|
1
|
Xu C, Xu X, Huang Y, Shang S, Ma L. RNA methylation: A new promising biomaker in cancer liquid biopsy. Biochim Biophys Acta Rev Cancer 2025; 1880:189337. [PMID: 40315965 DOI: 10.1016/j.bbcan.2025.189337] [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: 01/24/2025] [Revised: 04/24/2025] [Accepted: 04/25/2025] [Indexed: 05/04/2025]
Abstract
RNA methylation is a vital epigenetic modification that regulates gene expression by influencing RNA processes such as transcription, degradation, translation, and transport. Aberrant methylation, including modifications like m6A, m5C, m1A, m7G, and m3C, is closely linked to tumorigenesis and progression. Liquid biopsy, a non-invasive technique analyzing tumor markers in body fluids, offers significant potential for early diagnosis and dynamic monitoring. In this context, RNA methylation, due to its tumor-specific properties, is emerging as a valuable marker. However, significant challenges remain in its clinical application. This review explores the roles of RNA methylation in cancer, recent advances in detection technologies, and its potential as a liquid biopsy marker in tumor management. It highlights its promising applications in cancer diagnosis, prognosis, and personalized treatment in the era of precision oncology.
Collapse
Affiliation(s)
- Chenxin Xu
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xin Xu
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Yiwen Huang
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Shuang Shang
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Lifang Ma
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
| |
Collapse
|
|
2
|
Liu L, Ge D, Lin Y, Han Z, Zhao H, Cao L, Wu X, Ma G. Epigenetic regulation in oogenesis and fetal development: insights into m6A modifications. Front Immunol 2025; 16:1516473. [PMID: 40356909 PMCID: PMC12066277 DOI: 10.3389/fimmu.2025.1516473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 04/07/2025] [Indexed: 05/15/2025] Open
Abstract
The unique physiological structure of women has led to a variety of diseases that have attracted the attention of many people in recent years. Disturbances in the reproductive system microenvironment lead to the progression of various female tumours and pregnancy disorders. Numerous studies have shown that epigenetic modifications crucially influence both oogenesis and foetal development. m6A, a modification at the mRNA level, consists of three parts, namely, writers, erasers, and readers, which are involved in several biological functions, such as the nucleation and stabilisation of mRNAs, thereby regulating the development of reproductive system diseases. In this manuscript, we delineate the constituents of m6A, their biological roles, and advancements in understanding m6A within the maternal-foetal immunological context. In addition, we summarise the mechanism of m6A in gynaecological diseases and provide a new perspective for targeting m6A to delay the progression of reproductive system diseases in clinical practice.
Collapse
Affiliation(s)
- Lusheng Liu
- Department of Acupuncture and Moxibustion, Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Clinical Medical College of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Danxia Ge
- Department of Critical Care Medicine, Traditional Chinese Medicine Hospital of, Ningbo, Zhejiang, China
| | - Yumeng Lin
- Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Zhongyu Han
- Department of Acupuncture and Moxibustion, Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Heng Zhao
- Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Liqin Cao
- Department of Gynecology, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xi Wu
- Department of Gynecology, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guizhi Ma
- Department of Acupuncture and Moxibustion, Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| |
Collapse
|
|
3
|
Wang Z, Liu XC, Gao ZG, Shi WD, Wang WC. FOXD2-AS1 is modulated by METTL3 with the assistance of YTHDF1 to affect proliferation and apoptosis in esophageal cancer. ACTA PHARMACEUTICA (ZAGREB, CROATIA) 2025; 75:69-86. [PMID: 40208783 DOI: 10.2478/acph-2025-0009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 03/19/2025] [Indexed: 04/12/2025]
Abstract
This study aims to investigate the regulatory mechanisms of METTL3, YTHDF1, and the long non-coding RNA FOXD2-AS1 in the proliferation and apoptosis of esophageal cancer, with the goal of providing a basis for molecular diagnosis and targeted therapies. Gene expression was evaluated using qRT-PCR (METTL3/14) and Western blot analysis. The Cell Counting Kit-8 (CCK-8) assay, flow cytometry, and Transwell assay were employed to assess cell proliferation and apoptosis. The EpiQuik m6A RNA Methylation Quantification Kit was utilized to quantify total m6A levels. The interaction between YTHDF1, FOXD2-AS1, and METTL3 was confirmed using RNA Binding Protein Immunoprecipitation (RIP), Co-Immunoprecipitation (CO-IP), and RNA pull-down assays. Methylated RNA Immuno preci pitation (MeRIP) was employed to assess the m6A modification levels of FOXD2-AS1. Tissue samples from animal models were analyzed via Hematoxylin-eosin staining (HE) staining and immunohisto-chemistry to assess METTL3 expression. The expression of METTL3 was up-regulated in esophageal cancer tissues and cells. Flow cytometry and CCK-8 detection showed that silencing METTL3 could inhibit the proliferation of esophageal cancer cells but accelerate their apoptosis. MeRIP-qPCR and Prediction of m6A-modified sites indicated that METTL3 regulated the m6A modification of FOXD2-AS1. In vitro and in vivo experiments showed that YTHDF1 binds to METTL3 and regulates the m6A modification of FOXD2-AS1 to affect esophageal cancer. Our results indicate that METTL3 regulates FOXD2-AS1 in an m6A-dependent manner through its interaction with YTHDF1, thereby influencing EC proliferation and apoptosis. This suggests a potential therapeutic target for the treatment of esophageal cancer.
