types of adenine-related RNA modification writers -mediated molecular subtypes contribute to predicting clinical outcomes and treatment options in bladder cancer. Front Immunol 2023; 14:1152806. [PMID: 37638051 PMCID: PMC10450768 DOI: 10.3389/fimmu.2023.1152806] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 04/07/2023] [Indexed: 08/29/2023] Open
Abstract
Rationale RNA modifications, containing m6A, m1A, alternative polyadenylation and adenosine-to-inosine RNA editing, involve in critical cancerous immunity and cancerous processes. However, the functional roles of RNA modification writers in bladder cancer (BLCA) are largely unknown. Methods In this study, unsupervised clustering was used to identify novel RNA modification writers -mediated molecular subtypes in BLCA. A corresponding quantitative indicator called WriterScore was developed using univariate Cox and Least absolute shrinkage and selection operator (LASSO) analysis. Then, we systematically analyzed the correlation between RNA modification writer-related clusters (WriterScore) and immunological characteristics, classical molecular subtypes, clinicopathologic features and treatment options in BLCA. Finally, we validated the WriterScore in multiple other external BLCA datasets, clinical sample dataset in Shengjing Hospital and pancancer. Results Two RNA modification writer-related clusters and three DEGclusters were obtained. These RNA modification writer-related clusters (WriterScore) were strongly associated with immunological characteristics, classical molecular subtypes, clinicopathologic features of BLCA. Moreover, WriterScore can properly predict the clinical outcomes and immunotherapy of BLCA patients. Conclusion Our study systematically investigated the role of RNA modification writers and developed a significant WriterScore to guide several treatment options in BLCA, which might bring some potential benefits for BLCA patients.
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Affiliation(s)
- Yao Zhang
- Department of gynaecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ying Chen
- Department of Ultrasound, Xiaoshan Traditional Chinese Medical Hospital, Hangzhou, China
| | - Wen Wen
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China
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Tang Q, Li L, Wang Y, Wu P, Hou X, Ouyang J, Fan C, Li Z, Wang F, Guo C, Zhou M, Liao Q, Wang H, Xiang B, Jiang W, Li G, Zeng Z, Xiong W. RNA modifications in cancer. Br J Cancer 2023; 129:204-221. [PMID: 37095185 PMCID: PMC10338518 DOI: 10.1038/s41416-023-02275-1] [Citation(s) in RCA: 70] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 03/30/2023] [Accepted: 04/06/2023] [Indexed: 04/26/2023] Open
Abstract
Currently, more than 170 modifications have been identified on RNA. Among these RNA modifications, various methylations account for two-thirds of total cases and exist on almost all RNAs. Roles of RNA modifications in cancer are garnering increasing interest. The research on m6A RNA methylation in cancer is in full swing at present. However, there are still many other popular RNA modifications involved in the regulation of gene expression post-transcriptionally besides m6A RNA methylation. In this review, we focus on several important RNA modifications including m1A, m5C, m7G, 2'-O-Me, Ψ and A-to-I editing in cancer, which will provide a new perspective on tumourigenesis by peeking into the complex regulatory network of epigenetic RNA modifications, transcript processing, and protein translation.
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Affiliation(s)
- Qiling Tang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Lvyuan Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Yumin Wang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Pan Wu
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Xiangchan Hou
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Jiawei Ouyang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Chunmei Fan
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Zheng Li
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Fuyan Wang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Can Guo
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Ming Zhou
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Qianjin Liao
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
| | - Hui Wang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
| | - Bo Xiang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Weihong Jiang
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Guiyuan Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China.
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China.
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Xiao Y, Li J, Wu J. Development and validation of a novel prognostic signature based on m6A/m5C/m1A-related genes in hepatocellular carcinoma. BMC Med Genomics 2023; 16:177. [PMID: 37525171 PMCID: PMC10391842 DOI: 10.1186/s12920-023-01611-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 07/17/2023] [Indexed: 08/02/2023] Open
Abstract
BACKGROUND RNA methylation modification plays an important role in cancers. This study sought to examine the association between m6A/m5C/m1A-related genes and hepatocellular carcinoma (HCC). METHODS Gene expression and clinical data of HCC patients were obtained from the TCGA database. Unsupervised consensus clustering was performed according to the expression of m6A/m5C/m1A-related genes in HCC. The relationships among prognosis, clinicopathological features and molecular subtypes were analyzed. Least absolute shrinkage and selection operator (LASSO) regression analysis was used to establish the m6A/m5C/m1A-related gene prognostic signature. Furthermore, the prognostic signature was validated based on the ICGC dataset. RT‒qPCR was used to detect the expression of the model genes in HCC. Clinicopathological features, functional enrichment, gene mutations, immune cell infiltration, and immunotherapy response in different risk groups were analyzed. A nomogram based on risk score and stage was constructed to predict HCC patient prognosis. RESULTS Two m6A/m5C/m1A-related molecular subtypes were identified in HCC, and the prognosis of cluster C1 was worse than that of cluster C2 (p < 0.001). Highly expressed genes in cluster C1 are significantly correlated with G3-4, T3-4, stage III-IV (p < 0.05). An m6A/m5C/m1A-related prognostic signature was established and validated. The RT‒qPCR results showed that the risk signature genes were significantly upregulated in liver cancer tissue (p < 0.05). The prognosis of HCC patients in the high-risk group was worse than that of those in the low-risk group (p < 0.05). Multivariate Cox analysis indicated that the risk score was an independent factor predicting prognosis in HCC patients. ssGSEA revealed that the risk score correlated with the tumor immune microenvironment in HCC. Gene mutation analysis showed that the tumor mutation burden of patients in the high-risk group was much higher (p < 0.05), and the prognosis of HCC patients with high risk scores and high mutation burden was the worst (p = 0.007). A nomogram combining risk scores with clinicopathological features showed performed well in predicting HCC prognosis. CONCLUSIONS The m6A/m5C/m1A-related genes could predict the prognosis and tumor microenvironment features of HCC and can be important biomarkers relevant to the immunotherapy response.
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Affiliation(s)
- Yu Xiao
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China
| | - Jinluan Li
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.
| | - Junxin Wu
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.
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Kong Y, Yu J, Ge S, Fan X. Novel insight into RNA modifications in tumor immunity: Promising targets to prevent tumor immune escape. Innovation (N Y) 2023; 4:100452. [PMID: 37485079 PMCID: PMC10362524 DOI: 10.1016/j.xinn.2023.100452] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 05/23/2023] [Indexed: 07/25/2023] Open
Abstract
An immunosuppressive state is a typical feature of the tumor microenvironment. Despite the dramatic success of immune checkpoint inhibitor (ICI) therapy in preventing tumor cell escape from immune surveillance, primary and acquired resistance have limited its clinical use. Notably, recent clinical trials have shown that epigenetic drugs can significantly improve the outcome of ICI therapy in various cancers, indicating the importance of epigenetic modifications in immune regulation of tumors. Recently, RNA modifications (N6-methyladenosine [m6A], N1-methyladenosine [m1A], 5-methylcytosine [m5C], etc.), novel hotspot areas of epigenetic research, have been shown to play crucial roles in protumor and antitumor immunity. In this review, we provide a comprehensive understanding of how m6A, m1A, and m5C function in tumor immunity by directly regulating different immune cells as well as indirectly regulating tumor cells through different mechanisms, including modulating the expression of immune checkpoints, inducing metabolic reprogramming, and affecting the secretion of immune-related factors. Finally, we discuss the current status of strategies targeting RNA modifications to prevent tumor immune escape, highlighting their potential.
