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Lai J, Zhou Z, Hu K, Yu H, Su X, Niu X, Li H, Mao S. N6-methyladenosine methylation analysis of long noncoding RNAs and mRNAs in 5-FU-resistant colon cancer cells. Epigenetics 2024; 19:2298058. [PMID: 38145548 PMCID: PMC10761136 DOI: 10.1080/15592294.2023.2298058] [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: 07/03/2023] [Accepted: 12/13/2023] [Indexed: 12/27/2023] Open
Abstract
N6 methyladenosine (m6A), methylation at the sixth N atom of adenosine, is the most common and abundant modification in mammalian mRNAs and non-coding RNAs. Increasing evidence shows that the alteration of m6A modification level could regulate tumour proliferation, metastasis, self-renewal, and immune infiltration by regulating the related expression of tumour genes. However, the role of m6A modification in colorectal cancer (CRC) drug resistance is unclear. Here, MeRIP-seq and RNA-seq techniques were utilized to obtain mRNA, lncRNA expression, and their methylation profiles in 5-Fluorouracil (5-FU)-resistant colon cancer HCT-15 cells and control cells. In addition, we performed detailed bioinformatics analysis as well as in vitro experiments of lncRNA to explore the function of lncRNA with differential m6A in CRC progression and drug resistance. In this study, we obtained the m6A methylomic landscape of CRC cells and resistance group cells by MeRIP-seq and RNA-seq. We identified 3698 differential m6A peaks, of which 2224 were hypermethylated, and 1474 were hypomethylated. Among the lncRNAs, 60 were hypermethylated, and 38 were hypomethylated. GO and KEGG analysis annotations showed significant enrichment of endocytosis and MAPK signalling pathways. Moreover, knockdown of lncRNA ADIRF-AS1 and AL139035.1 promoted CRC proliferation and invasive metastasis in vitro. lncRNA- mRNA network showed that ADIRF-AS1 and AL139035.1 May play a key role in regulating drug resistance formation. We provide the first m6A methylation profile in 5-FU resistance CRC cells and analyse the functions of differential m6A-modified mRNAs and lncRNAs. Our results indicated that differential m6A RNAs were significantly associated with MAPK signalling and endocytosis after induction of 5-FU resistance. Knockdown of LncRNA ADIRF-AS1 and AL139035.1 promotes CRC progression and might be critical in regulating drug resistance formation.
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Affiliation(s)
- Jie Lai
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Department of General Surgery, Pingxiang People’s Hospital, Pingxiang, Jiangxi, China
| | - Zhiyong Zhou
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Kan Hu
- Department of General Surgery, Pingxiang People’s Hospital, Pingxiang, Jiangxi, China
| | - HongLong Yu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xingyao Su
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xiaoqiang Niu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Huizi Li
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Shengxun Mao
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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Jiang TQ, Wang H, Cheng WX, Xie C. Modulation of host N6-methyladenosine modification by gut microbiota in colorectal cancer. World J Gastroenterol 2024; 30:4175-4193. [PMID: 39493326 PMCID: PMC11525875 DOI: 10.3748/wjg.v30.i38.4175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 08/29/2024] [Accepted: 09/12/2024] [Indexed: 09/29/2024] Open
Abstract
As a research hotspot in the field of molecular biology, N6-methyladenosine (m6A) modification has made progress in the treatment of colorectal cancer (CRC), leukemia and other cancers. Numerous studies have demonstrated that the tumour microenvironment (TME) regulates the level of m6A modification in the host and activates a series of complex epigenetic signalling pathways through interactions with CRC cells, thus affecting the progression and prognosis of CRC. However, with the diversity in the composition of TME factors, this action is reciprocal and complex. Encouragingly, some studies have experimentally revealed that the intestinal flora can alter CRC cell proliferation by directly acting on m6A and thereby altering CRC cell proliferation. This review summarizes the data, supporting the idea that the intestinal flora can influence host m6A levels through pathways such as methyl donor metabolism and thus affect the progression of CRC. We also review the role of m6A modification in the diagnosis, treatment, and prognostic assessment of CRC and discuss the current status, limitations, and potential clinical value of m6A modification in this field. We propose that additional in-depth research on m6A alterations in CRC patients and their TME-related targeted therapeutic issues will lead to better therapeutic outcomes for CRC patients.
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Affiliation(s)
- Tian-Qi Jiang
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
- The First Clinical Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Hao Wang
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
- The First Clinical Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Wang-XinJun Cheng
- Queen Mary College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Chuan Xie
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
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Rong S, Dai B, Yang C, Lan Z, Wang L, Xu L, Chen W, Chen J, Wu Z. HNRNPC modulates PKM alternative splicing via m6A methylation, upregulating PKM2 expression to promote aerobic glycolysis in papillary thyroid carcinoma and drive malignant progression. J Transl Med 2024; 22:914. [PMID: 39380010 PMCID: PMC11459990 DOI: 10.1186/s12967-024-05668-9] [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: 03/19/2024] [Accepted: 09/04/2024] [Indexed: 10/10/2024] Open
Abstract
The heterogeneous nuclear ribonucleoprotein C (HNRNPC) plays a crucial role in tumorigenesis, yet its role in papillary thyroid carcinoma (PTC) remains elusive. Herein, we elucidated the function and molecular mechanism of HNRNPC in PTC tumorigenesis and progression. Our study unveiled a significant upregulation of HNRNPC in PTC, and knockdown of HNRNPC markedly inhibited the proliferation, invasion, and metastasis of BCPAP cells. Furthermore, HNRNPC modulated PKM alternative splicing in BCPAP cells primarily through m6A modification. Additionally, by upregulating PKM2 expression, HNRNPC promoted aerobic glycolysis in BCPAP cells, thereby facilitating malignant progression in PTC. In summary, our findings demonstrate that HNRNPC regulates PKM alternative splicing through m6A methylation modification and promotes the proliferation, invasion and metastasis of PTC through glucose metabolism pathways mediated by PKM2. These discoveries provide new biomarkers for screening and diagnosing PTC patients and offer novel therapeutic targets for personalized treatment strategies.
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Affiliation(s)
- Shikuo Rong
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
- Department of Thyroid and Hernia Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
- Department of Thyroid Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China.
| | - Bao Dai
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
- Department of Thyroid and Hernia Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Chunrong Yang
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Ziteng Lan
- Department of Thyroid and Hernia Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Linhe Wang
- Department of Thyroid and Hernia Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Lei Xu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
- Department of Thyroid and Hernia Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Weijian Chen
- Department of Thyroid and Hernia Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Jian Chen
- Department of Thyroid and Hernia Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
| | - Zeyu Wu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
- Department of Thyroid and Hernia Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
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Bian Y, Xu S, Gao Z, Ding J, Li C, Cui Z, Sun H, Li J, Pu J, Wang K. m 6A modification of lncRNA ABHD11-AS1 promotes colorectal cancer progression and inhibits ferroptosis through TRIM21/IGF2BP2/ FOXM1 positive feedback loop. Cancer Lett 2024; 596:217004. [PMID: 38838765 DOI: 10.1016/j.canlet.2024.217004] [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: 01/27/2024] [Revised: 05/20/2024] [Accepted: 05/25/2024] [Indexed: 06/07/2024]
Abstract
Long non-coding RNA (lncRNA) is closely related to a variety of human cancers, which may provide huge potential biomarkers for cancer diagnosis and treatment. However, the aberrant expression of most lncRNAs in colorectal cancer (CRC) remains elusive. This study aims to explore the clinical significance and potential mechanism of lncRNA ABHD11 antisense RNA 1 (ABHD11-AS1) in the colorectal cancer. Here, we demonstrated that lncRNA ABHD11-AS1 is high-expressed in colorectal cancer (CRC) patients, and strongly related with poor prognosis. Functionally, ABHD11-AS1 suppresses ferroptosis and promotes proliferation and migration in CRC both in vitro and in vivo. Mechanically, lncRNA ABHD11-AS1 interacted with insulin-like growing factor 2 mRNA-binding protein 2 (IGF2BP2) to enhance FOXM1 stability, forming an ABHD11-AS1/FOXM1 positive feedback loop. E3 ligase tripartite motif containing 21 (TRIM21) promotes the degradation of IGF2BP2 via the K48-ubiquitin-lysosome pathway and ABHD11-AS1 promotes the interaction between IGF2BP2 and TRIM21 as scaffold platform. Furthermore, N6 -adenosine-methyltransferase-like 3 (METTL3) upregulated the stabilization of ABHD11-AS1 through the m6A reader IGF2BP2. Our study highlights ABHD11-AS1 as a significant regulator in CRC and it may become a potential target in future CRC treatment.