Collapse
Affiliation(s)
- Zijin Wang
- 1Department of Cardiothoracic Surgery, Affiliated Hospital 6 of Nantong University The Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng Third People's Hospital, Yancheng Jiangsu, 224000 China
| | - Xing Chen Liu
- 1Department of Cardiothoracic Surgery, Affiliated Hospital 6 of Nantong University The Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng Third People's Hospital, Yancheng Jiangsu, 224000 China
| | - Zhen Gya Gao
- 1Department of Cardiothoracic Surgery, Affiliated Hospital 6 of Nantong University The Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng Third People's Hospital, Yancheng Jiangsu, 224000 China
| | - Wo Da Shi
- 1Department of Cardiothoracic Surgery, Affiliated Hospital 6 of Nantong University The Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng Third People's Hospital, Yancheng Jiangsu, 224000 China
| | - Wen Cai Wang
- 1Department of Cardiothoracic Surgery, Affiliated Hospital 6 of Nantong University The Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng Third People's Hospital, Yancheng Jiangsu, 224000 China
| |
Collapse
|
|
4
|
Liu L, Wang S, Chen X, Luo Q, Wang Z, Li J. Pan-cancer analysis of Methyltransferase-like 16 (METTL16) and validated in colorectal cancer. Aging (Albany NY) 2025; 17:588-606. [PMID: 40015977 PMCID: PMC11892929 DOI: 10.18632/aging.206210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 12/11/2024] [Indexed: 03/01/2025]
Abstract
Human Methyltransferase-like 16(METTL16) is an independent N6-methyladenosine (m6A) methyltransferase. Previous studies have proven METTL16 been linked with some types of cancers. However, comparative studies of the relevance of METTL16 across diverse tumors remain sparse. We comprehensively investigated the effect of METTL16 expression on tumor prognosis across human malignancies by analyzing multiple cancer-related databases like Tumor Immune Estimation Resource (TIMER) and human protein atlas (HPA). Bioinformatics data indicated that METTL16 was overexpressed in most of these human malignancies and was significantly associated with the prognosis of patients with cancer, especially in colorectal cancer (CRC). Subsequently, In vitro experiments, the utility of METTL16 that downregulation of its expression could result in reduced proliferation and migration of CRC cells. Our findings reveal novel insights into METTL16 expression and its biological functions in diverse cancer types, indicating that METTL16 could serve as a prognostic biomarker and plays an important role in colorectal cancer.
Collapse
Affiliation(s)
- Ling Liu
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Siying Wang
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Xuyu Chen
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Qian Luo
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Zhaoxia Wang
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Juan Li
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, China
| |
Collapse
|
|
5
|
Li P, Lin Y, Ma H, Zhang J, Zhang Q, Yan R, Fan Y. Epigenetic regulation in female reproduction: the impact of m6A on maternal-fetal health. Cell Death Discov 2025; 11:43. [PMID: 39904996 PMCID: PMC11794895 DOI: 10.1038/s41420-025-02324-z] [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: 09/02/2024] [Revised: 01/09/2025] [Accepted: 01/24/2025] [Indexed: 02/06/2025] Open
Abstract
With the development of public health, female diseases have become the focus of current concern. The unique reproductive anatomy of women leads to the development of gynecological diseases gradually become an important part of the socio-economic burden. Epigenetics plays an irreplaceable role in gynecologic diseases. As an important mRNA modification, m6A is involved in the maturation of ovum cells and maternal-fetal microenvironment. At present, researchers have found that m6A is involved in the regulation of gestational diabetes and other reproductive system diseases, but the specific mechanism is not clear. In this manuscript, we summarize the components of m6A, the biological function of m6A, the progression of m6A in the maternal-fetal microenvironment and a variety of gynecological diseases as well as the progression of targeted m6A treatment-related diseases, providing a new perspective for clinical treatment-related diseases.
Collapse
Affiliation(s)
- Peipei Li
- Department of Obstetrics and Gynecology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, China
| | - Yumeng Lin
- Health Management Center, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Hongyun Ma
- Department of Obstetrics and Gynecology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, China
| | - Jiao Zhang
- Department of Obstetrics and Gynecology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, China
| | - Qiaorui Zhang
- Department of Obstetrics and Gynecology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, China
| | - Ruihua Yan
- Department of Obstetrics and Gynecology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, China
| | - Yang Fan
- Department of Obstetrics and Gynecology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, China.
| |
Collapse
|
|
6
|
Sun X, Wang H, Pu X, Wu Y, Yuan X, Wang X, Lu H. Manipulating the tumour immune microenvironment by N6-methyladenosine RNA modification. Cancer Gene Ther 2024; 31:1315-1322. [PMID: 38834772 DOI: 10.1038/s41417-024-00791-7] [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: 01/18/2024] [Revised: 05/22/2024] [Accepted: 05/23/2024] [Indexed: 06/06/2024]
Abstract
N6-methyladenosine (m6A), a posttranscriptional regulatory mechanism, is the most common epigenetic modification in mammalian mRNA. M6A modifications play a crucial role in the developmental network of immune cells. The expression of m6A-related regulators often affects carcinogenesis and tumour suppression networks. In the tumour microenvironment, m6A-modified enzymes can affect the occurrence and progression of tumours by regulating the activation and invasion of tumour-associated immune cells. Immunotherapy, which utilises immune cells, has been demonstrated to be a powerful weapon in tumour treatment and is increasingly being used in the clinic. Here, we provide an updated and comprehensive overview of how m6A modifications affect invasive immune cells and their potential role in immune regulation. In addition, we summarise the regulation of epigenetic regulators associated with m6A modifications in tumour cells on the antitumour response of immune cells in the tumour immune microenvironment. These findings provide new insights into the role of m6A modifications in the immune response and tumour development, leading to the development of novel immunotherapies for cancer treatment.
Collapse
Affiliation(s)
- Xinyu Sun
- Department of Otorhinolaryngology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
- Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Huirong Wang
- Department of Otorhinolaryngology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xi Pu
- Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yuting Wu
- Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xiao Yuan
- Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xu Wang
- Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Hanqiang Lu
- Department of Otorhinolaryngology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.
| |
Collapse
|
|
7
|
Mu S, Zhao K, Zhong S, Wang Y. The Role of m6A Methylation in Tumor Immunity and Immune-Associated Disorder. Biomolecules 2024; 14:1042. [PMID: 39199429 PMCID: PMC11353047 DOI: 10.3390/biom14081042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 08/11/2024] [Accepted: 08/14/2024] [Indexed: 09/01/2024] Open
Abstract
N6-methyladenosine (m6A) represents the most prevalent and significant internal modification in mRNA, with its critical role in gene expression regulation and cell fate determination increasingly recognized in recent research. The immune system, essential for defense against infections and maintaining internal stability through interactions with other bodily systems, is significantly influenced by m6A modification. This modification acts as a key post-transcriptional regulator of immune responses, though its effects on different immune cells vary across diseases. This review delineates the impact of m6A modification across major system-related cancers-including those of the respiratory, digestive, endocrine, nervous, urinary reproductive, musculoskeletal system malignancies, as well as acute myeloid leukemia and autoimmune diseases. We explore the pathogenic roles of m6A RNA modifications within the tumor immune microenvironment and the broader immune system, highlighting how RNA modification regulators interact with immune pathways during disease progression. Furthermore, we discuss how the expression patterns of these regulators can influence disease susceptibility to immunotherapy, facilitating the development of diagnostic and prognostic models and pioneering new therapeutic approaches. Overall, this review emphasizes the challenges and prospective directions of m6A-related immune regulation in various systemic diseases throughout the body.