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Affiliation(s)
- Yuxin Kong
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200001, China
| | - Jie Yu
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200001, China
| | - Shengfang Ge
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200001, China
| | - Xianqun Fan
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200001, China
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He J, Xiao C, Li C, Yang F, Du C. Integrative analysis of bulk and single-cell RNA sequencing data reveals distinct subtypes of MAFLD based on N1-methyladenosine regulator expression. LIVER RESEARCH 2023; 7:145-155. [PMID: 39958950 PMCID: PMC11791902 DOI: 10.1016/j.livres.2023.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 04/15/2023] [Accepted: 06/05/2023] [Indexed: 02/18/2025]
Abstract
Background Metabolic dysfunction-associated fatty liver disease (MAFLD) is now the most prevalent chronic liver disease worldwide, with an increasing incidence rate. MAFLD is a heterogeneous disease that can have a low or high-risk profile for developing severe liver disease in its natural course. Recent evidence has highlighted the critical role of RNA methylation modification in the pathogenesis of various liver diseases. However, it remains unclear whether the RNA N1-methyladenosine (m1A) modification of immune cells could potentially contribute to the pathogenesis and heterogeneity of MAFLD. Materials and methods To address this issue, we conducted an integrated bioinformatics analysis of MAFLD bulk and single-cell RNA sequencing (scRNA-seq) data to pinpoint m1A regulators in the network. This was followed by a description of the immune landscape, pathway enrichment analysis, and molecular subtyping. Results The expression patterns of m1A regulatory genes stratify MAFLD into two molecular subtypes, Cluster 1 and Cluster 2. These subtypes demonstrate different immune cell infiltration with distinct inflammation characteristics, which suggest different immune-inflammatory responses in the liver. Notably, Cluster 2 is associated with pro-inflammation and may be more likely to lead to progressive stages of MAFLD. Through intersection analysis of weighted gene co-expression network analysis (WGCNA) and m1A regulatory genes, three true hub genes (ALKBH1, YTHDC1, and YTHDF3) were identified, all of which were strongly correlated with infiltrating immune cells. The specific signaling pathways involved in the three core genes were derived from genomic variation analysis. Furthermore, scRNA-seq data from 33,168 cells from six liver samples identified 26 cell clusters and eight cell types, with endothelial cells, macrophages, and monocytes showing the most significant differences between MAFLD and normal controls. The cell-cell communication network between immune cells and non-parenchymal cells was extremely sophisticated and changed significantly in MAFLD. Conclusions In summary, these findings demonstrate the involvement of m1A in MAFLD heterogeneity and emphasize the crucial role of m1A modulation of immune cells in regulating inflammation in MAFLD. These results may suggest potential therapeutic strategies for MAFLD.
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Affiliation(s)
- Jinyong He
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Province Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Cuicui Xiao
- Guangdong Province Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Cuiping Li
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Fan Yang
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Department of Infectious Diseases, The First People's Hospital of Kashi, The Affiliated Kashi Hospital of Sun Yat-sen University, Kashi, Xinjiang, China
| | - Cong Du
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Province Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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Qi F, Li J, Qi Z, Zhou B, Yang B, Zhang J, Qin W. Modeling cross-talk of RNA modification enzymes reveals tumor microenvironment-associated clinical significance and immunotherapy prediction in hepatobiliary malignancy. MedComm (Beijing) 2023; 4:e256. [PMID: 37090117 PMCID: PMC10113697 DOI: 10.1002/mco2.256] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 03/09/2023] [Accepted: 03/14/2023] [Indexed: 04/25/2023] Open
Abstract
RNA modification includes four main types, N6-methyladenosine, N1-methyladenosine, alternative polyadenylation (APA), and adenosine-to-inosine (A-to-I) RNA editing, involving 41 enzymes that serve as "writers", "readers" and "erasers". By collecting RNA modifying enzyme information in 1759 hepatobiliary malignancy (HBM) samples from 11 datasets, an RNA modification HBM Score (RH_score) was established based on unsupervised cluster analysis of RNA modification-associated differentially expressed genes (DEGs). We identified the imbalanced expression of 41 RNA modification enzymes in HBM, which was scientifically categorized into two groups: RH_Score high and RH_Score low. A high RH_Score was associated with a worse prognosis and more immature immune cells in the tumor microenvironment (TME), while a low RH_Score was associated with a better prognosis and more mature immune cells in the TME. Further analysis using single-cell databases showed that the high RH_Score was immune exhaustion in the TME. RH_Score was involved in transcriptional regulation and post-transcriptional events in HBM. Additionally, resistant and sensitive drugs were selected based on RNA modification, and anti-PD-L1 therapy responded better with low RH_Score. In conclusion, our study comprehensively analyzes RNA modification in HBM, which induces TME changes and transcriptional and posttranscriptional events, implying potential guiding significance in prognosis prediction and treatment options.
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Affiliation(s)
- Feng Qi
- Phase I Clinical Trial Center, Department of Oncology, Shanghai Medical CollegeFudan University Shanghai Cancer CenterFudan UniversityShanghaiChina
- Department of OncologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jia Li
- Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina
| | - Zhuoran Qi
- Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina
| | - Bin Zhou
- Department of Hepatic Surgery VIEastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghaiChina
| | - Biwei Yang
- Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina
| | - Jun Zhang
- Department of OncologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Wenxing Qin
- Phase I Clinical Trial Center, Department of Oncology, Shanghai Medical CollegeFudan University Shanghai Cancer CenterFudan UniversityShanghaiChina
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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.
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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.
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Marx O, Mankarious M, Yochum G. Molecular genetics of early-onset colorectal cancer. World J Biol Chem 2023; 14:13-27. [PMID: 37034132 PMCID: PMC10080548 DOI: 10.4331/wjbc.v14.i2.13] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/20/2022] [Accepted: 02/13/2023] [Indexed: 03/24/2023] Open
Abstract
Early-onset colorectal cancer (EOCRC) has been rising in global prevalence and incidence over the past several decades. Environmental influences, including generational lifestyle changes and rising obesity, contribute to these increased rates. While the rise in EOCRC is best documented in western countries, it is seen throughout the world, although EOCRC may have distinct genetic mutations in patients of different ethnic backgrounds. Pathological and molecular characterizations show that EOCRC has a distinct presentation compared with later-onset colorectal cancer (LOCRC). Recent studies have identified DNA, RNA, and protein-level alterations unique to EOCRC, revealing much-needed biomarkers and potential novel therapeutic targets. Many molecular EOCRC studies have been performed with Caucasian and Asian EOCRC cohorts, however, studies of other ethnic backgrounds are limited. In addition, certain molecular characterizations that have been conducted for LOCRC have not yet been repeated in EOCRC, including high-throughput analyses of histone modifications, mRNA splicing, and proteomics on large cohorts. We propose that the complex relationship between cancer and aging should be considered when studying the molecular underpinnings of EOCRC. In this review, we summarize current EOCRC literature, focusing on sporadic molecular alterations in tumors, and their clinical implications. We conclude by discussing current challenges and future directions of EOCRC research efforts.
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Affiliation(s)
- Olivia Marx
- Department of Biochemistry & Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
| | - Marc Mankarious
- Department of Surgery, Division of Colon & Rectal Surgery, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA 17033, United States
| | - Gregory Yochum
- Department of Biochemistry & Molecular Biology & Surgery, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
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Li J, Liu D, Ren J, Li G, Zhao Z, Zhao H, Yan Q, Duan J, Liu Z. Integrated analysis of RNA methylation regulators crosstalk and immune infiltration for predictive and personalized therapy of diabetic nephropathy. Hum Genomics 2023; 17:6. [PMID: 36765416 PMCID: PMC9912588 DOI: 10.1186/s40246-023-00457-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 02/04/2023] [Indexed: 02/12/2023] Open
Abstract
BACKGROUND RNA methylation is a widely known post-transcriptional regulation which exists in many cancer and immune system diseases. However, the potential role and crosstalk of five types RNA methylation regulators in diabetic nephropathy (DN) and immune microenvironment remain unclear. METHODS The mRNA expression of 37 RNA modification regulators and RNA modification regulators related genes were identified in 112 samples from 5 Gene Expression Omnibus datasets. Nonnegative Matrix Factorization clustering method was performed to determine RNA modification patterns. The ssGSEA algorithms and the expression of human leukocyte antigen were employed to assess the immune microenvironment characteristics. Risk model based on differentially expression genes responsible for the modification regulators was constructed to evaluate its predictive capability in DN patients. Furthermore, the results were validated by using immunofluorescence co-localizations and protein experiments in vitro. RESULTS We found 24 RNA methylation regulators were significant differently expressed in glomeruli in DN group compared with control group. Four methylation-related genes and six RNA regulators were introduced into riskScore model using univariate Logistic regression and integrated LASSO regression, which could precisely distinguish the DN and healthy individuals. Group with high-risk score was associated with high immune infiltration. Three distinct RNA modification patterns were identified, which has significant differences in immune microenvironment, biological pathway and eGFR. Validation analyses showed the METTL3, ADAR1, DNMT1 were upregulated whereas YTHDC1 was downregulated in DN podocyte cell lines comparing with cells cultured by the normal glucose. CONCLUSION Our study reveals that RNA methylation regulators and immune infiltration regulation play critical roles in the pathogenesis of DN. The bioinformatic analyses combine with verification in vitro could provide robust evidence for identification of predictive RNA methylation regulators in DN.