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Affiliation(s)
- Yibo Bian
- Department of Oncology, Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China; State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of digestive Disease, Fourth Military Medical University, Xi'an, 710032, China
| | - Shufen Xu
- Department of Oncology, Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Zhishuang Gao
- Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Jie Ding
- Department of Oncology, Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Chao Li
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, 200032, China
| | - Zhiwei Cui
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Haoyu Sun
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Juan Li
- Department of Oncology, Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Juan Pu
- Department of Oncology, Lianshui County People's Hospital, Huai'an, 223400, China.
| | - Keming Wang
- Department of Oncology, Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
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Esmaeili N, Bakheet A, Tse W, Liu S, Han X. Interaction of the intestinal cytokines-JAKs-STAT3 and 5 axes with RNA N6-methyladenosine to promote chronic inflammation-induced colorectal cancer. Front Oncol 2024; 14:1352845. [PMID: 39136000 PMCID: PMC11317299 DOI: 10.3389/fonc.2024.1352845] [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: 12/09/2023] [Accepted: 06/25/2024] [Indexed: 08/15/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers, with a high mortality rate worldwide. Mounting evidence indicates that mRNA modifications are crucial in RNA metabolism, transcription, processing, splicing, degradation, and translation. Studies show that N6-methyladenosine (m6A) is mammalians' most common epi-transcriptomic modification. It has been demonstrated that m6A is involved in cancer formation, progression, invasion, and metastasis, suggesting it could be a potential biomarker for CRC diagnosis and developing therapeutics. Cytokines, growth factors, and hormones function in JAK/STAT3/5 signaling pathway, and they could regulate the intestinal response to infection, inflammation, and tumorigenesis. Reports show that the JAK/STAT3/5 pathway is involved in CRC development. However, the underlying mechanism is still unclear. Signal Transducer and Activator of Transcription 3/5 (STAT3, STAT5) can act as oncogenes or tumor suppressors in the context of tissue types. Also, epigenetic modifications and mutations could alter the balance between pro-oncogenic and tumor suppressor activities of the STAT3/5 signaling pathway. Thus, exploring the interaction of cytokines-JAKs-STAT3 and/or STAT5 with mRNA m6A is of great interest. This review provides a comprehensive overview of the characteristics and functions of m6A and JAKs-STAT3/5 and their relationship with gastrointestinal (GI) cancers.
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Affiliation(s)
- Nardana Esmaeili
- Division of Hematology and Oncology, Department of Medicine, MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH, United States
- Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH, United States
| | - Ahmed Bakheet
- Division of Hematology and Oncology, Department of Medicine, MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH, United States
- Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH, United States
| | - William Tse
- Division of Hematology and Oncology, Department of Medicine, MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH, United States
| | - Shujun Liu
- Division of Hematology and Oncology, Department of Medicine, MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH, United States
| | - Xiaonan Han
- Division of Hematology and Oncology, Department of Medicine, MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH, United States
- Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH, United States
- Cancer Genomics and Epigenomics Program, Case Comprehensive Cancer Center, Case Western Reserve University (CWRU), Cleveland, OH, United States
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Zhu DH, Su KK, Ou-Yang XX, Zhang YH, Yu XP, Li ZH, Ahmadi-Nishaboori SS, Li LJ. Mechanisms and clinical landscape of N6-methyladenosine (m6A) RNA modification in gastrointestinal tract cancers. Mol Cell Biochem 2024; 479:1553-1570. [PMID: 38856795 PMCID: PMC11254988 DOI: 10.1007/s11010-024-05040-x] [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: 03/13/2024] [Accepted: 05/18/2024] [Indexed: 06/11/2024]
Abstract
Epigenetics encompasses reversible and heritable chemical modifications of non-nuclear DNA sequences, including DNA and RNA methylation, histone modifications, non-coding RNA modifications, and chromatin rearrangements. In addition to well-studied DNA and histone methylation, RNA methylation has emerged as a hot topic in biological sciences over the past decade. N6-methyladenosine (m6A) is the most common and abundant modification in eukaryotic mRNA, affecting all RNA stages, including transcription, translation, and degradation. Advances in high-throughput sequencing technologies made it feasible to identify the chemical basis and biological functions of m6A RNA. Dysregulation of m6A levels and associated modifying proteins can both inhibit and promote cancer, highlighting the importance of the tumor microenvironment in diverse biological processes. Gastrointestinal tract cancers, including gastric, colorectal, and pancreatic cancers, are among the most common and deadly malignancies in humans. Growing evidence suggests a close association between m6A levels and the progression of gastrointestinal tumors. Global m6A modification levels are substantially modified in gastrointestinal tumor tissues and cell lines compared to healthy tissues and cells, possibly influencing various biological behaviors such as tumor cell proliferation, invasion, metastasis, and drug resistance. Exploring the diagnostic and therapeutic potential of m6A-related proteins is critical from a clinical standpoint. Developing more specific and effective m6A modulators offers new options for treating these tumors and deeper insights into gastrointestinal tract cancers.
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Affiliation(s)
- Dan-Hua Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Kun-Kai Su
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Xiao-Xi Ou-Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yan-Hong Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Xiao-Peng Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Zu-Hong Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | | | - Lan-Juan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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Hou C, Liu J, Liu J, Yao D, Liang F, Qin C, Ma Z. METTL3-induced circ_0008345 contributes to the progression of colorectal cancer via the microRNA-182-5p/CYP1A2 pathway. BMC Cancer 2024; 24:728. [PMID: 38877514 PMCID: PMC11177402 DOI: 10.1186/s12885-024-12474-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 06/04/2024] [Indexed: 06/16/2024] Open
Abstract
BACKGROUND Circular RNA (circRNAs) have been found to play major roles in the progression of colorectal cancer (CRC). However, the functions of circ_0008345 (transcribed by PTK2) in regulating CRC development remain undefined. In this study, we aimed to explore the roles and underlying mechanisms of circ_0008345 in CRC. METHODS RNase R-treated total cellular RNA was used to verify the circular structure of circ_0008345, and a subcellular fractionation assay was performed to detect the subcellular localization of circ_0008345. RNA pull-down and dual-luciferase assays were used to verify the binding relation between microRNA (miR)-182-5p and circ_0008345 and/or CYP1A2. Colony formation assay, EdU, and Transwell assays were performed to detect the biological behavior of CRC cells in vitro, and CRC cells were injected into mice to observe the tumor formation. m6A immunoprecipitation was used to detect the m6A modification of circ_0008345 in CRC cells. RESULTS Circ_0008345, upregulated in CRC tissues and cells, was mainly present in the cytoplasm. Circ_0008345 bound to miR-182-5p, and miR-182-5p targeted CYP1A2, an oncogene in CRC. The colony formation, mobility, EdU-positive cell rate in vitro, and tumor growth in mice were inhibited after the knockdown of circ_0008345. However, the suppressing effects of sh-circ_0008345 on CRC and CYP1A2 expression were significantly reversed after further knockdown of miR-182-5p. METTL3 was the m6A modifier mediating circ_0008345 expression, and the suppression of METTL3 reduced the expression of circ_0008345. CONCLUSIONS METTL3-dependent m6A methylation upregulated circ_0008345, which blocked the inhibitory effect of miR-182-5p on CYP1A2, thereby exacerbating the malignant phenotype of CRC cells.
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Affiliation(s)
- Chaofeng Hou
- Department of Anorectal Surgery, Zhengzhou Central Hospital Affiliated to Zhengzhou University, No. 195, Tongbai North Road, Zhongyuan District, Zhengzhou, Henan, 450000, P.R. China
| | - Jinbo Liu
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, P.R. China
| | - Junwei Liu
- Department of Anorectal Surgery, Zhengzhou Central Hospital Affiliated to Zhengzhou University, No. 195, Tongbai North Road, Zhongyuan District, Zhengzhou, Henan, 450000, P.R. China
| | - Danjie Yao
- Department of Anorectal Surgery, Zhengzhou Central Hospital Affiliated to Zhengzhou University, No. 195, Tongbai North Road, Zhongyuan District, Zhengzhou, Henan, 450000, P.R. China
| | - Fang Liang
- Department of Oncology Rehabilitation, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, 450000, P.R. China
| | - Congpeng Qin
- Department of Anorectal Surgery, Zhengzhou Central Hospital Affiliated to Zhengzhou University, No. 195, Tongbai North Road, Zhongyuan District, Zhengzhou, Henan, 450000, P.R. China
| | - Zhiyong Ma
- Department of Anorectal Surgery, Zhengzhou Central Hospital Affiliated to Zhengzhou University, No. 195, Tongbai North Road, Zhongyuan District, Zhengzhou, Henan, 450000, P.R. China.
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Wang S, Yang Y, Jiang X, Zheng X, Wei Q, Dai W, Zhang X. Nurturing gut health: role of m6A RNA methylation in upholding the intestinal barrier. Cell Death Discov 2024; 10:271. [PMID: 38830900 PMCID: PMC11148167 DOI: 10.1038/s41420-024-02043-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 05/19/2024] [Accepted: 05/22/2024] [Indexed: 06/05/2024] Open
Abstract
The intestinal lumen acts as a critical interface connecting the external environment with the body's internal state. It's essential to prevent the passage of harmful antigens and bacteria while facilitating nutrient and water absorption. The intestinal barriers encompass microbial, mechanical, immunological, and chemical elements, working together to maintain intestinal balance. Numerous studies have associated m6A modification with intestinal homeostasis. This review comprehensively outlines potential mechanisms through which m6A modification could initiate, exacerbate, or sustain barrier damage from an intestinal perspective. The pivotal role of m6A modification in preserving intestinal equilibrium provides new insights, guiding the exploration of m6A modification as a target for optimizing preventive and therapeutic strategies for intestinal homeostasis.
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Affiliation(s)
| | - Yuzhong Yang
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Xiaohan Jiang
- Department of Pathology, Liuzhou People's Hospital Affiliated to Guangxi Medical University, Liuzhou, Guangxi, China
| | - Xiang Zheng
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Qiufang Wei
- Department of Pathology, Liuzhou People's Hospital Affiliated to Guangxi Medical University, Liuzhou, Guangxi, China
| | - Wenbin Dai
- Department of Pathology, Liuzhou People's Hospital Affiliated to Guangxi Medical University, Liuzhou, Guangxi, China.
| | - Xuemei Zhang
- Department of Pathology, Liuzhou People's Hospital Affiliated to Guangxi Medical University, Liuzhou, Guangxi, China.