Collapse
Affiliation(s)
- Siyu Mu
- Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang 110000, China; (S.M.); (S.Z.)
| | - Kaiyue Zhao
- Department of Hepatology, Beijing Tsinghua Changgeng Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China;
| | - Shanshan Zhong
- Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang 110000, China; (S.M.); (S.Z.)
| | - Yanli Wang
- Department of Infectious Diseases, The First Affiliated Hospital of China Medical University, Shenyang 110000, China
| |
Collapse
|
|
8
|
Hou R, Wang Y, Cao S, Sun X, Jiang L. N 6-Methyladenosine-Modified KREMEN2 Promotes Tumorigenesis and Malignant Progression of High-Grade Serous Ovarian Cancer. J Transl Med 2024; 104:102059. [PMID: 38615731 DOI: 10.1016/j.labinv.2024.102059] [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: 11/23/2023] [Revised: 03/20/2024] [Accepted: 04/05/2024] [Indexed: 04/16/2024] Open
Abstract
High-grade serous ovarian cancer (HGSOC) remains the most lethal female cancer by far. Herein, clinical HGSOC samples had higher N6-methyladenosine (m6A) modification than normal ovarian tissue, and its dysregulation had been reported to drive aberrant transcription and translation programs. However, Kringle-containing transmembrane protein 2 (KREMEN2) and its m6A modification have not been fully elucidated in HGSOC. In this study, the data from the high-throughput messenger RNA (mRNA) sequencing of clinical samples were processed using the weighted correlation network analysis and functional enrichment analysis. Results revealed that KREMEN2 was a driver gene in the tumorigenesis of HGSOC and a potential target of m6A demethylase fat-mass and obesity-associated protein (FTO). KREMEN2 and FTO levels were upregulated and downregulated, respectively, and correlation analysis showed a significant negative correlation in HGSOC samples. Importantly, upregulated KREMEN2 was remarkably associated with lymph node metastasis, distant metastasis, peritoneal metastasis, and high International Federation of Gynecology and Obstetrics stage (Ⅲ/Ⅳ), independent of the age of patients. KREMEN2 promoted the growth of HGSOC in vitro and in vivo, which was dependent on FTO. The methylated RNA immunoprecipitation qPCR and RNA immunoprecipitation assays were performed to verify the m6A level and sites of KREMEN2. FTO overexpression significantly decreased m6A modification in the 3' and 5' untranslated regions of KREMEN2 mRNA and downregulated its expression. In addition, we found that FTO-mediated m6A modification of KREMEN2 mRNA was recognized and stabilized by the m6A reader IGF2BP1 rather than by IGF2BP2 or IGF2BP3. This study highlights the m6A modification of KREMEN2 and extends the importance of RNA epigenetics in HGSOC.
Collapse
Affiliation(s)
- Rui Hou
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yadong Wang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shiyao Cao
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xinrui Sun
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Luo Jiang
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China.
| |
Collapse
|
|
9
|
Zhang Y, Ling Y, Zhou Y, Shi X, Shen F, Zhou J, Chen Y, Yang F, Gu Y, Wang J. Research Advances in the Roles of N6-Methyladenosine Modification in Ovarian Cancer. Cancer Control 2024; 31:10732748241256819. [PMID: 38755968 PMCID: PMC11102699 DOI: 10.1177/10732748241256819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 05/02/2024] [Accepted: 05/07/2024] [Indexed: 05/18/2024] Open
Abstract
Ovarian cancer (OC) is the most lethal gynecological tumor, characterized by its insidious and frequently recurring metastatic progression. Owing to limited early screening methods, over 70% of OC cases are diagnosed at advanced stages, typically stage III or IV. Recently, N6-methyladenosine (m6A) modification has emerged as a hotspot of epigenetic research, representing a significant endogenous RNA modification in higher eukaryotes. Numerous studies have reported that m6A-related regulatory factors play pivotal roles in tumor development through diverse mechanisms. Moreover, recent studies have indicated the aberrant expression of multiple regulatory factors in OC. Therefore, this paper comprehensively reviews research advancements concerning m6A in OC, aiming to elucidate the regulatory mechanism of m6A-associated regulators on pivotal aspects, such as proliferation, invasion, metastasis, and drug resistance, in OC. Furthermore, it discusses the potential of m6A-associated regulators as early diagnostic markers and therapeutic targets, thus contributing to the diagnosis and treatment of OC.