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Affiliation(s)
- Jia Li
- grid.207374.50000 0001 2189 3846Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052 People’s Republic of China ,grid.412633.10000 0004 1799 0733Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 People’s Republic of China ,Henan Province Research Center for Kidney Disease, Zhengzhou, 450052 People’s Republic of China ,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052 People’s Republic of China
| | - Dongwei Liu
- grid.207374.50000 0001 2189 3846Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052 People’s Republic of China ,grid.412633.10000 0004 1799 0733Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 People’s Republic of China ,Henan Province Research Center for Kidney Disease, Zhengzhou, 450052 People’s Republic of China ,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052 People’s Republic of China
| | - Jingjing Ren
- grid.207374.50000 0001 2189 3846Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052 People’s Republic of China ,grid.412633.10000 0004 1799 0733Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 People’s Republic of China ,Henan Province Research Center for Kidney Disease, Zhengzhou, 450052 People’s Republic of China ,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052 People’s Republic of China
| | - Guangpu Li
- grid.207374.50000 0001 2189 3846Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052 People’s Republic of China ,grid.412633.10000 0004 1799 0733Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 People’s Republic of China ,Henan Province Research Center for Kidney Disease, Zhengzhou, 450052 People’s Republic of China ,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052 People’s Republic of China
| | - Zihao Zhao
- grid.207374.50000 0001 2189 3846Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052 People’s Republic of China ,grid.412633.10000 0004 1799 0733Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 People’s Republic of China ,Henan Province Research Center for Kidney Disease, Zhengzhou, 450052 People’s Republic of China ,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052 People’s Republic of China
| | - Huanhuan Zhao
- grid.207374.50000 0001 2189 3846Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052 People’s Republic of China ,grid.412633.10000 0004 1799 0733Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 People’s Republic of China ,Henan Province Research Center for Kidney Disease, Zhengzhou, 450052 People’s Republic of China ,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052 People’s Republic of China
| | - Qianqian Yan
- grid.207374.50000 0001 2189 3846Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052 People’s Republic of China ,grid.412633.10000 0004 1799 0733Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 People’s Republic of China ,Henan Province Research Center for Kidney Disease, Zhengzhou, 450052 People’s Republic of China ,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052 People’s Republic of China
| | - Jiayu Duan
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People's Republic of China. .,Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China. .,Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, People's Republic of China. .,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People's Republic of China.
| | - Zhangsuo Liu
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People's Republic of China. .,Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China. .,Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, People's Republic of China. .,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People's Republic of China.
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Zhang R, Gan W, Zong J, Hou Y, Zhou M, Yan Z, Li T, Lv S, Zeng Z, Wang W, Zhang F, Yang M. Developing an m5C regulator-mediated RNA methylation modification signature to predict prognosis and immunotherapy efficacy in rectal cancer. Front Immunol 2023; 14:1054700. [PMID: 36911744 PMCID: PMC9992543 DOI: 10.3389/fimmu.2023.1054700] [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: 09/27/2022] [Accepted: 02/09/2023] [Indexed: 02/24/2023] Open
Abstract
Background Currently, a very small number of patients with colorectal cancer (CRC) respond to immune checkpoint inhibitor (ICI) treatment. Therefore, there is an urgent need to investigate effective biomarkers to determine the responsiveness to ICI treatment. Recently, aberrant 5-methylcytosine (m5C) RNA modification has emerged as a key player in the pathogenesis of cancer. Thus, we aimed to explore the predictive signature based on m5C regulator-related genes for characterizing the immune landscapes and predicting the prognosis and response to therapies. Methods The Cancer Genome Atlas (TCGA) cohort was used as the training set, while GEO data sets, real-time quantitative PCR (RT-qPCR) analysis from paired frozen tissues, and immunohistochemistry (IHC) data from tissue microarray (TMA) were used for validation. We constructed a novel signature based on three m5C regulator-related genes in patients with rectal adenocarcinoma (READ) using a least absolute shrinkage and selection operator (LASSO)-Cox regression and unsupervised consensus clustering analyses. Additionally, we correlated the three-gene signature risk model with the tumor immune microenvironment, immunotherapy efficiency, and potential applicable drugs. Results The m5C methylation-based signature was an independent prognostic factor, where low-risk patients showed a stronger immunoreactivity phenotype and a superior response to ICI therapy. Conversely, the high-risk patients had enriched pathways of cancer hallmarks and presented immune-suppressive state, which demonstrated that they are more insensitive to immunotherapy. Additionally, the signature markedly correlated with drug susceptibility. Conclusions We developed a reliable m5C regulator-based risk model to predict the prognosis, clarify the molecular and tumor microenvironment status, and identify patients who would benefit from immunotherapy or chemotherapy. Our study could provide vital guidance to improve prognostic stratification and optimize personalized therapeutic strategies for patients with rectal cancer.
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Affiliation(s)
- Rixin Zhang
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wenqiang Gan
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jinbao Zong
- Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, China.,Qingdao Hospital of Traditional Chinese Medicine, The Affiliated Qingdao Hiser Hospital of Qingdao University, Qingdao, China
| | - Yufang Hou
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mingxuan Zhou
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zheng Yan
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tiegang Li
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Silin Lv
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zifan Zeng
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weiqi Wang
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fang Zhang
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Min Yang
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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N1-methyladenosine modification in cancer biology: current status and future perspectives. Comput Struct Biotechnol J 2022; 20:6578-6585. [PMID: 36467585 PMCID: PMC9712505 DOI: 10.1016/j.csbj.2022.11.045] [Citation(s) in RCA: 85] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 11/22/2022] [Accepted: 11/22/2022] [Indexed: 11/27/2022] Open
Abstract
Post-transcriptional modifications in RNAs regulate their biological behaviors and functions. N1-methyladenosine (m1A), which is dynamically regulated by writers, erasers and readers, has been found as a reversible modification in tRNA, mRNA, rRNA and long non-coding RNA (lncRNA). m1A modification has impacts on the RNA processing, structure and functions of targets. Increasing studies reveal the critical roles of m1A modification and its regulators in tumorigenesis. Due to the positive relevance between m1A and cancer development, targeting m1A modification and m1A-related regulators has been of attention. In this review, we summarized the current understanding of m1A in RNAs, covering the modulation of m1A modification in cancer biology, as well as the possibility of targeting m1A modification as a potential target for cancer diagnosis and therapy.
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Liu H, Wang D, Yang Z, Li S, Wu H, Xiang J, Kan S, Hao M, Liu W. Regulation of epigenetic modifications in the head and neck tumour microenvironment. Front Immunol 2022; 13:1050982. [DOI: 10.3389/fimmu.2022.1050982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 10/14/2022] [Indexed: 12/24/2022] Open
Abstract
Head and neck tumours are common malignancies that are associated with high mortality. The low rate of early diagnosis and the high rates of local recurrence and distant metastasis are the main reasons for treatment failure. Recent studies have established that the tumour microenvironment (TME) can affect the proliferation and metastasis of head and neck tumours via several mechanisms, including altered expressions of certain genes and cytokines. Increasing evidence has shown that epigenetic modifications, such as DNA methylation, histone modification, RNA modification, and non-coding RNAs, can regulate the head and neck TME and thereby influence tumour development. Epigenetic modifications can regulate the expression of different genes and subsequently alter the TME to affect the progression of head and neck tumours. In addition, the cell components in the TME are regulated by epigenetic modifications, which, in turn, affect the behaviour of head and neck tumour cells. In this review, we have discussed the functions of epigenetic modifications in the head and neck TME. We have further examined the roles of such modifications in the malignancy and metastasis of head and neck tumours.