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Wu X, Chen X, Liu X, Jin B, Zhang Y, Wang Y, Xu H, Wan X, Zheng Y, Xu L, Xiao Y, Chen Z, Wang H, Mao Y, Lu X, Sang X, Zhao L, Du S. LINC02257 regulates colorectal cancer liver metastases through JNK pathway. Heliyon 2024; 10:e30841. [PMID: 38826728 PMCID: PMC11141284 DOI: 10.1016/j.heliyon.2024.e30841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 05/06/2024] [Accepted: 05/06/2024] [Indexed: 06/04/2024] Open
Abstract
Background Long noncoding RNAs (lncRNAs) have emerged as critical regulators of colorectal cancer (CRC) progression, but their roles and underlying mechanisms in colorectal cancer liver metastases (CRLMs) remain poorly understood. Methods To explore the expression patterns and functions of lncRNAs in CRLMs, we analyzed the expression profiles of lncRNAs in CRC tissues using the TCGA database and examined the expression patterns of lncRNAs in matched normal, CRC, and CRLM tissues using clinical samples. We further investigated the biological roles of LINC02257 in CRLM using in vitro and in vivo assays, and verified its therapeutic potential in a mouse model of CRLM. Results Our findings showed that LINC02257 was highly expressed in metastatic CRC tissues and its expression was negatively associated with overall survival. Functionally, LINC02257 promoted CRC cell growth, migration, metastasis, and inhibited cell apoptosis in vitro, and enhanced liver metastasis in vivo. Mechanistically, LINC02257 up-regulated phosphorylated c-Jun N-terminal kinase (JNK) to promote CRLM. Conclusions Our study revealed that LINC02257 played a key role in the proliferation and metastasis of CRC cells through the LINC02257/JNK axis. Targeting this axis may represent a promising therapeutic strategy for the treatment of liver metastases in patients with CRC.
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Affiliation(s)
- Xiangan Wu
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaokun Chen
- Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao Liu
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Bao Jin
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yuke Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yuxin Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Haifeng Xu
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xueshuai Wan
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yongchang Zheng
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Lai Xu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yi Xiao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Zhengju Chen
- Pooling Medical Research Institutes, Beijing, China
| | - Haiwen Wang
- Pooling Medical Research Institutes, Beijing, China
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xin Lu
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Lin Zhao
- Department of Medical Oncology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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10
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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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11
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Gao X, Ye J, Huang X, Huang S, Luo W, Zeng D, Li S, Tang M, Mai R, Li Y, Lin Y, Liang R. Research progress of the netrins and their receptors in cancer. J Cell Mol Med 2024; 28:e18241. [PMID: 38546656 PMCID: PMC10977403 DOI: 10.1111/jcmm.18241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 02/27/2024] [Accepted: 03/04/2024] [Indexed: 11/12/2024] Open
Abstract
Netrins, a family of secreted and membrane-associated proteins, can regulate axonal guidance, morphogenesis, angiogenesis, cell migration, cell survival, and tumorigenesis. Four secreted netrins (netrin 1, 3, 4 and 5) and two glycosylphosphatidylinositols-anchored membrane proteins, netrin-G1 and G2, have been identified in mammals. Netrins and their receptors can serve as a biomarker and molecular therapeutic target for pathological differentiation, diagnosis and prognosis of malignant cancers. We review here the potential roles of the netrins family and their receptors in cancer.
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Affiliation(s)
- Xing Gao
- Department of Digestive OncologyGuangxi Medical University Cancer HospitalNanningGuangxiChina
| | - Jiazhou Ye
- Department of Hepatobiliary SurgeryGuangxi Medical University Cancer HospitalNanningGuangxiChina
| | - Xi Huang
- Department of Digestive OncologyGuangxi Medical University Cancer HospitalNanningGuangxiChina
| | - Shilin Huang
- Department of Digestive OncologyGuangxi Medical University Cancer HospitalNanningGuangxiChina
| | - Wenfeng Luo
- Department of Digestive OncologyGuangxi Medical University Cancer HospitalNanningGuangxiChina
| | - Dandan Zeng
- Department of Digestive OncologyGuangxi Medical University Cancer HospitalNanningGuangxiChina
| | - Shizhou Li
- Department of Hepatobiliary SurgeryGuangxi Medical University Cancer HospitalNanningGuangxiChina
| | - Minchao Tang
- Department of Hepatobiliary SurgeryGuangxi Medical University Cancer HospitalNanningGuangxiChina
| | - Rongyun Mai
- Department of Hepatobiliary SurgeryGuangxi Medical University Cancer HospitalNanningGuangxiChina
| | - Yongqiang Li
- Department of Digestive OncologyGuangxi Medical University Cancer HospitalNanningGuangxiChina
| | - Yan Lin
- Department of Digestive OncologyGuangxi Medical University Cancer HospitalNanningGuangxiChina
| | - Rong Liang
- Department of Digestive OncologyGuangxi Medical University Cancer HospitalNanningGuangxiChina
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12
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Yang Y, Luo L, Zhou Z. The role of m6A RNA methylation regulator in meningioma. Aging (Albany NY) 2023; 15:12068-12084. [PMID: 37910780 PMCID: PMC10683626 DOI: 10.18632/aging.205163] [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: 03/07/2023] [Accepted: 10/04/2023] [Indexed: 11/03/2023]
Abstract
Meningiomas are common intracranial tumors, and the effect of surgical resection is often unsatisfactory. N6-Methyladenosine (m6A)-related regulator expression levels are related to cancer occurrence and development. This study aimed to investigate the roles of m6A RNA methylation regulators in meningiomas, as these are currently unclear. Two m6A methylation-regulated genes (METTL3 and IGF2BP2) were identified as survival-associated linear models for RiskScore through bioinformatics analysis. Univariate and multivariate Cox regression analyses showed that the overall survival of patients with meningioma in the high-risk group was substantially shorter than that in the low-risk group. Weighted gene co-expression network analysis constructed a co-expression network based on the m6A methylation model (RiskScore). Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes analyses identified the biological processes of hub module gene behavior, and Cytoscape constructed an m6A methylation-related gene regulatory network. In vitro experiments verified that the mRNA and protein expression levels of METTL3 and IGF2BP2 were lower in meningioma cells than in normal meningioma cells. Therefore, central regulators of m6A methylation (METTL3 and IGF2BP2) could potentially serve as novel therapeutic targets in meningioma. Subsequently, a novel methylation signature (RiskScore) was developed for prognostic prediction in patients with meningioma.
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Affiliation(s)
- Yu Yang
- Department of Neurosurgery, Jiangxi Provincial People’s Hospital, Nanchang 330006, Jiangxi, China
- The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, Jiangxi, China
| | - Liqin Luo
- The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, Jiangxi, China
- Nanchang First Retired Cadre Rest House of Jiangxi Military Region, Nanchang 330006, Jiangxi, China
| | - Zhiwu Zhou
- The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, Jiangxi, China
- Department of Gastrointestinal Surgery, Jiangxi Provincial People’s Hospital, Nanchang 330006, Jiangxi, China
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13
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Zhang D, Wu G, Yang L, Wu Q, Yuan L. The predictive significance of a 5-m6A RNA methylation regulator signature in colorectal cancer. Heliyon 2023; 9:e20172. [PMID: 37810844 PMCID: PMC10550633 DOI: 10.1016/j.heliyon.2023.e20172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 09/03/2023] [Accepted: 09/13/2023] [Indexed: 10/10/2023] Open
Abstract
Colorectal cancer attacks the colon or rectum, with increasing morbidity and mortality globally. The RNA modification 6-methyladenine (m6A) is related to RNA modifications, playing a critical role in colorectal cancer. We aimed to identify prognostic signatures for colorectal cancer using risk prediction algorithms, and to validate these signatures using independent datasets and clinical samples. In this study, 175 cases in GSE17536 were assigned into two clusters using consistent clustering and PCA analysis. A multivariate Cox risk regression model revealed that among 21 m6A RNA methylation regulators, RBM15B, FTO, IGF2BP2, ZCCHC4, and KIAA1429 were remarkably associated with colorectal cancer patients' overall survival (OS); however, Kaplan-Meier (KM) survival assessment showed no significant association between these five regulators and colorectal cancer patients' prognosis. A 5-m6A RNA methylation regulator signature was established using LASSO algorithm. Risk scores of cases in GSE17536, GSE17537 and GSE75500 were calculated, and lower risk scores were associated with better DSS/OS. receiver operating characteristic (ROC) curve and the nomogram revealed the satisfactory predictive efficiency of the risk score model. The risk score could distinguish cases in Cluster1 and Cluster2 and normal and tumor tissues based on GSE37182. The prognostic variables for colorectal cancer patients were assessed using both univariate and multivariate Cox's proportional hazard regression models, which revealed that the stage and risk score were significant risk factors. In this study, a comprehensive set of integrative bioinformatics analyses was conducted to investigate the prognostic and diagnostic potential of a panel of 5 m6A RNA methylated regulators in colorectal cancer patients. The conducted studies included the use of several statistical methods, such as the LASSO regression model, KM survival evaluation, ROC curve, and univariate and multivariate Cox's proportional hazard regression analyses. The findings from these analyses collectively established the prognostic marker, highlighting its significance in predicting patient outcomes and diagnosing colorectal cancer.