Collapse
Affiliation(s)
- Yuhong Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Clinical Research Center of Obstetrics and Gynecology, Jiangsu Key Laboratory of Clinical Immunology of Soochow University, Suzhou, China
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yufeng Ling
- Affiliated Hospital of Medical School, Nanjing University, Nanjing Stomatological Hospital, Nanjing, China
| | - Ying Zhou
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Clinical Research Center of Obstetrics and Gynecology, Jiangsu Key Laboratory of Clinical Immunology of Soochow University, Suzhou, China
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiu Shi
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Fangrong Shen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jinhua Zhou
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Youguo Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Fan Yang
- Department of Gynecology and Obstetrics, West China Second Hospital, University of Sichuan, Chengdu, China
- Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, University of Sichuan, Chengdu, China
| | - Yanzheng Gu
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Juan Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, China
| |
Collapse
|
|
10
|
Yu HY, Yang L, Liu YC, Yu AJ. Sulforaphene suppressed cell proliferation and promoted apoptosis of COV362 cells in endometrioid ovarian cancer. PeerJ 2023; 11:e16308. [PMID: 38025760 PMCID: PMC10668859 DOI: 10.7717/peerj.16308] [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: 08/10/2023] [Accepted: 09/26/2023] [Indexed: 12/01/2023] Open
Abstract
Aim N6-methyladenosine (m6A) RNA methylation exerts a regulatory effect on endometrioid ovarian cancer (EOC), but the specific m6A regulator genes in EOC remain to be explored. This study investigated that sulforaphene (Sul) is implicated in EOC development by regulating methyltransferase-like 3 (METTL3). Methods The dysregulated m6A RNA methylation genes in EOC were determined by methylated RNA immunoprecipitation (MeRIP-seq) and RNA sequencing. The roles of METTL3 and/or Sul on viability, proliferative ability, cell cycle, and apoptosis of EOC cells were determined by MTT, colony formation, flow cytometry, and TUNEL staining assay, respectively. The expression of METTL3 and apoptosis-related proteins in EOC cells was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assays. Results Five m6A RNA methylation regulators (METTL3, ELF3, IGF2BP2, FTO, and METTL14) were differentially expressed in EOC, among which METTL3 had the highest expression level. Silencing METTL3 reduced the clonal expansion and viability of EOC cells, and caused the cells to arrest in the G0/G1 phase. This also promoted apoptosis in the EOC cells and activated the FAS/FADD and mitochondrial apoptosis pathways. In contrast, overexpressing METTL3 had the opposite effect. Sul, in a dose-dependent manner, reduced the viability of EOC cells but promoted their apoptosis. Sul also increased the levels of IGF2BP2 and FAS, while decreasing the levels of KRT8 and METTL3. Furthermore, Sul was able to reverse the effects of METTL3 overexpression on EOC cells. Conclusions Sul could suppress cell proliferation and promote apoptosis of EOC cells by inhibiting the METTL3 to activate the FAS/FADD and apoptosis-associated pathways.
Collapse
Affiliation(s)
- Hui-Yan Yu
- Zhejiang Cancer Hospital, Zhejiang, China
| | - Li Yang
- Zhejiang Cancer Hospital, Zhejiang, China
| | - Yuan-Cai Liu
- Zhejiang Chinese Medical University, Zhejiang, China
| | - Ai-Jun Yu
- Zhejiang Cancer Hospital, Zhejiang, China
| |
Collapse
|
|
11
|
Li C, Liu J, Lyu Y, Ling S, Luo Y. METTL16 Inhibits the Malignant Progression of Epithelial Ovarian Cancer through the lncRNA MALAT1/ β-Catenin Axis. Anal Cell Pathol (Amst) 2023; 2023:9952234. [PMID: 37927399 PMCID: PMC10625488 DOI: 10.1155/2023/9952234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 07/02/2023] [Accepted: 07/11/2023] [Indexed: 11/07/2023] Open
Abstract
Epithelial ovarian cancer (EOC) ranks third in the incidence of gynecological malignancies. m6A methylation as RNA modification plays a crucial role in the evolution, migration, and invasion of various tumors. However, the role of m6A methylation in ovarian cancer (OC) only recently has begun to be appreciated. Therefore, we used various bioinformatic methods to screen the public GEO datasets of epithelial ovarian cancer (EOC) for m6A methylation-related regulators. We identified methyltransferase 16 (METTL16) that was dramatically downregulated in EOC as such a regulator. We also identified metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a known target lncRNA of METTL16, in these five GEO datasets. RT-qPCR and immunohistochemical staining confirmed that compared with the normal ovarian tissues and cells, METTL16 was significantly downregulated, while lncRNA MALAT1 was significantly upregulated, in 30 EOC tissues of our own validation cohorts and EOC cell lines, revealing a negative correlation between METTL16 and lncRNA MALAT1. Moreover, our analysis unveiled a correlation between downregulated METTL16 and the known adverse prognostic factors of EOC patients in our own cohorts. The CCK-8, EdU, scratch wound healing, and transwell invasion assays revealed that METTL16 significantly suppressed the proliferating, migrating, and invading abilities of OC cells. The inhibitory effects of METTL16 on the in vivo tumor growth of EOC cells were measured by subcutaneous tumor formation assay in mice. Furthermore, the RIP, RNA stability assay, western blotting, and cytoimmunofluorescence staining showed that METTL16 hindered the growth of EOC cells through promoting the degradation of MALAT1 by binding that, in turn, upregulates β-catenin protein and promotes nuclear transport of β-catenin protein in EOC cells. This study suggests that METTL16 acts as a tumor suppressor gene of EOC by achieving its inhibitory function on the malignant progression of EOC through the METTL16/MALAT1/β-catenin axis that are new targets for EOC diagnosis and therapy.
Collapse
Affiliation(s)
- Changshu Li
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu 241001, Anhui, China
| | - Ji Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu 241001, Anhui, China
| | - Yuanyuan Lyu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu 241001, Anhui, China
| | - Shizhang Ling
- The Translational Research Institute for Neurological Disorders, Wuhu 241001, Anhui, China
- Interdisciplinary Research Center of Neuromedicine and Chemical Biology of Wannan Medical College and Anhui Normal University, Wuhu, Anhui 241001, China
- Department of Neurosurgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui 241001, China
| | - Yonghong Luo
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu 241001, Anhui, China
| |
Collapse
|
|
12
|
Ye L, Yao X, Xu B, Chen W, Lou H, Tong X, Fang S, Zou R, Hu Y, Wang Z, Xiang D, Lin Q, Feng S, Xue X, Guo G. RNA epigenetic modifications in ovarian cancer: The changes, chances, and challenges. WILEY INTERDISCIPLINARY REVIEWS. RNA 2023; 14:e1784. [PMID: 36811232 DOI: 10.1002/wrna.1784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 01/19/2023] [Accepted: 01/25/2023] [Indexed: 02/23/2023]
Abstract
Ovarian cancer (OC) is the most common female cancer worldwide. Patients with OC have high mortality because of its complex and poorly understood pathogenesis. RNA epigenetic modifications, such as m6 A, m1 A, and m5 C, are closely associated with the occurrence and development of OC. RNA modifications can affect the stability of mRNA transcripts, nuclear export of RNAs, translation efficiency, and decoding accuracy. However, there are few overviews that summarize the link between m6 A RNA modification and OC. Here, we discuss the molecular and cellular functions of different RNA modifications and how their regulation contributes to the pathogenesis of OC. By improving our understanding of the role of RNA modifications in the etiology of OC, we provide new perspectives for their use in OC diagnosis and treatment. This article is categorized under: RNA Processing > RNA Editing and Modification RNA in Disease and Development > RNA in Disease.