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Wei W, Liu C, Wang C, Wang M, Jiang W, Zhou Y, Zhang S. Comprehensive pan-cancer analysis of N7-methylguanosine regulators: Expression features and potential implications in prognosis and immunotherapy. Front Genet 2022; 13:1016797. [PMID: 36339001 PMCID: PMC9633684 DOI: 10.3389/fgene.2022.1016797] [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: 08/11/2022] [Accepted: 10/11/2022] [Indexed: 11/27/2022] Open
Abstract
Although immunotherapy has made great strides in cancer therapy, its effectiveness varies widely among individual patients as well as tumor types, and there is an urgent need to develop biomarkers for effectively assessing immunotherapy response. In recent years, RNA methylation regulators have demonstrated to be novel potential biomarkers for prognosis as well as immunotherapy of cancers, such as N6-methyladenine (m6A) and 5-methylcytosine (m5C). N7-methylguanosine (m7G) is a prevalent RNA modification in eukaryotes, but the relationship between m7G regulators and prognosis as well as tumor immune microenvironment is still unclear. In this study, a pan-cancer analysis of 26 m7G regulators across 17 cancer types was conducted based on the bioinformatics approach. On the one hand, a comprehensive analysis of expression features, genetic variations and epigenetic regulation of m7G regulators was carried out, and we found that the expression tendency of m7G regulators were different among tumors and their aberrant expression in cancers could be affected by single nucleotide variation (SNV), copy number variation (CNV), DNA methylation and microRNA (miRNA) separately or simultaneously. On the other hand, the m7Gscore was modeled based on single sample gene set enrichment analysis (ssGSEA) for evaluating the relationships between m7G regulators and cancer clinical features, hallmark pathways, tumor immune microenvironment, immunotherapy response as well as pharmacotherapy sensitivity, and we illustrated that the m7Gscore exhibited tight correlations with prognosis, several immune features, immunotherapy response and drug sensitivity in most cancers. In conclusion, our pan-cancer analysis revealed that m7G regulators may exert critical roles in the tumor progression and immune microenvironment, and have the potential as biomarkers for predicting prognosis, immunotherapy response as well as candidate drug compounds for cancer patients.
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Affiliation(s)
- Wei Wei
- Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Chao Liu
- Department of Vascular Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Caihong Wang
- Department of Pathology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Meng Wang
- Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Wei Jiang
- Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yaqian Zhou
- College of Chemistry and Materials Science, Northwest University, Xi’an, Shaanxi, China
| | - Shuqun Zhang
- Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
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Yuan S, Gao Y, Xia Y, Wang Z, Wang X. DNA methylation regulator-mediated modification pattern defines tumor microenvironment immune infiltration landscape in colon cancer. Front Genet 2022; 13:1008644. [PMID: 36276973 PMCID: PMC9582351 DOI: 10.3389/fgene.2022.1008644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Emerging evidence implies a non-negligible role of DNA methylation in tumor immunity, however, its comprehensive impact on tumor microenvironment (TME) formation and immune activation remains unclear. In this study, we integrated 24 DNA methylation regulators among 754 colon cancer patients to distinguish different modification patterns via an unsupervised clustering method, and explore their TME immune characteristics. Three DNA methylation modification patterns with distinct prognosis and biological behaviors were identified, consistent with three known phenotypes of immune-inflamed, immune-excluded, and immune-desert. We then determined a DNA methylation gene signature and constructed a DNA methylation score (DMS) to quantify modification patterns individually through principal component analysis algorithms. DMS-low group had characteristics of specific molecular subtypes, including microsatellite instability, CpG island methylator phenotype positive, and mutant BRAF, presented by increased mutation burden, activation of DNA damage repair and immune-related pathways, highly TME immune cells infiltration, and hence, a preferable prognosis. Further, low DMS was also demonstrated to be correlated to better response and prolonged survival of anti-PD-L1 antibody, indicating that DMS could be considered as an effective predictive tool for immunotherapy. In conclusion, our work presented a landscape of different DNA methylation modification patterns, and their vital role in the formation of TME diversity and complexity, which could help to enhance understanding of TME immune infiltration characteristics and more importantly, guide immunotherapy strategies more effectively and personalized.
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Affiliation(s)
- Shijin Yuan
- Department of Medical Oncology, Cancer Institute of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Shijin Yuan, ; Xian Wang,
| | - Yuzhen Gao
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yan Xia
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhuo Wang
- Department of Medical Oncology, Cancer Institute of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xian Wang
- Department of Medical Oncology, Cancer Institute of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Shijin Yuan, ; Xian Wang,
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Zhang X, Wang Y, Dong B, Jiang Y, Liu D, Xie K, Yu Y. Expression pattern and clinical value of Key RNA methylation modification regulators in ischemic stroke. Front Genet 2022; 13:1009145. [PMID: 36263422 PMCID: PMC9574037 DOI: 10.3389/fgene.2022.1009145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 09/16/2022] [Indexed: 11/13/2022] Open
Abstract
Ischemic stroke (IS) is one of the major causes of death and disability worldwide, and effective diagnosis and treatment methods are lacking. RNA methylation, a common epigenetic modification, plays an important role in disease progression. However, little is known about the role of RNA methylation modification in the regulation of IS. The aim of this study was to investigate RNA methylation modification patterns and immune infiltration characteristics in IS through bioinformatics analysis. We downloaded gene expression profiles of control and IS model rat brain tissues from the Gene Expression Omnibus database. IS profiles were divided into two subtypes based on RNA methylation regulators, and functional enrichment analyses were conducted to determine the differentially expressed genes (DEGs) between the subtypes. Weighted gene co-expression network analysis was used to explore co-expression modules and genes based on DEGs. The IS clinical diagnosis model was successfully constructed and four IS characteristic genes (GFAP, GPNMB, FKBP9, and CHMP5) were identified, which were significantly upregulated in IS samples. Characteristic genes were verified by receiver operating characteristic curve and real-time quantitative PCR analyses. The correlation between characteristic genes and infiltrating immune cells was determined by correlation analysis. Furthermore, GPNMB was screened using the protein-protein interaction network, and its regulatory network and the potential therapeutic drug chloroquine were predicted. Our finding describes the expression pattern and clinical value of key RNA methylation modification regulators in IS and novel diagnostic and therapeutic targets of IS from a new perspective.
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Affiliation(s)
- Xinyue Zhang
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Institute of Anesthesiology, Tianjin, China
| | - Yuanlin Wang
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Institute of Anesthesiology, Tianjin, China
| | - Beibei Dong
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Institute of Anesthesiology, Tianjin, China
| | - Yi Jiang
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Institute of Anesthesiology, Tianjin, China
| | - Dan Liu
- School of Medicine, Nankai University, Tianjin, China
| | - Keliang Xie
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Institute of Anesthesiology, Tianjin, China
- Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Yonghao Yu
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Institute of Anesthesiology, Tianjin, China
- *Correspondence: Yonghao Yu,
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36
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Ma S, Zhu J, Wang M, Zhu J, Wang W, Xiong Y, Jiang R, Liu L, Jiang T. Comprehensive analysis of m7G modification patterns based on potential m7G regulators and tumor microenvironment infiltration characterization in lung adenocarcinoma. Front Genet 2022; 13:996950. [PMID: 36246663 PMCID: PMC9559715 DOI: 10.3389/fgene.2022.996950] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
Background: The non-negligible role of epigenetic modifications in cancer development and tumor microenvironment (TME) has been demonstrated in recent studies. Nonetheless, the potential regulatory role of N7-methylguanosine (m7G) modification in shaping and impacting the TME remains unclear. Methods: A comprehensive analysis was performed to explore the m7G modification patterns based on 24 potential m7G regulators in 817 lung adenocarcinoma (LUAD) patients, and the TME landscape in distinct m7G modification patterns were evaluated. The m7G score was established based on principal component analysis (PCA) to quantify m7G modification patterns and evaluate the TME cell infiltrating characteristics of individual tumors. Further, correlation analyses of m7Gscore with response to chemotherapy and immunotherapy were performed. Results: We identified three distinct m7G modification patterns with the biological pathway enrichment and TME cell infiltrating characteristics corresponded to immune-desert, immune-inflamed and immune-excluded phenotype, respectively. We further demonstrated the m7Gscore could predict the TME infiltrating characteristics, tumor mutation burden (TMB), response to immunotherapy and chemotherapy, as well as prognosis of individual tumors. High m7Gscore was associated with increased component of immune cell infiltration, low TMB and survival advantage, while low m7Gscore was linked to decreased immune cell infiltration and increased TMB. Additionally, patients with lower m7Gscore demonstrated significant therapeutic advantages. Conclusion: This study demonstrated the regulatory mechanisms of m7G modification on TME formation and regulation of lung adenocarcinoma. Identification of individual tumor m7G modification patterns will contribute to the understanding of TME characterization and guiding more effective immunotherapy strategies.