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Affiliation(s)
- Dan Zhang
- Clinical Nursing Teaching and Research Section, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, PR China
| | - Guotao Wu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lichao Yang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qiang Wu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lianwen Yuan
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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14
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Hajipour A, Ardekanizadeh NH, Roumi Z, Shekari S, Aminnezhad Kavkani B, Shalmani SHM, Bahar B, Tajadod S, Ajami M, Tabesh GA, Gholamalizadeh M, Doaei S. The effect of FTO gene rs9939609 polymorphism on the association between colorectal cancer and different types of dietary fat intake: a case-control study. J Physiol Anthropol 2023; 42:17. [PMID: 37543622 PMCID: PMC10404375 DOI: 10.1186/s40101-023-00333-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 07/17/2023] [Indexed: 08/07/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common cancers in the world. Some dietary factors such as fat intake have been identified as the risk factors for CRC. This study aimed to investigate the effect of fat mass and obesity-associated (FTO) gene rs9939609 polymorphism on the association between CRC and different types of dietary fats. METHODS This case-control study was performed on 135 CRC cases and 294 healthy controls in Tehran, Iran. Data on demographic factors, anthropometric measurements, physical activity, the intake of different types of dietary fats, and FTO gene rs9939609 polymorphism was collected from all participants. The association between cancer and dietary fat intake in individuals with different FTO genotypes was assessed using different models of logistic regression. RESULTS Oleic acid intake was higher in the case group compared to the control group in both people with TT (7.2±3.46 vs. 5.83±3.06 g/d, P=0.02) and AA/AT genotypes (8.7±6.23 vs. 5.57 ±3.2 g/d, P<0.001). Among carriers of AA/AT genotypes of FTO rs9939609 polymorphism, a positive association was found between CRC and higher intakes of oleic acid (OR=1.12, CI95% 1.03-1.21, P=0.01) and cholesterol (OR=1.01, CI95% 1.00-1.02; P=0.01) after adjusting for age, sex, physical activity, alcohol use, smoking, calorie intake, and body mass index. CONCLUSION Higher intakes of cholesterol and oleic acid were associated with a higher risk of CRC in FTO-risk allele carriers. The association of CRC and dietary fat may be influenced by the FTO genotype. Further longitudinal studies are warranted to confirm these findings.
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Affiliation(s)
- Azadeh Hajipour
- School of Health, Qazvin University of Medical Sciences, Qazvin, Iran
| | | | - Zahra Roumi
- Department of Nutrition, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Soheila Shekari
- Department of Nutrition, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | | | | | - Bojlul Bahar
- Nutrition Sciences and Applied Food Safety Studies, Research Centre for Global Development, School of Sport & Health Sciences, University of Central Lancashire, Preston, UK
| | - Shirin Tajadod
- Department of Nutrition, School of Public Health, International Campus, Iran University of Medical Sciences, Tehran, Iran
| | - Marjan Ajami
- Department of Food and Nutrition Policy and Planning National Nutrition and Food Technology Research Institute School of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ghasem Azizi Tabesh
- Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Gholamalizadeh
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Saeid Doaei
- Department of Community Nutrition, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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15
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Chen W, Deng J, Zhou Y. The construction of a novel ferroptosis-related lncRNA model to predict prognosis in colorectal cancer patients. Medicine (Baltimore) 2023; 102:e33114. [PMID: 36897681 PMCID: PMC9997773 DOI: 10.1097/md.0000000000033114] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 02/07/2023] [Indexed: 03/11/2023] Open
Abstract
Colorectal cancer (CRC) is the most common gastrointestinal tumor with poor prognosis. Ferroptosis is a pivotal form of programmed iron-dependent cell death different from autophagy and apoptosis, and long noncoding RNA (lncRNA) can influence the prognosis of CRC via regulating ferroptosis. To explore the role and prognostic value of the constructed ferroptosis-related lncRNA model in CRC, a prognostic model was constructed and validated by screening ferroptosis-related lncRNAs associated with prognosis based on the transcriptome data and survival data of CRC patients in The Cancer Genome Atlas database. Regarding the established prognostic models, differences in signaling pathways and immune infiltration, as well as differences in immune function, immune checkpoints, and N6-methyladenosine-related genes were also analyzed. A total of 6 prognostic ferroptosis-related lncRNAs were obtained, including AP003555.1, AC010973.2, LINC01857, AP001469.3, ITGB1-DT and AC129492.1. Univariate independent prognostic analysis, multivariate independent prognostic analysis and receiver operating characteristic curves showed that ferroptosis-related lncRNAs could be recognized as independent prognostic factors. The Kaplan-Meier survival curves and the risk curves showed that the survival time of the high-risk group was shorter. Gene set enrichment analysis enrichment analysis showed that ATP-binding cassette transporters, taste transduction and VEGF signaling pathway were more active in high-risk groups that than in low-risk groups. However, the citrate cycle tricarboxylic acid cycle, fatty acid metabolism and peroxisome were significantly more active in the low-risk group than in the high-risk group. In addition, there were also differences in immune infiltration in the high-low-risk groups based on different methods, including antigen-presenting cell co-stimulation, chemokine receptor, parainflammation, and Type II IFN Response. Further analysis of Immune checkpoints showed that most of the Immune checkpoints such as TNFRSF18, LGALS9 and CTLA4 in the high-risk group were significantly higher than those in the low-risk group, and the expressions of N6-methyladenosine related genes METTL3, YTHDH2 and YTHDC1 were also significantly different in the high-risk group. Ferroptosis-related lncRNAs are closely related to the survival of colorectal cancer patients, which can be used as new biomarkers and potential therapeutic targets for the prognosis of colorectal cancer.
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Affiliation(s)
- Weihong Chen
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, China
| | - Jianzhi Deng
- College of Information Science and Engineering, Guilin University of Technology, Guilin, Guangxi, China
| | - Yuehan Zhou
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, China
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16
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Qu X, Tan H, Mao J, Yang M, Xu J, Yan X, Wu W. Identification of a novel prognostic signature correlated with epithelial-mesenchymal transition, N6-methyladenosine modification, and immune infiltration in colorectal cancer. Cancer Med 2023; 12:5926-5938. [PMID: 36281556 PMCID: PMC10028107 DOI: 10.1002/cam4.5384] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 08/16/2022] [Accepted: 10/11/2022] [Indexed: 12/03/2022] Open
Abstract
OBJECTIVE Colorectal cancer (CRC) is a commonly diagnosed human malignancy worldwide. Both epithelial-mesenchymal transition (EMT) and N6-methyladenosine (m6A) modification play a crucial role in CRC development. This study aimed to construct a prognostic signature based on the genes related to EMT and m6A modification. METHOD Firstly, the mRNA expression profiling of CRC tissues was analyzed using TCGA and GEO databases. The prognostic hub genes related to EMT and m6A modification were selected using weighted correlation network and cox regression analysis. The prognostic signature was constructed based on hub genes, followed by validation in three external cohorts. Finally, the expression of the representative hub gene was detected in clinical samples, and its biological role was investigated using assays in vivo and in vitro. RESULTS A prognostic signature was constructed using the following genes: YAP1, FAM3C, NUBPL, GLO1, JARID2, NFKB1, CDKN1B, HOOK1, and GIPC2. The signature effectively stratified the clinical outcome of CRC patients in the training cohort and two validation cohorts. The subgroup analysis demonstrated the signature could identify high-risk population from CRC patients within stage I-II or III-IV, female, male and elder patients. The signature was correlated with the infiltration of some immune cells (such as macrophage and regulatory T cells) and gene mutation counts. Finally, the hub gene GIPC2 was found to be downregulated in CRC tissues and most CRC cells lines. GIPC2 overexpression inhibited the malignant characteristics of CRC cells in vitro and in vivo through upregulating E-cadherin and downregulating N-cadherin, Vimentin, and Snail, while the opposite results were observed for GIPC2 knockdown in CRC cells. CONCLUSION Our present study for the first time constructed a novel prognostic signature related to EMT, m6A modification, and immune infiltration for CRC risk stratification. In addition, GIPC2 is identified as a promising clinical biomarker or therapeutical target for CRC.
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Affiliation(s)
- Xiao Qu
- Department of Gastrointestinal Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Honghong Tan
- Department of VIP Clinic, General Division, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai East Hospital Ji'an Hospital, Ji'an, China
| | - Jingxian Mao
- Department of Oncology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Mengxue Yang
- Department of Oncology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Jian Xu
- Department of Oncology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Xuebing Yan
- Department of Oncology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Wenjuan Wu
- Department of Oncology, Northern Jiangsu People's Hospital affiliated to Yangzhou University, Yangzhou University, Yangzhou, China
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17
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Jiang X, Jin Z, Yang Y, Zheng X, Chen S, Wang S, Zhang X, Qu N. m6A modification on the fate of colorectal cancer: functions and mechanisms of cell proliferation and tumorigenesis. Front Oncol 2023; 13:1162300. [PMID: 37152066 PMCID: PMC10162644 DOI: 10.3389/fonc.2023.1162300] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 03/30/2023] [Indexed: 05/09/2023] Open
Abstract
N6-methyladenosine (m6A) is the most pervasive RNA modification in eukaryotic cells. The dynamic and reversible m6A modification of RNA plays a critical role in the occurrence and progression of tumors by regulating RNA metabolism, including translocation, mRNA stability or decay, pre-mRNA splicing, and lncRNA processing. Numerous studies have shown that m6A modification is involved in the development of various cancers. This review aims to summarize the significant role of m6A modification in the proliferation and tumorigenesis of CRC, as well as the potential of modulating m6A modification for tumor treatment. These findings may offer new therapeutic strategies for clinical implementation of m6A modification in CRC in the near future.