Collapse
Affiliation(s)
- 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
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xuyang Yao
- First Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Binbing Xu
- First Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Wenwen Chen
- 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
| | - Han Lou
- 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
| | - Su Fang
- 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
| | - Ruanmin Zou
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Yingying Hu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhibin Wang
- 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
| | - Dan Xiang
- 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
| | - Qiaoai Lin
- 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
| | - Shiyu Feng
- 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
| | - 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
| |
Collapse
|
|
13
|
Qi YN, Liu Z, Hong LL, Li P, Ling ZQ. Methyltransferase-like proteins in cancer biology and potential therapeutic targeting. J Hematol Oncol 2023; 16:89. [PMID: 37533128 PMCID: PMC10394802 DOI: 10.1186/s13045-023-01477-7] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 07/10/2023] [Indexed: 08/04/2023] Open
Abstract
RNA modification has recently become a significant process of gene regulation, and the methyltransferase-like (METTL) family of proteins plays a critical role in RNA modification, methylating various types of RNAs, including mRNA, tRNA, microRNA, rRNA, and mitochondrial RNAs. METTL proteins consist of a unique seven-beta-strand domain, which binds to the methyl donor SAM to catalyze methyl transfer. The most typical family member METTL3/METTL14 forms a methyltransferase complex involved in N6-methyladenosine (m6A) modification of RNA, regulating tumor proliferation, metastasis and invasion, immunotherapy resistance, and metabolic reprogramming of tumor cells. METTL1, METTL4, METTL5, and METTL16 have also been recently identified to have some regulatory ability in tumorigenesis, and the rest of the METTL family members rely on their methyltransferase activity for methylation of different nucleotides, proteins, and small molecules, which regulate translation and affect processes such as cell differentiation and development. Herein, we summarize the literature on METTLs in the last three years to elucidate their roles in human cancers and provide a theoretical basis for their future use as potential therapeutic targets.
Collapse
Affiliation(s)
- Ya-Nan Qi
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450052, P.R. China
| | - Zhu Liu
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou, 310022, Zhejiang, P.R. China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, P.R. China
| | - Lian-Lian Hong
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou, 310022, Zhejiang, P.R. China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, P.R. China
| | - Pei Li
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450052, P.R. China.
| | - Zhi-Qiang Ling
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou, 310022, Zhejiang, P.R. China.
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, P.R. China.
| |
Collapse
|
|
14
|
Luo J, Wang X, Chen Z, Zhou H, Xiao Y. The role and mechanism of JAK2/STAT3 signaling pathway regulated by m6A methyltransferase KIAA1429 in osteosarcoma. J Bone Oncol 2023; 39:100471. [PMID: 36915895 PMCID: PMC10006691 DOI: 10.1016/j.jbo.2023.100471] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/22/2023] [Accepted: 02/16/2023] [Indexed: 02/19/2023] Open
Abstract
Osteosarcoma (OS) is the most malignant bone tumor which mainly occurs in childhood or adolescence. The previous studies indicated that OS is difficult to treat. KIAA1429 is one of the components of m6A complex that regulating the process of m6A modification, which plays a crucial role in tumorigenesis. But the mechanism of KIAA1429 regulating OS cell identity was not entirely clear, which needs further investigate. RT-qPCR and western blotting were applied to determine KIAA1429 expression station in OS cells and tissues. To further detect the KIAA1429 function in OS cells, the ability of proliferation, migration and invasion were analyzed by Edu, wound-healing and transwell experiments respectively. Besides, RNA sequencing was also used to further find the downstream of KIAA1429 regulation and small molecule inhibitor was added to explore the specific role of signaling pathway. Our data found that KIAA1429 is up-regulated in human OS cell lines compared to the human osteoblast cells. Meanwhile, the deletion of KIAA1429 significantly decreased cell proliferation, migration, and invasion. Interestingly, the JAK2/STAT3 signal pathway was involved in KIAA1429 regulation on OS cell characters. The KIAA1429 eliminated OS cells exhibited a decreased activity of JAK2/STAT3 signal. And the addition of JAK2/STAT3 stimulator (colivelin) could distinctly rescue the decreased OS cells' proliferation, migration, and invasion upon KIAA1429 knockdown. In summary, these data demonstrated that KIAA1429/JAK2/STAT3 axis may a new target for OS therapy.
Collapse
Affiliation(s)
- Jiaquan Luo
- Department of Spine Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi Province 341099, China
| | - Xuhua Wang
- Department of Spine Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi Province 341099, China
| | - Zhaoyuan Chen
- Department of Spine Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi Province 341099, China
| | - Huaqiang Zhou
- Department of Spine Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi Province 341099, China
| | - Yihui Xiao
- Department of Spine Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi Province 341099, China
| |
Collapse
|
|
15
|
Huang E, Chen L. RNA N 6-methyladenosine modification in female reproductive biology and pathophysiology. Cell Commun Signal 2023; 21:53. [PMID: 36894952 PMCID: PMC9996912 DOI: 10.1186/s12964-023-01078-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 02/12/2023] [Indexed: 03/11/2023] Open
Abstract
Gene expression and posttranscriptional regulation can be strongly influenced by epigenetic modifications. N6-methyladenosine, the most extensive RNA modification, has been revealed to participate in many human diseases. Recently, the role of RNA epigenetic modifications in the pathophysiological mechanism of female reproductive diseases has been intensively studied. RNA m6A modification is involved in oogenesis, embryonic growth, and foetal development, as well as preeclampsia, miscarriage, endometriosis and adenomyosis, polycystic ovary syndrome, premature ovarian failure, and common gynaecological tumours such as cervical cancer, endometrial cancer, and ovarian cancer. In this review, we provide a summary of the research results of m6A on the female reproductive biology and pathophysiology in recent years and aim to discuss future research directions and clinical applications of m6A-related targets. Hopefully, this review will add to our understanding of the cellular mechanisms, diagnostic biomarkers, and underlying therapeutic strategies of female reproductive system diseases. Video Abstract.