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Affiliation(s)
- Shouzheng Ma
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
| | - Jun Zhu
- Department of General Surgery, The Southern Theater Air Force Hospital, Guangzhou, China
| | - Mengmeng Wang
- Department of Drug and Equipment, Lintong Rehabilitation and Convalescent Centre, Xi’an, China
| | - Jianfei Zhu
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
| | - Wenchen Wang
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
| | - Yanlu Xiong
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
| | - Runmin Jiang
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
| | - Lei Liu
- Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
- *Correspondence: Lei Liu, ; Tao Jiang,
| | - Tao Jiang
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
- *Correspondence: Lei Liu, ; Tao Jiang,
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RNA modifications: importance in immune cell biology and related diseases. Signal Transduct Target Ther 2022; 7:334. [PMID: 36138023 PMCID: PMC9499983 DOI: 10.1038/s41392-022-01175-9] [Citation(s) in RCA: 177] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/23/2022] [Accepted: 08/31/2022] [Indexed: 11/16/2022] Open
Abstract
RNA modifications have become hot topics recently. By influencing RNA processes, including generation, transportation, function, and metabolization, they act as critical regulators of cell biology. The immune cell abnormality in human diseases is also a research focus and progressing rapidly these years. Studies have demonstrated that RNA modifications participate in the multiple biological processes of immune cells, including development, differentiation, activation, migration, and polarization, thereby modulating the immune responses and are involved in some immune related diseases. In this review, we present existing knowledge of the biological functions and underlying mechanisms of RNA modifications, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanosine (m7G), N4-acetylcytosine (ac4C), pseudouridine (Ψ), uridylation, and adenosine-to-inosine (A-to-I) RNA editing, and summarize their critical roles in immune cell biology. Via regulating the biological processes of immune cells, RNA modifications can participate in the pathogenesis of immune related diseases, such as cancers, infection, inflammatory and autoimmune diseases. We further highlight the challenges and future directions based on the existing knowledge. All in all, this review will provide helpful knowledge as well as novel ideas for the researchers in this area.
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Lu H, Zheng LY, Wu LY, Chen J, Xu N, Mi SC. The immune escape signature predicts the prognosis and immunotherapy sensitivity for pancreatic ductal adenocarcinoma. Front Oncol 2022; 12:978921. [PMID: 36147906 PMCID: PMC9486201 DOI: 10.3389/fonc.2022.978921] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/16/2022] [Indexed: 01/30/2023] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies worldwide. Immune escape is considered to be a reason for immunotherapy failure in PDAC. In this study, we explored the correlation between immune escape-related genes and the prognosis of PDAC patients. Methods 1163 PDAC patients from four public databases, including The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), Array-express, and Gene Expression Omnibus (GEO), were included in our study. Cox regression analysis was used to identify the 182 immune genes which were significantly associated with overall survival (OS). And then we established an immune escape-related gene prognosis index (IEGPI) score using several datasets as the training cohort and validated it using the validation cohort. Kaplan-Meier (KM) and Cox regression analysis were used to detect the relationship of IEGPI score with OS. We further explored the relationship between the IEGPI and immune indexes. And the prediction value of response for immunotherapy in Tumor Immune Dysfunction and Exclusion (TIDE) dataset. Results We establish an IEGPI score based on 27 immune escape genes which were significantly related to the prognosis of OS in PDAC patients. Patients in the high-IEGPI group had a significantly worse overall survival rate compared with that in the low-IEGPI groups by KM curves and cox-regression. 5 of the 32 cancer types in TCGA could be significantly distinguished in survival rates through the low- and high-IEGPI groups. Moreover, the correlation between the IEGPI score was negatively correlated with an immune score in several datasets. And higher IEGPI better recurrence-free survival (RFS) and OS in the patients after patients were treated with both PD-1 and CTLA4 in the public datasets (P<0.05). Intriguingly, by using RT-PCR, we verified that the gene of PTPN2, CEP55, and JAK2 were all higher in the BxPC-3 and PANC-1 than HPDE5 cells. Lastly, we found that the IEGPI score was higher in K-rasLSL.G12D/+, p53LSL.R172H/+, Pdx1Cre (KPC) mice model with anti-PD-L1 than that without anti-PD-L1. Conclusion Using the immune escape-related genes, our study established and validated an IEGPI score in PDAC patients from the public dataset. IEGPI score has the potential to serve as a prognostic marker and as a tool for selecting tumor patients suitable for immunotherapy in clinical practice.
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Zhu M, Huang C, Wu X, Gu Y, Hu X, Ma D, Zhong W. Aging-based molecular classification and score system in ccRCC uncovers distinct prognosis, tumor immunogenicity, and treatment sensitivity. Front Immunol 2022; 13:877076. [PMID: 36032073 PMCID: PMC9402984 DOI: 10.3389/fimmu.2022.877076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 07/21/2022] [Indexed: 12/24/2022] Open
Abstract
Objective Aging is a complex biological process and a major risk factor for cancer development. This study was conducted to develop a novel aging-based molecular classification and score system in clear cell renal cell carcinoma (ccRCC). Methods Integrative analysis of aging-associated genes was performed among ccRCC patients in the TCGA and E-MTAB-1980 cohorts. In accordance with the transcriptional expression matrix of 173 prognostic aging-associated genes, aging phenotypes were clustered with the consensus clustering approach. The agingScore was generated to quantify aging phenotypes with principal component analysis. Tumor-infiltrating immune cells and the cancer immunity cycle were quantified with the ssGSEA approach. Immunotherapy response was estimated through the TIDE algorithm, and a series of tumor immunogenicity indicators were computed. Drug sensitivity analysis was separately conducted based on the GDSC, CTRP, and PRISM analyses. Results Three aging phenotypes were established for ccRCC, with diverse prognosis, clinical features, immune cell infiltration, tumor immunogenicity, immunotherapeutic response, and sensitivity to targeted drugs. The agingScore was developed, which enabled to reliably and independently predict ccRCC prognosis. Low agingScore patients presented more undesirable survival outcomes. Several small molecular compounds and three therapeutic targets, namely, CYP11A1, SAA1, and GRIK4, were determined for the low agingScore patients. Additionally, the high agingScore patients were more likely to respond to immunotherapy. Conclusion Overall, our findings introduced an aging-based molecular classification and agingScore system into the risk stratification and treatment decision-making in ccRCC.
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Affiliation(s)
- Maoshu Zhu
- Department of Central Laboratory, the Fifth Hospital of Xiamen, Xiamen, China
| | - Chaoqun Huang
- Department of Central Laboratory, the Fifth Hospital of Xiamen, Xiamen, China
| | - Xinhong Wu
- Department of Central Laboratory, the Fifth Hospital of Xiamen, Xiamen, China
| | - Ying Gu
- Department of Pharmacy, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Xiaoxu Hu
- Affiliated Primary School to Renmin University of China, Beijing, China
| | - Dongna Ma
- Key Laboratory of the Ministry of Education for Coastal and Wetland Ecosystems, College of the Environment and Ecology, Xiamen University, Xiamen, China
- *Correspondence: Weimin Zhong, ; Dongna Ma,
| | - Weimin Zhong
- Department of Central Laboratory, the Fifth Hospital of Xiamen, Xiamen, China
- *Correspondence: Weimin Zhong, ; Dongna Ma,
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40
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Zhang H, Hong Z, Li P, Jiang H, Wu P, Chen J. Identification and Validation of an Immune Evasion Molecular Subgroup of Patients With Colon Cancer for Implications of Immunotherapy. Front Genet 2022; 13:811660. [PMID: 35991554 PMCID: PMC9389216 DOI: 10.3389/fgene.2022.811660] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 06/20/2022] [Indexed: 12/09/2022] Open
Abstract
Immune evasion (IEV) plays a critical role in the development and progression of colon cancer. However, studies to predict the prognosis of colon cancer via IEV-related genes are limited. Therefore, based on the 182 IEV-related genes, we used the univariate and Lasso Cox regression model to construct the IEV-related genes signature (IEVSig) of 16 prognostic IEV-related genes using the Gene Expression Omnibus and The Cancer Genome Atlas online databases. We found that IEVSig was an independent prognostic factor, and patients with high IEVSig had higher TNM stage and shorter recurrence-free survival than their counterparts. Kyoto Encyclopedia of Genes and Genomes and gene set enrichment analyses revealed that patients with high and low IEVSig had significantly different enrichment pathways. Immune cell infiltration analysis showed that nine immune cells obviously increased in the high-IEVSig group, whereas five immune cells increased in the low-IEVSig group. Immunotherapy cohort analysis revealed that patients with high IEVSig had a higher proportion of progressive disease or stable disease after receiving immunotherapy than patients with low IEVSig. Furthermore, patients with low IEVSig had higher tumor mutation load and neoantigen burden, which indicated an improved response to immunotherapy, than patients with high IEVSig. Thus, an IEV-related prognostic signature was established to predict the prognosis of patients with colon cancer and derive a prediction marker to offer insights into therapeutic strategies.