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Affiliation(s)
- Xiaohan Jiang
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Ziyao Jin
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuzhong Yang
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Xiang Zheng
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Shaohua Chen
- Department of Breast and Thyroid Surgery, Liuzhou People’s Hospital Affiliated to Guangxi Medical University, Liuzhou, China
| | - Shuaijie Wang
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Xuemei Zhang
- Department of Pathology, Liuzhou People’s Hospital Affiliated to Guangxi Medical University, Liuzhou, China
- *Correspondence: Xuemei Zhang, ; Nanfang Qu,
| | - Nanfang Qu
- Department of Gastroenterology, Affiliated Hospital of Guilin Medical University, Guilin, China
- *Correspondence: Xuemei Zhang, ; Nanfang Qu,
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18
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Zhang Y, Gu P, Xie Y, Fan L, You X, Yang S, Yao Y, Chen W, Ma J. Insights into the mechanism underlying crystalline silica-induced pulmonary fibrosis via transcriptome-wide m 6A methylation profile. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 247:114215. [PMID: 36306621 DOI: 10.1016/j.ecoenv.2022.114215] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 10/14/2022] [Accepted: 10/18/2022] [Indexed: 06/16/2023]
Abstract
Silicosis is one of the most severe interstitial lung fibrosis diseases worldwide, caused by crystalline silica exposure. While the mechanisms and pathogenesis underlying silicosis remained unknown. N6-methyladenosine (m6A) methylation has received significant attention in a variety of human diseases. However, whether m6A methylation is involved in silicosis has not been clarified. In this study, we conducted methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and transcriptome sequencing (RNA-Seq) to profile the m6A modification in normal and silicosis mouse models (n = 3 pairs). The global levels of m6A methylation were further assessed by m6A RNA methylation quantification kits, and the major regulators of m6A RNA methylation were verified by qRT-PCR. Our results showed that long-term exposure to crystalline silica led to silicosis, accompanied by increasing levels of m6A methylation. Upregulation of METTL3 and downregulation of ALKBH5, FTO, YTHDF1, and YTHDF3 might contribute to aberrant m6A modification. Compared with controls, 359 genes showed differential m6A methylation peaks in silicosis (P < 0.05 and FC ≥ 2). Among them, 307 genes were hypermethylated, and 52 genes were hypomethylated. RNA-Seq analysis revealed 1091 differentially expressed genes between the two groups, 789 genes were upregulated and 302 genes were downregulated in the lungs of silicosis mice (P < 0.05 and FC ≥ 2). In the conjoint analysis of MeRIP-Seq and RNA-Seq, we identified that 18 genes showed significant changes in both m6A modification and mRNA expression. The functional analysis further noted that these 18 m6A-mediated mRNAs regulated pathways that were closely related to "phagosome", "antigen processing and presentation", and "apoptosis". All findings suggested that m6A methylation played an essential role in the formation of silicosis. Our discovery with multi-omics approaches not only gives clues for the epigenetic mechanisms underlying the pathogenesis of silicosis but also provides novel and viable strategies for the prevention and treatment of silicosis.
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Affiliation(s)
- Yingdie Zhang
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Pei Gu
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Yujia Xie
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Lieyang Fan
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Xiaojie You
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Shiyu Yang
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Yuxin Yao
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Weihong Chen
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Jixuan Ma
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
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FMR1 promotes the progression of colorectal cancer cell by stabilizing EGFR mRNA in an m 6A-dependent manner. Cell Death Dis 2022; 13:941. [PMID: 36347844 PMCID: PMC9643526 DOI: 10.1038/s41419-022-05391-7] [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: 07/01/2022] [Revised: 10/27/2022] [Accepted: 10/28/2022] [Indexed: 11/09/2022]
Abstract
FMR1, a new m6A reader, is known to be involved in the regulation of cancer progression. However, its role, regulatory mechanism, and clinical significance in colorectal cancer (CRC) are elusive. Here, we showed that FMR1 was upregulated in CRC, and it promoted proliferation and metastasis of CRC cells in vitro and in vivo. Mechanically, FMR1 recognized the m6A-modification site in EGFR mRNA, a key molecule in cancer occurrence and targeted therapy, sustained its stability and maintained its expression in an m6A-dependent manner, thereby promoting the tumorigenesis and metastasis of CRC. And the effect of FMR1 knockdown in CRC cells could be abolished by METTL3. Furthermore, FMR1 shRNA plasmid carried by attenuated Salmonella has an effective anti-tumor effect in vivo. Collectively, we identified the METTL3/FMR1/EGFR axis in the progression of CRC. This novel mechanism indicated that the METTL3/FMR1/EGFR axis is a potential target for early therapeutic intervention in CRC progression.
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20
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N6-methyladenosine-modified circular RNA QSOX1 promotes colorectal cancer resistance to anti-CTLA-4 therapy through induction of intratumoral regulatory T cells. Drug Resist Updat 2022; 65:100886. [DOI: 10.1016/j.drup.2022.100886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 10/12/2022] [Accepted: 10/19/2022] [Indexed: 11/18/2022]
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21
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Liu S, Chen L, Zhang Y, Zhou Y, He Y, Chen Z, Qi S, Zhu J, Chen X, Zhang H, Luo Y, Qiu Y, Tao L, Zhu F. M6AREG: m6A-centered regulation of disease development and drug response. Nucleic Acids Res 2022; 51:D1333-D1344. [PMID: 36134713 PMCID: PMC9825441 DOI: 10.1093/nar/gkac801] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 08/27/2022] [Accepted: 09/06/2022] [Indexed: 01/30/2023] Open
Abstract
As the most prevalent internal modification in eukaryotic RNAs, N6-methyladenosine (m6A) has been discovered to play an essential role in cellular proliferation, metabolic homeostasis, embryonic development, etc. With the rapid accumulation of research interest in m6A, its crucial roles in the regulations of disease development and drug response are gaining more and more attention. Thus, a database offering such valuable data on m6A-centered regulation is greatly needed; however, no such database is as yet available. Herein, a new database named 'M6AREG' is developed to (i) systematically cover, for the first time, data on the effects of m6A-centered regulation on both disease development and drug response, (ii) explicitly describe the molecular mechanism underlying each type of regulation and (iii) fully reference the collected data by cross-linking to existing databases. Since the accumulated data are valuable for researchers in diverse disciplines (such as pathology and pathophysiology, clinical laboratory diagnostics, medicinal biochemistry and drug design), M6AREG is expected to have many implications for the future conduct of m6A-based regulation studies. It is currently accessible by all users at: https://idrblab.org/m6areg/.
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Affiliation(s)
- Shuiping Liu
- Correspondence may also be addressed to Shuiping Liu.
| | | | | | | | - Ying He
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China
| | - Zhen Chen
- College of Pharmaceutical Sciences, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, China,Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Hangzhou 330110, China
| | - Shasha Qi
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China
| | - Jinyu Zhu
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China
| | - Xudong Chen
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China
| | - Hao Zhang
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China
| | - Yongchao Luo
- College of Pharmaceutical Sciences, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, China,Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Hangzhou 330110, China
| | - Yunqing Qiu
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310000, China
| | - Lin Tao
- Correspondence may also be addressed to Lin Tao.
| | - Feng Zhu
- To whom correspondence should be addressed. Tel: +86 189 8946 6518; Fax: +86 571 8820 8444;
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22
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Shi B, Liu WW, Yang K, Jiang GM, Wang H. The role, mechanism, and application of RNA methyltransferase METTL14 in gastrointestinal cancer. Mol Cancer 2022; 21:163. [PMID: 35974338 PMCID: PMC9380308 DOI: 10.1186/s12943-022-01634-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 08/08/2022] [Indexed: 11/10/2022] Open
Abstract
Gastrointestinal cancer is the most common human malignancy characterized by high lethality and poor prognosis. Emerging evidences indicate that N6-methyladenosine (m6A), the most abundant post-transcriptional modification in eukaryotes, exerts important roles in regulating mRNA metabolism including stability, decay, splicing, transport, and translation. As the key component of the m6A methyltransferase complex, methyltransferase-like 14 (METTL14) catalyzes m6A methylation on mRNA or non-coding RNA to regulate gene expression and cell phenotypes. Dysregulation of METTL14 was deemed to be involved in various aspects of gastrointestinal cancer, such as tumorigenesis, progression, chemoresistance, and metastasis. Plenty of findings have opened up new avenues for exploring the therapeutic potential of gastrointestinal cancer targeting METTL14. In this review, we systematically summarize the recent advances regarding the biological functions of METTL14 in gastrointestinal cancer, discuss its potential clinical applications and propose the research forecast.
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Affiliation(s)
- Bin Shi
- Department of Anorectal Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Heifei, China
| | - Wei-Wei Liu
- School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Ke Yang
- School of Clinical Medicine, Clinical College of Anhui Medical University, Hefei, China
| | - Guan-Min Jiang
- Department of Clinical Laboratory, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, China.
| | - Hao Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. .,Core Unit of National Clinical Research Center for Laboratory Medicine, Heifei, China.