Collapse
Affiliation(s)
- Erqing Huang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Lijuan Chen
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| |
Collapse
|
|
16
|
Wu Q, Li G, Gong L, Cai J, Chen L, Xu X, Liu X, Zhao J, Zeng Y, Gao R, Yu L, Wang Z. Identification of miR-30c-5p as a tumor suppressor by targeting the m 6 A reader HNRNPA2B1 in ovarian cancer. Cancer Med 2023; 12:5055-5070. [PMID: 36259156 PMCID: PMC9972042 DOI: 10.1002/cam4.5246] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 07/30/2022] [Accepted: 08/07/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND microRNAs (miRNAs) and N6-methyladenosine (m6 A) play important roles in ovarian cancer (OvCa). However, the mechanisms by which miRNAs regulate m6 A in OvCa have not been elucidated so far. METHODS To screen m6 A-related miRNAs, Pearson's correlation analysis of miRNAs and m6 A regulators was implemented using The Cancer Genome Atlas database (TCGA). To determine the level of m6 A, RNA m6 A quantitative assays were used. Then, colony formation assays, EdU assays, wound healing assays, and Transwell assays were performed. The dual-luciferase reporter assay was used to confirm the miRNA target genes. Protein-protein interaction (PPI) analysis of the target genes was performed, and hub genes were discovered using the cytoHubba/Cytoscape software. The underlying molecular mechanisms were explored by bioinformatics and RNA stability assays. RESULTS A total of 126 miRNAs were identified as m6 A-related miRNAs by Pearson's correlation analysis. Among them, the high level of miR-30c-5p was associated with good prognosis in OvCa patients. In vitro, the miR-30c-5p agomir lowered the m6 A level and inhibited OvCa cell proliferation, migration, and invasion. The hub target genes of miR-30c-5p were identified as (i) XPO1, (ii) AGO1, (iii) HNRNPA2B1, of which m6 A reader HNRNPA2B1 was highly expressed in OvCa tissues and related with poor prognosis. In vitro, knockdown of HNRNPA2B1 significantly reduced m6 A level and hampered the proliferation and migration of OvCa cells. The inhibition of m6 A reader HNRNPA2B1 attenuated the suppression of proliferation and migration and the low m6 A level induced by the miR-30c-5p downregulation. Mechanistically, m6 A reader HNRNPA2B1 might regulate CDK19 mRNA stability to alter m6 A level. CONCLUSIONS miR-30c-5p inhibits OvCa progression and reduces the m6 A level by inhibiting m6 A reader HNRNPA2B1, thus providing new insights into the m6 A regulatory mechanism in OvCa.
Collapse
Affiliation(s)
- Qiulei Wu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guoqing Li
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lanqing Gong
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Cai
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Le Chen
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaohan Xu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoli Liu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Zhao
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ya Zeng
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Gao
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lili Yu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zehua Wang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
17
|
Wu J, Wang X, Li X. N6-methyladenosine methylation regulator FTO promotes oxidative stress and induces cell apoptosis in ovarian cancer. Epigenomics 2022; 14:1509-1522. [PMID: 36815224 DOI: 10.2217/epi-2022-0403] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023] Open
Abstract
Aims: This study aimed to reveal the possible molecular mechanism of n6-methyladenosine (m6A) methylation regulator FTO in the biological activities of ovarian cancer (OC) based on The Cancer Genome Atlas, Genotype-Tissue Expression and Gene Expression Omnibus databases. Materials & methods: A risk score model was constructed to predict the prognosis of patients with OC. The key m6A methylation regulator was screened out based on OC-related microarray datasets. Results: 22 m6A methylation regulators were differentially expressed and interacted with each other in OC. FTO, a key m6A methylation regulator, was singled out. In vivo experiments verified that FTO promoted oxidative stress and apoptosis of OC cells to inhibit tumor growth in nude mice. Conclusion: This study highlighted the tumor-suppressive mechanism of m6A methylation regulator FTO in OC.
Collapse
Affiliation(s)
- Jun Wu
- The Fifth Department of Gynecology, Ningbo Women's & Children's Hospital, Ningbo, 315012, P.R. China
| | - Xiaoqin Wang
- The Fifth Department of Gynecology, Ningbo Women's & Children's Hospital, Ningbo, 315012, P.R. China
| | - Xin Li
- The Fifth Department of Gynecology, Ningbo Women's & Children's Hospital, Ningbo, 315012, P.R. China
| |
Collapse
|
|
18
|
Chen J, Guo B, Liu X, Zhang J, Zhang J, Fang Y, Zhu S, Wei B, Cao Y, Zhan L. Roles of N6-methyladenosine (m6A) modifications in gynecologic cancers: mechanisms and therapeutic targeting. Exp Hematol Oncol 2022; 11:98. [DOI: 10.1186/s40164-022-00357-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 11/01/2022] [Indexed: 11/14/2022] Open
Abstract
AbstractUterine and ovarian cancers are the most common gynecologic cancers. N6−methyladenosine (m6A), an important internal RNA modification in higher eukaryotes, has recently become a hot topic in epigenetic studies. Numerous studies have revealed that the m6A-related regulatory factors regulate the occurrence and metastasis of tumors and drug resistance through various mechanisms. The m6A-related regulatory factors can also be used as therapeutic targets and biomarkers for the early diagnosis of cancers, including gynecologic cancers. This review discusses the role of m6A in gynecologic cancers and summarizes the recent advancements in m6A modification in gynecologic cancers to improve the understanding of the occurrence, diagnosis, treatment, and prognosis of gynecologic cancers.