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Affiliation(s)
- Hongbin Zhang
- Endoscopy Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Correspondence: Hongbin Zhang,
| | - Zaifa Hong
- Department of Hepato-Biliary-Pancreatic and Vascular Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Peipei Li
- Department of Hepato-Biliary-Pancreatic Surgery, Xiamen Hospital, Beijing University of Chinese Medicine, Xiamen, China
| | - Han Jiang
- Department of General Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Pengfei Wu
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jinzhong Chen
- Endoscopy Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
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Methyladenosine Modification in RNAs: From Regulatory Roles to Therapeutic Implications in Cancer. Cancers (Basel) 2022; 14:cancers14133195. [PMID: 35804965 PMCID: PMC9264946 DOI: 10.3390/cancers14133195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Cancer remains a burden to the public health all over the world. An increasing number of studies have concentrated on the role of methyladenosine modifications on cancers. Methyladenosine modifications mainly include N6-methyladenosine (m6A), N1-methyladenosine (m1A), and 2’-O-methyladenosine (m6Am), of which dynamic changes could modulate the metabolism of RNAs in eukaryotic cells. Mounting evidence has confirmed the crucial role of methyladenosine modification in cancer, offering possibilities for cancer therapy. In this review, we discussed the regulatory role of methyladenosine modification on cancer, as well as their potential for treatment. Abstract Methyladenosine modifications are the most abundant RNA modifications, including N6-methyladenosine (m6A), N1-methyladenosine (m1A), and 2’-O-methyladenosine (m6Am). As reversible epigenetic modifications, methyladenosine modifications in eukaryotic RNAs are not invariable. Drastic alterations of m6A are found in a variety of diseases, including cancers. Dynamic changes of m6A modification induced by abnormal methyltransferase, demethylases, and readers can regulate cancer progression via interfering with the splicing, localization, translation, and stability of mRNAs. Meanwhile, m6A, m1A, and m6Am modifications also exert regulatory effects on noncoding RNAs in cancer progression. In this paper, we reviewed recent findings concerning the underlying biomechanism of methyladenosine modifications in oncogenesis and metastasis and discussed the therapeutic potential of methyladenosine modifications in cancer treatments.
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Wu Y, Jiang D, Zhang H, Yin F, Guo P, Zhang X, Bian C, Chen C, Li S, Yin Y, Böckler D, Zhang J, Han Y. N1-Methyladenosine (m1A) Regulation Associated With the Pathogenesis of Abdominal Aortic Aneurysm Through YTHDF3 Modulating Macrophage Polarization. Front Cardiovasc Med 2022; 9:883155. [PMID: 35620523 PMCID: PMC9127271 DOI: 10.3389/fcvm.2022.883155] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 04/20/2022] [Indexed: 11/30/2022] Open
Abstract
Objectives This study aimed to identify key AAA-related m1A RNA methylation regulators and their association with immune infiltration in AAA. Furthermore, we aimed to explore the mechanism that m1A regulators modulate the functions of certain immune cells as well as the downstream target genes, participating in the progression of AAA. Methods Based on the gene expression profiles of the GSE47472 and GSE98278 datasets, differential expression analysis focusing on m1A regulators was performed on the combined dataset to identify differentially expressed m1A regulatory genes (DEMRGs). Additionally, CIBERSORT tool was utilized in the analysis of the immune infiltration landscape and its correlation with DEMRGs. Moreover, we validated the expression levels of DEMRGs in human AAA tissues by real-time quantitative PCR (RT-qPCR). Immunofluorescence (IF) staining was also applied in the validation of cellular localization of YTHDF3 in AAA tissues. Furthermore, we established LPS/IFN-γ induced M1 macrophages and ythdf3 knockdown macrophages in vitro, to explore the relationship between YTHDF3 and macrophage polarization. At last, RNA immunoprecipitation-sequencing (RIP-Seq) combined with PPI network analysis was used to predict the target genes of YTHDF3 in AAA progression. Results Eight DEMRGs were identified in our study, including YTHDC1, YTHDF1-3, RRP8, TRMT61A as up-regulated genes and FTO, ALKBH1 as down-regulated genes. The immune infiltration analysis showed these DEMRGs were positively correlated with activated mast cells, plasma cells and M1 macrophages in AAA. RT-qPCR analysis also verified the up-regulated expression levels of YTHDC1, YTHDF1, and YTHDF3 in human AAA tissues. Besides, IF staining result in AAA adventitia indicated the localization of YTHDF3 in macrophages. Moreover, our in-vitro experiments found that the knockdown of ythdf3 in M0 macrophages inhibits macrophage M1 polarization but promotes macrophage M2 polarization. Eventually, 30 key AAA-related target genes of YTHDF3 were predicted, including CD44, mTOR, ITGB1, STAT3, etc. Conclusion Our study reveals that m1A regulation is significantly associated with the pathogenesis of human AAA. The m1A “reader,” YTHDF3, may participate in the modulating of macrophage polarization that promotes aortic inflammation, and influence AAA progression by regulating the expression of its target genes.
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Affiliation(s)
- Yihao Wu
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Deying Jiang
- Department of Vascular Surgery, Dalian Municipal Central Hospital, Dalian, China
| | - Hao Zhang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Fanxing Yin
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Panpan Guo
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Xiaoxu Zhang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Ce Bian
- Department of Cardiovascular Surgery, The General Hospital of the PLA Rocket Force, Beijing, China
| | - Chen Chen
- School of Biomedical Sciences, University of Queensland, St Lucia, Brisbane, QLD, Australia
| | - Shuixin Li
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Yuhan Yin
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Dittmar Böckler
- Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Jian Zhang
- Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, China
- *Correspondence: Jian Zhang
| | - Yanshuo Han
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
- Yanshuo Han ; orcid.org/0000-0002-4897-2998
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Gao Y, Wang H, Chen S, An R, Chu Y, Li G, Wang Y, Xie X, Zhang J. Single-cell N 6-methyladenosine regulator patterns guide intercellular communication of tumor microenvironment that contribute to colorectal cancer progression and immunotherapy. J Transl Med 2022; 20:197. [PMID: 35509079 PMCID: PMC9066909 DOI: 10.1186/s12967-022-03395-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 04/17/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND N6-methyladenosine (m6A) RNA methylation plays a critical role in key genetic events for various cancers; yet, how m6A functions within the tumor microenvironment (TME) remains to be elucidated. METHODS A total of 65,362 single cells from single-cell RNA-seq data derived from 33 CRC tumor samples were analyzed by nonnegative matrix factorization (NMF) for 23 m6A RNA methylation regulators. CRC and Immunotherapy cohorts from public repository were used to determine the prognosis and immune response of TME clusters. RESULTS The fibroblasts, macrophages, T and B cells were respectively grouped into 4 to 5 subclusters and then classified according to various biological processes and different marker genes. Furthermore, it revealed that the m6A RNA methylation regulators might be significantly related to the clinical and biological features of CRC, as well as the pseudotime trajectories of main TME cell types. Bulk-seq analysis suggested that these m6A-mediated TME cell subclusters had significant prognostic value for CRC patients and distinguished immune response for patients who underwent ICB therapy, especially for the CAFs and macrophages. Notably, CellChat analysis revealed that RNA m6A methylation-associated cell subtypes of TME cells manifested diverse and extensive interaction with tumor epithelial cells. Further analysis showed that ligand-receptor pairs, including MIF - (CD74 + CXCR4), MIF - (CD74 + CD44), MDK-NCL and LGALS9 - CD45, etc. mediated the communication between m6A associated subtypes of TME cells and tumor epithelial cells. CONCLUSIONS Taken together, our study firstly revealed the m6A methylation mediated intercellular communication of the tumor microenvironment in the regulation of tumor growth and antitumor immunomodulatory processes.