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23
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Zhang Z, Wang L, Zhao L, Wang Q, Yang C, Zhang M, Wang B, Jiang K, Ye Y, Wang S, Shen Z. N6-methyladenosine demethylase ALKBH5 suppresses colorectal cancer progression potentially by decreasing PHF20 mRNA methylation. Clin Transl Med 2022; 12:e940. [PMID: 35979628 PMCID: PMC9386323 DOI: 10.1002/ctm2.940] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 05/30/2022] [Accepted: 06/06/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND As the most widespread mRNAs modification, N6-methyladenosine (m6 A) is dynamically and reversibly modulated by methyltransferases and demethylases. ALKBH5 is a major demethylase, and plays vital roles in the progression of cancers. However, the role and mechanisms of ALKBH5 in colorectal cancer (CRC) is unclear. RESULTS Herein, we discovered that in CRC, downregulated ALKBH5 was closely related to poor prognosis of CRC patients. Functionally, our results demonstrated that knockdown of ALKBH5 enhanced the proliferation, migration and invasion of LOVO and RKO in vitro, while overexpression of ALKBH5 inhibited the functions of these cells. The results also demonstrated that knockdown of ALKBH5 promoted subcutaneous tumorigenesis of LOVO in vivo, while overexpression of ALKBH5 suppressed this ability. Mechanistically, results from joint analyses of MeRIP-seq and RNA-seq indicated that PHF20 mRNA was a key molecule that was regulated by ALKBH5-mediated m6 A modification. Further experiments indicated that ALKBH5 may inhibit stability of PHF20 mRNA by removing the m6 A modification of PHF20 mRNA 3'UTR. CONCLUSIONS ALKBH5 suppresses CRC progression by decreasing PHF20 mRNA methylation. ALKBH5-mediated m6 A modification of PHF20 mRNA can serve as a hopeful strategy for the intervention and treatment of CRC.
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Affiliation(s)
- Zhen Zhang
- Department of Gastroenterological SurgeryPeking University People's HospitalBeijingChina
- Laboratory of Surgical OncologyBeijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment ResearchPeking University People's HospitalBeijingChina
| | - Ling Wang
- Department of Medical OncologyAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouChina
| | - Long Zhao
- Department of Gastroenterological SurgeryPeking University People's HospitalBeijingChina
- Laboratory of Surgical OncologyBeijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment ResearchPeking University People's HospitalBeijingChina
| | - Quan Wang
- Department of Gastroenterological SurgeryPeking University People's HospitalBeijingChina
- Laboratory of Surgical OncologyBeijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment ResearchPeking University People's HospitalBeijingChina
| | - Changjiang Yang
- Department of Gastroenterological SurgeryPeking University People's HospitalBeijingChina
- Laboratory of Surgical OncologyBeijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment ResearchPeking University People's HospitalBeijingChina
| | - Mengmeng Zhang
- Department of Gastroenterological SurgeryPeking University People's HospitalBeijingChina
- Laboratory of Surgical OncologyBeijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment ResearchPeking University People's HospitalBeijingChina
| | - Bo Wang
- Department of Gastroenterological SurgeryPeking University People's HospitalBeijingChina
- Laboratory of Surgical OncologyBeijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment ResearchPeking University People's HospitalBeijingChina
| | - Kewei Jiang
- Department of Gastroenterological SurgeryPeking University People's HospitalBeijingChina
- Laboratory of Surgical OncologyBeijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment ResearchPeking University People's HospitalBeijingChina
| | - Yingjiang Ye
- Department of Gastroenterological SurgeryPeking University People's HospitalBeijingChina
- Laboratory of Surgical OncologyBeijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment ResearchPeking University People's HospitalBeijingChina
| | - Shan Wang
- Department of Gastroenterological SurgeryPeking University People's HospitalBeijingChina
- Laboratory of Surgical OncologyBeijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment ResearchPeking University People's HospitalBeijingChina
| | - Zhanlong Shen
- Department of Gastroenterological SurgeryPeking University People's HospitalBeijingChina
- Laboratory of Surgical OncologyBeijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment ResearchPeking University People's HospitalBeijingChina
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24
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Characterization of m6A Methylation Modification Patterns in Colorectal Cancer Determines Prognosis and Tumor Microenvironment Infiltration. J Immunol Res 2022; 2022:8766735. [PMID: 35692505 PMCID: PMC9177296 DOI: 10.1155/2022/8766735] [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: 02/18/2022] [Accepted: 04/21/2022] [Indexed: 12/04/2022] Open
Abstract
Cumulative studies have suggested that dysregulation of m6A regulators and immunity is highly linked to the prognosis of patients with cancer. However, the potential contribution of m6A modification patterns to the tumor microenvironment (TME) and the therapeutic efficacy of immunotherapy for colorectal cancer (CRC) remain elusive. A comprehensive analysis of the m6A modification profiles of 458 patients with CRC was performed by clustering 21 genes encoding m6A methylation regulators and linking the m6A modification pattern with TME characteristics. Using principal component analysis (PCA), a risk model was constructed to quantify individual m6A modification patterns in patients with CRC. The results indicated that the expression profiles and genetic mutations of 21 genes encoding m6A methylation regulators in CRC were characterized by a high degree of heterogeneity. Three m6A clusters had significant differences in prognosis, m6A modification patterns, and TME characteristics. Furthermore, a risk model, termed m6Ascore, was developed by PCA to quality m6A methylation patterns at an individual level. The m6Ascore could stratify patients into high- and low-m6Ascore groups. Further analyses demonstrated that the m6Ascore had a good predictive performance for overall survival and clinical efficacy of immunotherapy in patients with CRC. Finally, the predictive value of the model was validated by external cohorts. In conclusion, the comprehensive characterization of m6A methylation modification patterns might contribute to our understanding of the TME in CRC and the development of personalized antitumor immunotherapy in the future.
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25
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Ma B, Wang K, Liang Y, Meng Q, Li Y. Molecular Characteristics, Oncogenic Roles, and Relevant Immune and Pharmacogenomic Features of EVA1B in Colorectal Cancer. Front Immunol 2022; 13:809837. [PMID: 35250982 PMCID: PMC8888821 DOI: 10.3389/fimmu.2022.809837] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 01/24/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE EVA1B, a protein coding gene, is a critical paralog of EVA1A gene. Herein, our study was conducted to investigate the role of EVA1B in colorectal cancer (CRC) progression and prognosis. METHODS Pan-cancer analysis was conducted to analyze expression, genetic and epigenetic alterations, and immunological characteristics of EVA1B. Especially, immunological characteristics and mutational landscape were compared between high and low EVA1B expression groups in the combined TCGA-COAD and TCGA-READ datasets. Through random survival forest analysis, an EVA1B-derived genomic model was developed, and its prognostic value was verified in the external datasets (GSE14333, GSE39582, and GSE87211). Drug sensitivity was compared between high- and low-risk subpopulations. A nomogram was conducted through integrating independent factors. RESULTS EVA1B expression presented a remarkable upregulation in most cancer types, especially CRC. EVA1B expression was significantly correlated to DNA methyltransferases, DNA mismatch repair genes, m6A regulators, TMB, and MSI across pan-cancer. High EVA1B expression indicated an undesirable CRC patients' prognosis. Additionally, its upregulation was correlated to enhanced immune cell infiltration, increased stromal and immune activation, and elevated activities of cancer immunity cycle. Higher frequencies of amplification and deletion were investigated in high EVA1B expression subpopulation. Following verification, the EVA1B-derived genomic model reliably predicted patients' prognosis and drug responses. The nomogram (age, stage, EVA1B-derived risk score) was conducted to quantify an individual's survival probability. Furthermore, our experimental validation based on immunohistochemistry indicated that EVA1B overexpression is correlated with CRC tumorigenesis and poor outcomes in our CRC patients' cohort. CONCLUSION Collectively, our findings provided valuable resource for guiding the mechanisms and therapeutic analysis of EVA1B in CRC.
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Affiliation(s)
- Bin Ma
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Kangchun Wang
- Department of Organ Transplantation and Hepatobiliary, the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yu Liang
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Qingkai Meng
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Yongmin Li
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
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26
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Wu Y, Wang Z, Shen J, Yan W, Xiang S, Liu H, Huang W. The role of m6A methylation in osteosarcoma biological processes and its potential clinical value. Hum Genomics 2022; 16:12. [PMID: 35436972 PMCID: PMC9017037 DOI: 10.1186/s40246-022-00384-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 03/23/2022] [Indexed: 12/28/2022] Open
Abstract
Osteosarcoma (OS) is the most common primary malignant bone tumor in children and young adults and has a poor prognosis. Recent developments in the field of high-throughput sequencing technology, particularly in methylated RNA immunoprecipitation sequencing (MeRIP-seq), have led to renewed interest in RNA methylation. Among the various RNA modifications, N6-methyladenosine (m6A) modifications are the most common. Emerging evidence suggests that m6A methylation can affect the complexity of cancer progression by regulating biological functions related to cancer. In this review, we will shed light on recent findings regarding the biological function of m6A methylation in OS and discuss future research directions and potential clinical applications of RNA methyltransferases in OS.
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Affiliation(s)
- Yanjiao Wu
- Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China.,Guangdong Provincial Key Laboratory of Medical Biomechanics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zhiyun Wang
- Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
| | - Jianlin Shen
- The Precision Medicine Institute, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Wei Yan
- Department of Anatomy, Hebei Medical University, Shijiazhuang, China
| | - Shurong Xiang
- Guangdong Provincial Key Laboratory of Medical Biomechanics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Huan Liu
- Department of Orthopaedics, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China.
| | - Wenhua Huang
- Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China. .,Guangdong Provincial Key Laboratory of Medical Biomechanics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China. .,Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Southern Medical University, Guangzhou, China. .,Guangdong Innovation Platform for Translation of 3D Printing Application, Southern Medical University, Guangzhou, China.