Collapse
|
|
19
|
Matr3 reshapes m6A modification complex to alleviate macrophage inflammation during atherosclerosis. Clin Immunol 2022; 245:109176. [DOI: 10.1016/j.clim.2022.109176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 10/20/2022] [Accepted: 10/31/2022] [Indexed: 11/09/2022]
|
|
20
|
Heterogeneous nuclear ribonucleoprotein A/B: an emerging group of cancer biomarkers and therapeutic targets. Cell Death Dis 2022; 8:337. [PMID: 35879279 PMCID: PMC9314375 DOI: 10.1038/s41420-022-01129-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/11/2022] [Accepted: 07/13/2022] [Indexed: 11/20/2022]
Abstract
Heterogeneous nuclear ribonucleoprotein A/B (hnRNPA/B) is one of the core members of the RNA binding protein (RBP) hnRNPs family, including four main subtypes, A0, A1, A2/B1 and A3, which share the similar structure and functions. With the advance in understanding the molecular biology of hnRNPA/B, it has been gradually revealed that hnRNPA/B plays a critical role in almost the entire steps of RNA life cycle and its aberrant expression and mutation have important effects on the occurrence and progression of various cancers. This review focuses on the clinical significance of hnRNPA/B in various cancers and systematically summarizes its biological function and molecular mechanisms.
Collapse
|
|
21
|
Wu W, Zhou S, Liu T, Liang D. Mitochondrial transcription factor B2 overexpression increases M2 macrophage infiltration via cytosolic mitochondrial DNA-stimulated Interleukin-6 secretion in ovarian cancer. Bioengineered 2022; 13:12211-12223. [PMID: 35577351 PMCID: PMC9275939 DOI: 10.1080/21655979.2022.2074615] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Mitochondrial transcription factor B2 (TFB2M) is a protein modulating both mitochondrial DNA (mtDNA) transcription and compacting. In this study, we explored the expression profile of TFB2M in ovarian cancer, its association with infiltration of tumor-associated macrophages (TAMs), and its influence on macrophage polarization. Serial sections of ovarian cancer tissue arrays were stained to detect TFB2M and CD163 expression. Epithelial ovarian cancer cell line OVISE and CAOV4 were used to assess the influence of TFB2M on IL-6 expression. THP-1 cells were utilized as an in vitro model for macrophage migration and polarization. Results showed that higher TFB2M expression is associated with poor survival in ovarian cancer patients. IHC staining confirmed a moderately positive correlation between TFB2M expression and the infiltration of CD163-positive cells in 68 primary ovarian cancer cases. TFB2M overexpression was associated with increased mtDNA outside the mitochondria and elevated IL-6 expression in ovarian cancer cells. When cytosolic mtDNA was selectively inhibited by DNase I, TFB2M-induced IL-6 upregulation was canceled. TFB2M overexpression could activate the nuclear factor kappa-B (NF-κB) signaling pathway via promoting nucleus entry of p65 and p-p65, which was abrogated by inhibiting cytosolic mtDNA, TLR9, or NF-κB signaling pathway. Conditioned medium from OIVSE cells with TFB2M overexpression could induce macrophage migration and M2 polarization. However, these inducing effects were abrogated by DNase I, TLR9 inhibitor, and anti-IL-6 R pretreatment. In conclusion, this study showed a novel role of TFB2M in the immunosuppressive tumor microenvironment. It promotes M2 macrophage infiltration via a cytosolic mtDNA/TLR9/NF-κB/IL-6 pathway in ovarian cancer.
Collapse
Affiliation(s)
- Weilu Wu
- Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Shijie Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Tianmin Liu
- Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Dongni Liang
- Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| |
Collapse
|
|
22
|
Huang W, Kong F, Li R, Chen X, Wang K. Emerging Roles of m 6A RNA Methylation Regulators in Gynecological Cancer. Front Oncol 2022; 12:827956. [PMID: 35155260 PMCID: PMC8831694 DOI: 10.3389/fonc.2022.827956] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 01/13/2022] [Indexed: 12/17/2022] Open
Abstract
Gynecological cancers seriously affect the reproductive system of females; diseases include ovarian tumors, uterine tumors, endometrial cancers, cervical cancers, and vulva and vaginal tumors. At present, the diagnosis methods of gynecological cancer are insufficiently sensitive and specific, leading to failure of early disease detection. N6-methyladenosine (m6A) plays various biological functions in RNA modification and is currently studied extensively. m6A modification controls the fate of transcripts and regulates RNA metabolism and biological processes through the interaction of m6A methyltransferase (“writer”) and demethylase (“erasers”) and the binding protein decoding m6A methylation (“readers”). In the field of epigenetics, m6A modification is a dynamic process of reversible regulation of target RNA through its regulatory factors. It plays an important role in many diseases, especially cancer. However, its role in gynecologic cancers has not been fully investigated. Thus, we review the regulatory mechanism, biological functions, and therapeutic prospects of m6A RNA methylation regulators in gynecological cancers.
Collapse
Affiliation(s)
- Wanjun Huang
- Department of Obstetrics and Gynecology, Taizhou Central Hospital (Taizhou University, Hospital), Taizhou, China
| | - Fanhua Kong
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-based Medical Materials, Wuhan, China
| | - Ruolan Li
- Department of Obstetrics and Gynecology, Taizhou Central Hospital (Taizhou University, Hospital), Taizhou, China
| | - Xiang Chen
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Kunpeng Wang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| |
Collapse
|
|
23
|
Nasrullah, Hussain A, Ahmed S, Rasool M, Shah AJ. DNA methylation across the tree of life, from micro to macro-organism. Bioengineered 2022; 13:1666-1685. [PMID: 34986742 PMCID: PMC8805842 DOI: 10.1080/21655979.2021.2014387] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 11/30/2021] [Indexed: 12/12/2022] Open
Abstract
DNA methylation is a process in which methyl (CH3) groups are added to the DNA molecule. The DNA segment does not change in the sequence, but DNA methylation could alter the action of DNA. Different enzymes like DNA methyltransferases (DNMTs) take part in methylation of cytosine/adenine nucleosides in DNA. In prokaryotes, DNA methylation is performed to prevent the attack of phage and also plays a role in the chromosome replication and repair. In fungi, DNA methylation is studied to see the transcriptional changes, as in insects, the DNA methylation is not that well-known, it plays a different role like other organisms. In mammals, the DNA methylation is related to different types of cancers and plays the most important role in the placental development and abnormal DNA methylation connected with diseases like cancer, autoimmune diseases, and rheumatoid arthritis.