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Affiliation(s)
- Yuzhen Gao
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Qingchun East Road, Jianggan District, Hangzhou, 310016, Zhejiang, China.,Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, 310013, Zhejiang, China
| | - Hao Wang
- Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.,Institution of Gastroenterology, Zhejiang University, Hangzhou, 310009, Zhejiang, China
| | - Shipeng Chen
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China
| | - Rui An
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Qingchun East Road, Jianggan District, Hangzhou, 310016, Zhejiang, China.,Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, 310013, Zhejiang, China
| | - Yadong Chu
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Qingchun East Road, Jianggan District, Hangzhou, 310016, Zhejiang, China.,Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, 310013, Zhejiang, China
| | - Guoli Li
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Qingchun East Road, Jianggan District, Hangzhou, 310016, Zhejiang, China.,Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, 310013, Zhejiang, China
| | - Yanzhong Wang
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Qingchun East Road, Jianggan District, Hangzhou, 310016, Zhejiang, China.,Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, 310013, Zhejiang, China
| | - Xinyou Xie
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Qingchun East Road, Jianggan District, Hangzhou, 310016, Zhejiang, China. .,Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, 310013, Zhejiang, China.
| | - Jun Zhang
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Qingchun East Road, Jianggan District, Hangzhou, 310016, Zhejiang, China. .,Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, 310013, Zhejiang, China.
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Xiong W, Li C, Wan B, Zheng Z, Zhang Y, Wang S, Fan J. N6-Methyladenosine Regulator-Mediated Immue Patterns and Tumor Microenvironment Infiltration Characterization in Glioblastoma. Front Immunol 2022; 13:819080. [PMID: 35359993 PMCID: PMC8961865 DOI: 10.3389/fimmu.2022.819080] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 02/22/2022] [Indexed: 12/12/2022] Open
Abstract
Background Epigenetic modifications, according to emerging evidence, perform a critical role for cellular immune response and tumorigenesis. Nonetheless, the role of N6-methyladenosine modification in shaping of the glioblastoma tumor microenvironment is unknown. Methods N6-methyladenosine(m6A) methylation patterns in GBM patients were evaluated via multiple omics analysis of 15 m6A regulators and systematically correlated with tumor immune features. For quantification of N6-methyladenosine methylation patterns of individual patients, GM-score was developed and correlated with clinical and immunological characteristics. Results Glioblastoma has two different m6A methylation patterns that are strongly associated with TME characteristics, tumor subtype, immunotherapy response, and patient prognosis. High-GM-score is associated with an immune tolerance phenotype dominated by the IDH1 wild molecular subtype and the Mesenchymal tissue subtype, as well as a high infiltration of immune cells and stromal cells and a poor prognosis. Furthermore, despite higher immune checkpoint expression, individuals with a high-GM-score have a poorer response to anti-CTLA4 immunotherapy regimens due to T-cells dysfunctional. Low-GM-score individuals had an immunodeficient phenotype dominated by IDH mutant molecular subtypes and Proneural tissue subtypes, with less immune cell infiltration and a better prognosis. Furthermore, patients with low-GM-scores had higher microsatellite instability (MSI) and t-cell exclusion scores, as well as a better response to anti-CTLA4 immunotherapy regimens. Conclusion This study demonstrated that m6A modification patterns play an important role in the shaping of TME complexity and diversity. The GM-score could identify m6A modification patterns in individual patients, resulting in a more personalization and efficacious anti-tumor immunotherapy strategy.
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Affiliation(s)
- Wu Xiong
- Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Nanjing Medical University, Nanjing, China
| | - Cong Li
- Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Nanjing Medical University, Nanjing, China
| | - Bowen Wan
- Department of Orthopaedics, Subei People’s Hospital of Jiangsu, Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Ziyang Zheng
- Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Nanjing Medical University, Nanjing, China
| | - Yingfei Zhang
- Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Nanjing Medical University, Nanjing, China
| | - Siming Wang
- Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Nanjing Medical University, Nanjing, China
| | - Jin Fan
- Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Nanjing Medical University, Nanjing, China
- *Correspondence: Jin Fan,
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Uncovering the Immune Cell Infiltration Landscape in Low-Grade Glioma for Aiding Immunotherapy. JOURNAL OF ONCOLOGY 2022; 2022:3370727. [PMID: 35310911 PMCID: PMC8933094 DOI: 10.1155/2022/3370727] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/21/2022] [Indexed: 12/15/2022]
Abstract
Objective Low-grade glioma (LGG) mainly threatens the elderly population, with undesirable prognoses. This study uncovered the immune cell infiltration (ICI) landscape in LGG. Methods RNA-seq profiles of LGG were retrieved from TCGA and CGGA databases. CIBERSORTx and ESTIMATE algorithms were employed to characterize the ICI landscape in LGG tissues. Through unsupervised clustering analysis, ICI subtypes were clustered. ICI scores were computed via principal component analysis (PCA). The differences in survival, tumor-infiltrating immune cells, stromal scores, immune scores, immune checkpoint genes, immune activity genes, and tumor mutation burden (TMB) were assessed between high and low ICI score groups. Results Three ICI subtypes were constructed in LGG, with distinct survival outcomes, PD-L1 expression, and infiltration levels of immune cells. Furthermore, ICI scores were developed. Both in TCGA and CGGA datasets, low ICI scores were indicative of undesirable outcomes. High ICI scores were significantly correlated to increased infiltration levels of memory B cells, CD8 T cells, CD4 naïve T cells, T follicular helper cells, macrophages M0, and eosinophils, while low ICI scores were characterized by increased infiltration levels of naïve B cells, plasma cells, CD4 memory resting T cells, Tregs, resting NK cells, macrophages M2, and activated dendritic cells. High ICI scores exhibited correlations with lower immune activity genes and immune checkpoint genes. Furthermore, TMB was distinctly reduced in the high ICI score group. Conclusion The ICI scores may serve as a promising prognostic index and predictive indicator for immunotherapies, extending our understanding of immune microenvironment in LGG.
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Zhang S, Xiong Y, Zheng C, Long J, Zhou H, Zeng Z, Ouyang Y, Tang F. Crosstalk Between Four Types of RNA Modification Writers Characterizes the Tumor Immune Microenvironment Infiltration Patterns in Skin Cutaneous Melanoma. Front Cell Dev Biol 2022; 10:821678. [PMID: 35155433 PMCID: PMC8826580 DOI: 10.3389/fcell.2022.821678] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 01/10/2022] [Indexed: 11/13/2022] Open
Abstract
The “writers” of four types of adenosine (A)-related RNA modifications (N6-methyladenosine, N1-methyladenosine, alternative polyadenylation, as well as A-to-inosine RNA editing) are closely related to the tumorigenesis and progression of many cancer types, including skin cutaneous melanoma (SKCM). However, the potential roles of the crosstalk between these RNA modification “writers” in the tumor microenvironment (TME) remain unclear. The RNA modification patterns were identified using an unsupervised clustering method. Subsequently, based on differentially expressed genes responsible for the aforementioned RNA modification patterns, an RNA modification “writer” scoring model (W_Score) was constructed to quantify the RNA modification-associated subtypes in individual patients. Moreover, a correlation analysis for W_Score and the TME characteristics, clinical features, molecular subtypes, drug sensitivities, immune responses, and prognosis was performed. We identified three RNA modification patterns, corresponding to distinct tumor immune microenvironment characteristics and survival outcomes. Based on the W_Score score, which was extracted from the RNA modification-related signature genes, patients with SKCM were divided into high- and low-W_Score groups. The low-W_Score group was characterized by better survival outcomes and strengthened immunocyte infiltration. Further analysis showed that the low-W_Score group was positively associated with higher tumor mutation burden and PD-L1 expression. Of note, two immunotherapy cohorts demonstrated that patients with low W_Score exhibited long-term clinical benefits and an enhanced immune response. This study is the first to systematically analyze four types of A-related RNA modifications in SKCM, revealing that these “writers” essentially contribute to TME complexity and diversity. We quantitatively evaluated the RNA modification patterns in individual tumors, which could aid in developing personalized immunotherapy strategies for patients.