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27
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Huang Y, Huang C, Jiang X, Yan Y, Zhuang K, Liu F, Li P, Wen Y. Exploration of Potential Roles of m5C-Related Regulators in Colon Adenocarcinoma Prognosis. Front Genet 2022; 13:816173. [PMID: 35281843 PMCID: PMC8908034 DOI: 10.3389/fgene.2022.816173] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/26/2022] [Indexed: 12/24/2022] Open
Abstract
Objectives: The purpose of this study was to investigate the role of 13 m5C-related regulators in colon adenocarcinoma (COAD) and determine their prognostic value. Methods: Gene expression and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) datasets. The expression of m5C-related regulators was analyzed with clinicopathological characteristics and alterations within m5C-related regulators. Subsequently, different subtypes of patients with COAD were identified. Then, the prognostic value of m5C-related regulators in COAD was confirmed via univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression analyses. The prognostic value of risk scores was evaluated using the Kaplan-Meier method, receiver operating characteristic (ROC) curve. The correlation between the two m5C-related regulators, risk score, and clinicopathological characteristics were explored. Additionally, Gene Set Enrichment Analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and Gene Ontology (GO) analysis were performed for biological functional analysis. Finally, the expression level of two m5C-related regulators in clinical samples and cell lines was detected by quantitative reverse transcription-polymerase chain reaction and through the Human Protein Atlas database. Results: m5C-related regulators were found to be differentially expressed in COAD with different clinicopathological features. We observed a high alteration frequency in these genes, which were significantly correlated with their mRNA expression levels. Two clusters with different prognostic features were identified. Based on two independent prognostic m5C-related regulators (NSUN6 and ALYREF), a risk signature with good predictive significance was constructed. Univariate and multivariate Cox regression analyses suggested that the risk score was an independent prognostic factor. Furthermore, this risk signature could serve as a prognostic indicator for overall survival in subgroups of patients with different clinical characteristics. Biological processes and pathways associated with cancer, immune response, and RNA processing were identified. Conclusion: We revealed the genetic signatures and prognostic values of m5C-related regulators in COAD. Together, this has improved our understanding of m5C RNA modification and provided novel insights to identify predictive biomarkers and develop molecular targeted therapy for COAD.
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Affiliation(s)
- Yuancheng Huang
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chaoyuan Huang
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaotao Jiang
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yanhua Yan
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Kunhai Zhuang
- Department of Gastroenterology, Baiyun Branch of the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fengbin Liu
- Department of Gastroenterology, Baiyun Branch of the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Fengbin Liu, ; Peiwu Li, ; Yi Wen,
| | - Peiwu Li
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Fengbin Liu, ; Peiwu Li, ; Yi Wen,
| | - Yi Wen
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Fengbin Liu, ; Peiwu Li, ; Yi Wen,
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28
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Huang JB, Hu BB, He R, He L, Zou C, Man CF, Fan Y. Analysis of N6-Methyladenosine Methylome in Adenocarcinoma of Esophagogastric Junction. Front Genet 2022; 12:787800. [PMID: 35140740 PMCID: PMC8820482 DOI: 10.3389/fgene.2021.787800] [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: 11/08/2021] [Accepted: 12/30/2021] [Indexed: 11/21/2022] Open
Abstract
Background: From previous studies, we found that there are more than 100 types of RNA modifications in RNA molecules. m6A methylation is the most common. The incidence rate of adenocarcinoma of the esophagogastric junction (AEG) at home and abroad has increased faster than that of stomach cancer at other sites in recent years. Here, we systematically analyze the modification pattern of m6A mRNA in adenocarcinoma at the esophagogastric junction. Methods: m6A sequencing, RNA sequencing, and bioinformatics analysis were used to describe the m6A modification pattern in adenocarcinoma and normal tissues at the esophagogastric junction. Results: In AEG samples, a total of 4,775 new m6A peaks appeared, and 3,054 peaks disappeared. The unique m6A-related genes in AEG are related to cancer-related pathways. There are hypermethylated or hypomethylated m6A peaks in AEG in differentially expressed mRNA transcripts. Conclusion: This study preliminarily constructed the first m6A full transcriptome map of human AEG. This has a guiding role in revealing the mechanism of m6A-mediated gene expression regulation.
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Comprehensive Analysis of N6-Methyladenosine-Related lncRNA Signature for Predicting Prognosis and Immune Cell Infiltration in Patients with Colorectal Cancer. DISEASE MARKERS 2021; 2021:8686307. [PMID: 34745388 PMCID: PMC8568524 DOI: 10.1155/2021/8686307] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 10/07/2021] [Indexed: 12/13/2022]
Abstract
Background Colorectal cancer (CRC) is the third most common tumor worldwide. Aberrant N6-methyladenosine (m6A) modification can influence the progress of the CRC. Additionally, long noncoding RNA (lncRNA) plays a critical role in CRC and has a close relationship with m6A modification. However, the prognostic potential of m6A-related lncRNAs in CRC patients still remains to be clarified. Methods We use “limma” R package, “glmnet” R package, and “survival” R package to screen m6A-related-lncRNAs with prognostic potential. Then, we comprehensively analysed and integrated the related lncRNAs in different TNM stages from TCGA database using the LASSO Cox regression. Meanwhile, the relationship between functional enrichment of m6A-related lncRNAs and immune microenvironment in CRC was also investigated using the TCGA database. A prognostic model was constructed and validated to determine the association between m6A-related lncRNAs in different TNM stages and the prognosis of CRC. Result We demonstrated that three related m6A lncRNAs in different TNM stages were associated with the prognosis of CRC patients. Patients from the TCGA database were classified into the low-risk and the high-risk groups based on the expression of these lncRNAs. The patients in the low-risk group had longer overall survival than the patients in the high-risk group (P < 0.001). We further constructed and validated a prognostic nomogram based on these genes with a C-index of 0.80. The receiver operating characteristic curves confirmed the predictive capacity of the model. Meanwhile, we also found that the low-risk group has the correlation with the dendritic cell (DC). Finally, we discovered the relationship between the m6A regulators and the three lncRNAs. Conclusion The prognostic model based on three m6A-related lncRNAs exhibits superior predictive performance, providing a novel prognostic model for the clinical evaluation of CRC patients.
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Ge Y, Liu T, Wang C, Zhang Y, Xu S, Ren Y, Feng Y, Yin L, Pu Y, Liang G. N6-methyladenosine RNA modification and its interaction with regulatory non-coding RNAs in colorectal cancer. RNA Biol 2021; 18:551-561. [PMID: 34674600 DOI: 10.1080/15476286.2021.1974749] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
As one of the most common forms of RNA modification, N6-methyladenosine (m6A) RNA modification has attracted increasing research interest in recent years. This reversible RNA modification added a new dimension to the post-transcriptional regulation of gene expression. In colorectal cancer (CRC), the role of m6A modification has been extensively studied, not only on mRNAs but also on non-coding RNAs (ncRNAs). In the present review, we depicted the role of m6A modification in CRC, systematically elaborate the interaction between m6A modification and regulatory ncRNAs in function and mechanism. Moreover, we discussed the potential applications in clinical.
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Affiliation(s)
- Yiling Ge
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, PR China
| | - Tong Liu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, PR China
| | - Chuntao Wang
- Science and technology department, Jiangsu Vocational College of Medicine, Yancheng, Jiangsu, PR China
| | - Yanqiu Zhang
- Department of Environmental Occupational Health, Taizhou Center for Disease Control and Prevention, Taizhou, PR China
| | - Siyi Xu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, PR China
| | - Yiyi Ren
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, PR China
| | - Yanlu Feng
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, PR China
| | - Lihong Yin
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, PR China
| | - Yuepu Pu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, PR China
| | - Geyu Liang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, PR China
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Povedano E, Gamella M, Torrente-Rodríguez RM, Ruiz-Valdepeñas Montiel V, Montero-Calle A, Solís-Fernández G, Navarro-Villoslada F, Pedrero M, Peláez-García A, Mendiola M, Hardisson D, Feliú J, Barderas R, Pingarrón JM, Campuzano S. Multiplexed magnetic beads-assisted amperometric bioplatforms for global detection of methylations in nucleic acids. Anal Chim Acta 2021; 1182:338946. [PMID: 34602192 DOI: 10.1016/j.aca.2021.338946] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/22/2021] [Accepted: 08/11/2021] [Indexed: 12/14/2022]
Abstract
This work reports the first electrochemical bioplatform developed for the multidetection of 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in DNA, DNA N6-methyladenine (6mA) and RNA N6-methyladenosine (m6A) methylations at global level. Direct competitive immunoassays were implemented on the surface of magnetic beads (MBs) and optimized for the single amperometric determination of different targets varying in length, sequence and number of methylations on screen-printed carbon electrodes. After evaluating the sensitivity and selectivity of such determinations and the confirmation of no cross-reactivity, a multiplexed disposable platform allowing the simultaneous determination of the mentioned four methylation events in only 45 min has been prepared. The multiplexed bioplatform was successfully applied to the determination of m6A in cellular total RNA and of 5-mC, 5-hmC and 6mA in genomic DNA extracted from tissues. The developed bioplatform showed its usefulness to discriminate the aggressiveness of cancerous cells and between healthy and tumor tissues of colorectal cancer patients.