Collapse
Affiliation(s)
- Nasrullah
- Center for Advanced Studies in Vaccinology & Biotechnology (Casvab), University of Baluchistan, Quetta- Pakistan. E-mails:
| | - Abrar Hussain
- Department of Biotechnology, Faculty of Life Sciences, Buitems, Quetta-Pakistan. E-mails:
| | - Sagheer Ahmed
- Department of Basic Medical Sciences, Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan. E-mails:
| | - Mahmood Rasool
- Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. E-mails:
| | - Abdul Jabbar Shah
- Department of Pharmaceutical Sciences, Comsats University, Abbottabad. E-mails:
| |
Collapse
|
|
24
|
Wang Y, Chen Z. Long noncoding RNA UBA6-AS1 inhibits the malignancy of ovarian cancer cells via suppressing the decay of UBA6 mRNA. Bioengineered 2022; 13:178-189. [PMID: 34951345 PMCID: PMC8805991 DOI: 10.1080/21655979.2021.2011640] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 11/23/2021] [Indexed: 11/06/2022] Open
Abstract
Ovarian cancer (OC) is one of the most common cancer in women worldwide. A recent study reported that long noncoding RNA (lncRNA) Ubiquitin like modifier activating enzyme 6 antisense RNA 1 (UBA6-AS1) is significantly correlated with the prognosis of patients with OC and also involved in N6-methyladenosine (m6A) regulation. However, its influence on OC progression and the underlying mechanism is still not well demonstrated. Here, we found that UBA6-AS1 directly associated with UBA6 mRNA and inhibited its decay. Further mechanism investigation revealed that UBA6-AS1 increased the m6A methylation of UBA6 mRNA via recruiting RNA binding motif protein 15 (RBM15). Insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) was identified as the m6A reader protein of UBA6-AS1-RBM15-mediated m6A modification of UBA6 mRNA, which enhanced the stability of UBA6 mRNA. Functionally, UBA6-AS1 suppressed the proliferation, migration and invasion of OC cells via UBA6. Moreover, UBA6-AS1 positively correlated with UBA6 expression in OC tissues. Downregulation of UBA6-AS1 or UBA6 expression indicated poor. Collectively, we have identified a tumor-suppressive lncRNA that regulates its target mRNA via a m6A mechanism, highlighting the role that lncRNAs can play in OC progression.
Collapse
Affiliation(s)
- Yaogang Wang
- Department of Gynaecology and Obstetrics, Hanchuan People’s Hospital, Hanchuan, Hubei Province, China
| | - Zhigao Chen
- Department of Gynaecology and Obstetrics, Hanchuan People’s Hospital, Hanchuan, Hubei Province, China
| |
Collapse
|
|
25
|
Wang Y. Mesenchymal stem cells (MSC) delays the occurrence of graft-versus-host disease(GVHD) in the inhibition of hematopoietic stem cells in major histocompatibility complex semi-consistent mice by regulating the expression of IFN-γ/IL-6. Bioengineered 2021; 12:4500-4507. [PMID: 34308757 PMCID: PMC8806439 DOI: 10.1080/21655979.2021.1955549] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 07/09/2021] [Indexed: 12/03/2022] Open
Abstract
In recent years, because of its low immunogenicity and immunosuppression, mesenchymal stem cells (MSCs) have become a potential cell therapy for Graft-versus-host disease (GVHD). However, many experiments now focus on the interference of MSCs on T-cell proliferation in vitro and the prevention of GVHD in vivo. However, whether MSCs can effectively treat GVHD, the timing and conditions of treatment are not systematically studied. In order to clarify the therapeutic effect of MSC on GVHD, In this paper, mice were selected to build a model for study, and group control method was used. Experimental research proved that four mice died after transplantation with allogeneic hematopoietic stem cells treated by IFN- γ, and their white blood cell number remained basically unchanged, and their weight changed slightly. In addition, three groups of mice after allogeneic hematopoietic stem cell transplantation were used the incidence of GVHD was X2 = 20.6, indicating that the incidence of GVHD was significantly reduced and the survival rate of mice was significantly increased.
Collapse
Affiliation(s)
- Ying Wang
- Department of Hematology, the Seventh Affiliated Hopital, Sun Yat-sen University, Shenzhen, China
| |
Collapse
|
|
26
|
Hu N, Ji H. N6-methyladenosine (m6A)-mediated up-regulation of long noncoding RNA LINC01320 promotes the proliferation, migration, and invasion of gastric cancer via miR495-5p/RAB19 axis. Bioengineered 2021; 12:4081-4091. [PMID: 34288797 PMCID: PMC8806595 DOI: 10.1080/21655979.2021.1953210] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Gastric cancer is one of the most common malignant tumors. Long non-coding RNAs play crucial roles in gastric cancer progression. This study investigated the effect of LINC01320 on malignant behaviors of gastric cancer cells and explored its possible molecular mechanism. LINC01320 expression in gastric cancer tissues and cell lines was measured by qRT-PCR. Cell proliferation, transwell, and cell cloning assays were used to detect the effect of LINC01320 on the proliferation, migration, and invasion abilities, respectively, of gastric cancer cells. Bioinformatics analysis was used to predict the binding of miR-495-5p with LINC01320 and RAB19. A luciferase reporter assay was performed to verify their interactions. Finally, the N6-methyladenosine (m6A) modification of LINC01320 by METTL14 was identified through RIP experiments. LINC01320 was highly expressed in gastric cancer tissues and cells. LINC01320 overexpression promoted the proliferation, migration, and invasion of gastric cancer cells, while LINC01320 knockdown exerted the opposite effects. Moreover, miR-495-5p was predicted and demonstrated to target LINC01320 and RAB19. LINC01320 sponged miR-495-5p to regulate the expression of RAB19. Additionally, LINC01320-induced increases in cell viability, migration, and invasion of gastric cancer were alleviated by miR-495-5p and silenced RAB19. Furthermore, epigenetic studies showed that METTL14-mediated m6A modification led to LINC01320 up-regulation. METTL14 regulated the m6A modification of LINC01320. Overexpressed LINC01320 contributed to the aggressive phenotype of gastric cancer cells via regulating the miR-495-5p/RAB19 axis. This finding may provide new potential targets for treating gastric cancer.
Collapse
Affiliation(s)
- Naijun Hu
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Hong Ji
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| |
Collapse
|