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Affiliation(s)
- Shichao Zhang
- Key Laboratory of Infectious Immune and Antibody Engineering in Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, China
| | - Yu Xiong
- Key Laboratory of Infectious Immune and Antibody Engineering in Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, China
| | - Chaochao Zheng
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, China
| | - Jinhua Long
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, China
| | - Houming Zhou
- Key Laboratory of Infectious Immune and Antibody Engineering in Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, China
| | - Zhu Zeng
- Key Laboratory of Infectious Immune and Antibody Engineering in Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, China
- *Correspondence: Fuzhou Tang, ; Yan Ouyang, ; Zhu Zeng,
| | - Yan Ouyang
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, China
- *Correspondence: Fuzhou Tang, ; Yan Ouyang, ; Zhu Zeng,
| | - Fuzhou Tang
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, China
- *Correspondence: Fuzhou Tang, ; Yan Ouyang, ; Zhu Zeng,
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Ouyang W, Jiang Y, Bu S, Tang T, Huang L, Chen M, Tan Y, Ou Q, Mao L, Mai Y, Yao H, Yu Y, Lin X. A Prognostic Risk Score Based on Hypoxia-, Immunity-, and Epithelialto-Mesenchymal Transition-Related Genes for the Prognosis and Immunotherapy Response of Lung Adenocarcinoma. Front Cell Dev Biol 2022; 9:758777. [PMID: 35141229 PMCID: PMC8819669 DOI: 10.3389/fcell.2021.758777] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 12/28/2021] [Indexed: 12/14/2022] Open
Abstract
Background: Lung adenocarcinoma (LUAD), the most common subtype of non-small cell lung cancer (NSCLC), is associated with poor prognosis. However, current stage-based clinical methods are insufficient for survival prediction and decision-making. This study aimed to establish a novel model for evaluating the risk of LUAD based on hypoxia, immunity, and epithelial-mesenchymal transition (EMT) gene signatures. Methods: In this study, we used data from TCGA-LUAD for the training cohort and GSE68465 and GSE72094 for the validation cohorts. Immunotherapy datasets GSE135222, GSE126044, and IMvigor210 were obtained from a previous study. Using bioinformatic and machine algorithms, we established a risk model based on hypoxia, immune, and EMT gene signatures, which was then used to divide patients into the high and low risk groups. We analyzed differences in enriched pathways between the two groups, following which we investigated whether the risk score was correlated with stemness scores, genes related to m6A, m5C, m1A and m7G modification, the immune microenvironment, immunotherapy response, and multiple anti-cancer drug sensitivity. Results: Overall survival differed significantly between the high-risk and low-risk groups (HR = 4.26). The AUCs for predicting 1-, 3-, and 5-year survival were 0.763, 0.766, and 0.728, respectively. In the GSE68465 dataset, the HR was 2.03, while the AUCs for predicting 1-, 3-, and 5-year survival were 0.69, 0.651, and 0.618, respectively. The corresponding values in the GSE72094 dataset were an HR of 2.36 and AUCs of 0.653, 0.662, and 0.749, respectively. The risk score model could independently predict OS in patients with LUAD, and highly correlated with stemness scores and numerous m6A, m5C, m1A and m7G modification-related genes. Furthermore, the risk model was significantly correlated with multiple immune microenvironment characteristics. In the GSE135222 dataset, the HR was 4.26 and the AUC was 0.702. Evaluation of the GSE126044 and IMvigor210 cohorts indicated that PD-1/PD-LI inhibitor treatment may be indicated in patients with low risk scores, while anti-cancer therapy with various drugs may be indicated in patients with high risk scores. Conclusion: Our novel risk model developed based on hypoxia, immune, and EMT gene signatures can aid in predicting clinical prognosis and guiding treatment in patients with LUAD.
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Affiliation(s)
- Wenhao Ouyang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Department of Pulmonary and Critical Care Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yupeng Jiang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shiyi Bu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Department of Pulmonary and Critical Care Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Tiantian Tang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Department of Pulmonary and Critical Care Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Linjie Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Department of Pulmonary and Critical Care Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ming Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Department of Pulmonary and Critical Care Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yujie Tan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Qiyun Ou
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Department of Ultrasound in Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Luhui Mao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yingjie Mai
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Herui Yao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yunfang Yu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Artificial Intelligence and Digital Media Programme, Division of Science and Technology, Beijing Normal University-Hong Kong Baptist University United International College, Hong Kong Baptist University, Zhuhai, China
| | - Xiaoling Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Department of Pulmonary and Critical Care Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
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He W, Wang B, He J, Zhao Y, Zhao W. SSR4 as a prognostic biomarker and related with immune infiltration cells in colon adenocarcinoma. Expert Rev Mol Diagn 2021; 22:223-231. [PMID: 34904499 DOI: 10.1080/14737159.2022.2019015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
BACKGROUND Signal sequence receptor subunit delta (SSR4) gene is reported to encode the translocon-associated protein δ and related with the human immune regulation. However, the expression of SSR4 in colon adenocarcinoma (COAD) and its correlation with clinical treatment remains unclear. RESEARCH DESIGN AND METHODS SSR4 mRNA expression level and its relationship with tumor infiltrating lymphocytes (TILs) in COAD were evaluated through several databases. Furthermore, the study collected 238 cases of COAD tissue samples to detect the association of SSR4 protein expression level in TILs with clinical pathological information, and the prognosis of COAD. RESULTS SSR4 mRNA was significantly highly expressed in COAD tissues and significantly correlated with several types of TILs in COAD. Moreover, SSR4 highly expressed in many types of TILs, especially highly expressed in plasma cell from COAD patients with advanced TNM stage. High SSR4 protein expression in TILs was associated with lymph node metastasis, distant metastasis, American Joint Committee on Cancer (AJCC) staging, and Response Evaluation Criteria in Solid Tumors (RECIST) efficacy. COAD patients with high SSR4 expression in TILs had better overall survival. CONCLUSIONS In conclusion, high SSR4 mRNA and protein expression in TILs can be used as a prognostic biomarker for predicting better overall survival and treatment efficacy in COAD patients.
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Affiliation(s)
- Weiwei He
- Department of Oncology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Bin Wang
- Department of Pathology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Jikai He
- Research Center for the Prevention and Treatment of Drug Resistant Microbial Infecting, Youjiang Medical University for Nationalities, Baise, China
| | - Youcai Zhao
- Department of Pathology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Wei Zhao
- Department of Pathology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.,Research Center for the Prevention and Treatment of Drug Resistant Microbial Infecting, Youjiang Medical University for Nationalities, Baise, China
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Wang B, Niu L, Wang Z, Zhao Z. RNA m1A Methyltransferase TRMT6 Predicts Poorer Prognosis and Promotes Malignant Behavior in Glioma. Front Mol Biosci 2021; 8:692130. [PMID: 34631793 PMCID: PMC8493077 DOI: 10.3389/fmolb.2021.692130] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 08/11/2021] [Indexed: 12/26/2022] Open
Abstract
Background: Glioma is the most prevalent central nervous system tumor in humans, and its prognosis remains unsatisfactory due to a lack of effective therapeutic targets. The ectopic expression of N1-methyladenosine (m1A) regulators is a key participant in tumorigenesis and progression. However, the m1A regulator expression status, prognostic value, and relationship with tumor clinical features in glioma remain unclear. Methods: Public datasets were used to analyze the mRNA and protein expression levels of m1A regulators. Kaplan-Meier and Cox regression analyses were performed to confirm the prognostic value of m1A regulators in glioma. Cellular experiments were conducted to verify the effect of TRMT6 on cell function. A comprehensive bioinformatics analysis was conducted to identify the potential molecular mechanisms regulated by TEMT6 in glioma. Results: We found that the dysregulation of m1A regulators was closely associated with tumorigenesis and progression in glioma. Furthermore, TRMT6 might be a powerful and independent biomarker for prognosis in glioma. Our study showed that inhibition of TRMT6 suppressed the proliferation, migration, and invasion of glioma cells. Mechanistically, TRMT6 may be involved in glioma progression by regulating cell cycle, PI3K-AKT, TGF-beta, MTORC1, NOTCH, and MYC pathways. Conclusions: Variation in m1A regulators was closely associated with malignant progression in glioma. Silencing TRMT6 suppressed the cell proliferation, migration, and invasion in glioma. m1A regulators, especially TRMT6, might play an essential role in the malignant progression of glioma.
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Affiliation(s)
- Beibei Wang
- Pathology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lihua Niu
- Pathology Department, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhengyang Wang
- Pathology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhihua Zhao
- Pathology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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