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Affiliation(s)
- Eloy Povedano
- Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain
| | - Maria Gamella
- Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain
| | - Rebeca M Torrente-Rodríguez
- Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain
| | | | - Ana Montero-Calle
- Chronic Disease Programme, UFIEC, Instituto de Salud Carlos III, 28220, Madrid, Spain
| | | | - Fernando Navarro-Villoslada
- Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain
| | - María Pedrero
- Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain
| | - Alberto Peláez-García
- Department of Pathology, Hospital Universitario La Paz, IdiPAZ, 28046, Madrid, Spain
| | - Marta Mendiola
- Department of Pathology, Hospital Universitario La Paz, IdiPAZ, 28046, Madrid, Spain; Center for Biomedical Research in the Cancer Network (Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - David Hardisson
- Department of Pathology, Hospital Universitario La Paz, IdiPAZ, 28046, Madrid, Spain; Center for Biomedical Research in the Cancer Network (Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)), Instituto de Salud Carlos III, 28029, Madrid, Spain; Faculty of Medicine, Universidad Autónoma de Madrid, 28029, Madrid, Spain
| | - Jaime Feliú
- Center for Biomedical Research in the Cancer Network (Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)), Instituto de Salud Carlos III, 28029, Madrid, Spain; Translational Oncology Group Hospital Universitario La Paz IdiPAZ, 28046, Madrid, Spain
| | - Rodrigo Barderas
- Chronic Disease Programme, UFIEC, Instituto de Salud Carlos III, 28220, Madrid, Spain.
| | - José M Pingarrón
- Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
| | - Susana Campuzano
- Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
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Zhao H, Jiang J, Wang M, Xuan Z. Genome-Wide Identification of m6A-Associated Single-Nucleotide Polymorphisms in Colorectal Cancer. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2021; 14:887-892. [PMID: 34305406 PMCID: PMC8297552 DOI: 10.2147/pgpm.s314373] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 06/30/2021] [Indexed: 12/15/2022]
Abstract
Background N6-methyladenosine (m6A)-associated single-nucleotide polymorphisms (SNPs) play important roles in cancers, with previous research suggesting potential associations between m6A-SNPs and cancer. However, the relationship between the genetic determinants of m6A modification and colorectal cancer (CRC) remains unclear. Methods An integrative method combining raw data and summary statistics of genome-wide association studies with expression quantitative trait loci (eQTL) and differential expression data was applied to screen potential candidate CRC-associated m6A-SNPs. Results A total of 402 m6A-SNPs were identified as being associated with CRC (p < 0.001), with 98 showing eQTL signals. In particular, three genes were found to harbor CRC-associated m6A-SNPs: rs178184 in NOVA1, rs35782901 in HTR4, and rs60571683 in SLCO1B3. These genes were differentially expressed in at least one publicly available dataset (p < 0.05), with NOVA1 (p = 3.41×10-11) and HTR4 (p = 5.56×10-7) being significantly downregulated in CRC (dataset: GSE89076), and SLCO1B3 was significantly overexpressed (datasets: GSE32323 [p = 3.27×10-5], GSE21510 [p = 1.09×10-6], and GSE89076 [p = 7.63×10-6]). Conclusion This study identified three m6A-SNPs (rs178184, rs35782901, and rs60571683) that may be associated with CRC. However, the lack of analysis of primary CRC samples in order to further elucidate the underlying pathogenesis is a major limitation of this study. Future investigations are needed to validate these CRC-associated m6A-SNPs and explore the m6A-mediated pathogenic mechanism in CRC.
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Affiliation(s)
- Hongying Zhao
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People's Republic of China
| | - Jinying Jiang
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People's Republic of China
| | - Mingshan Wang
- Departments of Infection Diseases, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People's Republic of China
| | - Zixue Xuan
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People's Republic of China
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Li J, Wang F, Liu Y, Wang H, Ni B. N 6-methyladenosine (m 6A) in pancreatic cancer: Regulatory mechanisms and future direction. Int J Biol Sci 2021; 17:2323-2335. [PMID: 34239358 PMCID: PMC8241726 DOI: 10.7150/ijbs.60115] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 05/21/2021] [Indexed: 12/26/2022] Open
Abstract
N6-methyladenosine (m6A), the most abundant RNA modification in eukaryotes, plays a pivotal role in regulating many cellular and biological processes. Aberrant m6A modification has recently been involved in carcinogenesis in various cancers, including pancreatic cancer. Pancreatic cancer is one of the deadliest cancers. It is a heterogeneous malignant disease characterized by a plethora of diverse genetic and epigenetic events. Increasing evidence suggests that dysregulation of m6A regulatory factors, such as methyltransferases, demethylases, and m6A-binding proteins, profoundly affects the development and progression of pancreatic cancer. In addition, m6A regulators and m6A target transcripts may be promising early diagnostic and prognostic cancer biomarkers, as well as therapeutic targets. In this review, we highlight the biological functions and mechanisms of m6A in pancreatic cancer and discuss the potential of m6A modification in clinical applications.
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Affiliation(s)
- Jian Li
- Department of Pathophysiology, College of High Altitude, Army Medical University (Third Military Medical University), Chongqing 400038, PR China
- Department of General Surgery, Air Force Hospital of Western Theater Command, Chengdu 610021, PR China
| | - Fangjuan Wang
- Department of Cardiology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, PR China
| | - Yongkang Liu
- Department of General Surgery, Air Force Hospital of Western Theater Command, Chengdu 610021, PR China
| | - Huaizhi Wang
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 401120, PR China
| | - Bing Ni
- Department of Pathophysiology, College of High Altitude, Army Medical University (Third Military Medical University), Chongqing 400038, PR China
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Sun K, Du Y, Hou Y, Zhao M, Li J, Du Y, Zhang L, Chen C, Yang H, Yan F, Su R. Saikosaponin D exhibits anti-leukemic activity by targeting FTO/m 6A signaling. Theranostics 2021; 11:5831-5846. [PMID: 33897884 PMCID: PMC8058711 DOI: 10.7150/thno.55574] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 03/14/2021] [Indexed: 02/06/2023] Open
Abstract
Purpose: The implementation of targeted therapies for acute myeloid leukemia (AML) has been challenging. Fat mass and obesity associated protein (FTO), an mRNA N6-methyladenosine (m6A) demethylase, functions as an oncogene that promotes leukemic oncogene-mediated cell transformation and leukemogenesis. Here, we investigated the role of Saikosaponin-d (SsD) in broad anti-proliferation effects in AML and evaluated the m6A demethylation activity by targeting FTO of SsD. Methods: It was examined whether and how SsD regulates FTO/m6A signaling in AML. The pharmacologic activities and mechanisms of actions of SsD in vitro, in mice, primary patient cells, and tyrosine kinase inhibitors-resistant cells were determined. Results: SsD showed a broadly-suppressed AML cell proliferation and promoted apoptosis and cell-cycle arrest both in vitro and in vivo. Mechanistically, SsD directly targeted FTO, thereby increasing global m6A RNA methylation, which in turn decreased the stability of downstream gene transcripts, leading to the suppression of relevant pathways. Importantly, SsD also overcame FTO/m6A-mediated leukemia resistance to tyrosine kinase inhibitors. Conclusion: Our findings demonstrated that FTO-dependent m6A RNA methylation mediated the anti-leukemic actions of SsD, thereby opening a window to develop SsD as an epitranscriptome-base drug for leukemia therapy.
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Affiliation(s)
- Kaiju Sun
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130017, China
| | - Yangyang Du
- State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry (NMAC), International Research Center for Chemistry-Medicine Joint Innovation, College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, China
| | - Yuzhu Hou
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130017, China
| | - Mingyue Zhao
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130017, China
| | - Jiajia Li
- Department of Obstetrics and Gynecology, First Hospital, Jilin University, 130021, P. R. China
| | - Yazhe Du
- Department of blood specialty, First Hospital, Jilin University, 130021, China
| | - Lingxiao Zhang
- State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry (NMAC), International Research Center for Chemistry-Medicine Joint Innovation, College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, China
| | - Changbao Chen
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130017, China
| | - Hongmei Yang
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130017, China
| | - Fei Yan
- State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry (NMAC), International Research Center for Chemistry-Medicine Joint Innovation, College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, China
| | - Rui Su
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130017, China
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Chen C, Yuan W, Zhou Q, Shao B, Guo Y, Wang W, Yang S, Guo Y, Zhao L, Dang Q, Yang X, Wang G, Kang Q, Ji Z, Liu J, Sun Z. N6-methyladenosine-induced circ1662 promotes metastasis of colorectal cancer by accelerating YAP1 nuclear localization. Theranostics 2021; 11:4298-4315. [PMID: 33754062 PMCID: PMC7977475 DOI: 10.7150/thno.51342] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 02/05/2021] [Indexed: 12/13/2022] Open
Abstract
Tumor metastasis is the leading cause of death in patients with colorectal cancer (CRC). Circular RNAs (circRNAs) have been shown to be involved in cancer progression. However, the regulatory mechanisms of circRNAs involved in CRC tumor metastasis are currently unknown. Methods: High-throughput sequencing was performed on 6 pairs of CRC and adjacent normal tissues to identify the expression profiles of mRNA and circRNA. circ1662 was assessed by RNA-ISH and IHC of a tissue chip. The function of circ1662 in CRC was evaluated by knocking down or overexpressing circ1662. MeRIP-qPCR, RIP-qPCR, and RNA pull-down were performed to determine the relationship between METTL3, circ1662, and YAP1. Results: A novel circRNA, circ1662, exhibited significantly higher expression in CRC tissues than paired normal tissues. High circ1662 expression was correlated with poor prognosis and tumor depth in patients with CRC. Functionally, circ1662 promoted CRC cell invasion and migration by controlling EMT in vitro and in vivo. Mechanistically, circ1662 directly bound to YAP1 and accelerated its nuclear accumulation to regulate the SMAD3 pathway. Additionally, circ1662 enhanced CRC invasion and migration depending on YAP1 and SMAD3. Interestingly, METTL3 induced circ1662 expression by binding its flanking sequences and installing m6A modifications. Clinically, circ1662 expression strongly correlated with METTL3 and YAP1 protein expression. Moreover, YAP1 expression was negatively correlated with SMAD3 expression. Conclusions: METTL3-induced circ1662 promoted CRC cell invasion and migration by accelerating YAP1 nuclear transport. This result implies that circ1662 is a new prognostic and therapeutic marker for CRC metastasis.
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