Cross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer
Abstract Background The four major RNA adenosine modifications, i.e., m6A, m1A, alternative polyadenylation, and adenosine-to-inosine RNA editing, are mediated mostly by the “writer” enzymes and constitute critical mechanisms of epigenetic regulation in immune response and tumorigenesis. However, th...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-02-01
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| Series: | Molecular Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12943-021-01322-w |
| _version_ | 1818870905896435712 |
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| author | Huifang Chen Jiameng Yao Rujuan Bao Yu Dong Ting Zhang Yanhua Du Gaoyang Wang Duan Ni Zhenzhen Xun Xiaoyin Niu Youqiong Ye Hua-Bing Li |
| author_facet | Huifang Chen Jiameng Yao Rujuan Bao Yu Dong Ting Zhang Yanhua Du Gaoyang Wang Duan Ni Zhenzhen Xun Xiaoyin Niu Youqiong Ye Hua-Bing Li |
| author_sort | Huifang Chen |
| collection | DOAJ |
| description | Abstract Background The four major RNA adenosine modifications, i.e., m6A, m1A, alternative polyadenylation, and adenosine-to-inosine RNA editing, are mediated mostly by the “writer” enzymes and constitute critical mechanisms of epigenetic regulation in immune response and tumorigenesis. However, the cross-talk and potential roles of these “writers” in the tumor microenvironment (TME), drug sensitivity, and immunotherapy remain unknown. Methods We systematically characterized mRNA expression and genetic alterations of 26 RNA modification “writers” in colorectal cancer (CRC), and evaluated their expression pattern in 1697 CRC samples from 8 datasets. We used an unsupervised clustering method to assign the samples into two patterns of expression of RNA modification “writers”. Subsequently, we constructed the RNA modification “writer” Score (WM_Score) model based on differentially expressed genes (DEGs) responsible for the RNA modification patterns to quantify the RNA modification-related subtypes of individual tumors. Furthermore, we performed association analysis for WM_Score and characteristics of TME, consensus molecular subtypes (CMSs), clinical features, transcriptional and post-transcriptional regulation, drug response, and the efficacy of immunotherapy. Results We demonstrated that multi-layer alterations of RNA modification “writer” are associated with patient survival and TME cell-infiltrating characteristics. We identified two distinct RNA modification patterns, characterized by a high and a low WM_Score. The WM_Score-high group was associated with worse patient overall survival and with the infiltration of inhibitory immune cells, such as M2 macrophages, EMT activation, and metastasis, while the WM_Score-low group was associated with a survival advantage, apoptosis, and cell cycle signaling pathways. WM_Score correlated highly with the regulation of transcription and post-transcriptional events contributing to the development of CRC. In response to anti-cancer drugs, WM_Score highly negatively correlated (drug sensitive) with drugs which targeted oncogenic related pathways, such as MAPK, EGFR, and mTOR signaling pathways, positively correlated (drug resistance) with drugs which targeted in apoptosis and cell cycle. Importantly, the WM_Score was associated with the therapeutic efficacy of PD-L1 blockade, suggesting that the development of potential drugs targeting these “writers” to aid the clinical benefits of immunotherapy. Conclusions Our study is the first to provide a comprehensive analysis of four RNA modifications in CRC. We revealed the potential function of these writers in TME, transcriptional and post-transcriptional events, and identified their therapeutic liability in targeted therapy and immunotherapy. This work highlights the cross-talk and potential clinical utility of RNA modification “writers” in cancer therapy. |
| first_indexed | 2024-12-19T12:14:27Z |
| format | Article |
| id | doaj.art-b3d0ca45a3fa4330843d44dc2dd36ef2 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-19T12:14:27Z |
| publishDate | 2021-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-b3d0ca45a3fa4330843d44dc2dd36ef22022-12-21T20:22:04ZengBMCMolecular Cancer1476-45982021-02-0120112110.1186/s12943-021-01322-wCross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancerHuifang Chen0Jiameng Yao1Rujuan Bao2Yu Dong3Ting Zhang4Yanhua Du5Gaoyang Wang6Duan Ni7Zhenzhen Xun8Xiaoyin Niu9Youqiong Ye10Hua-Bing Li11Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineThe Charles Perkins Centre, University of SydneyShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineAbstract Background The four major RNA adenosine modifications, i.e., m6A, m1A, alternative polyadenylation, and adenosine-to-inosine RNA editing, are mediated mostly by the “writer” enzymes and constitute critical mechanisms of epigenetic regulation in immune response and tumorigenesis. However, the cross-talk and potential roles of these “writers” in the tumor microenvironment (TME), drug sensitivity, and immunotherapy remain unknown. Methods We systematically characterized mRNA expression and genetic alterations of 26 RNA modification “writers” in colorectal cancer (CRC), and evaluated their expression pattern in 1697 CRC samples from 8 datasets. We used an unsupervised clustering method to assign the samples into two patterns of expression of RNA modification “writers”. Subsequently, we constructed the RNA modification “writer” Score (WM_Score) model based on differentially expressed genes (DEGs) responsible for the RNA modification patterns to quantify the RNA modification-related subtypes of individual tumors. Furthermore, we performed association analysis for WM_Score and characteristics of TME, consensus molecular subtypes (CMSs), clinical features, transcriptional and post-transcriptional regulation, drug response, and the efficacy of immunotherapy. Results We demonstrated that multi-layer alterations of RNA modification “writer” are associated with patient survival and TME cell-infiltrating characteristics. We identified two distinct RNA modification patterns, characterized by a high and a low WM_Score. The WM_Score-high group was associated with worse patient overall survival and with the infiltration of inhibitory immune cells, such as M2 macrophages, EMT activation, and metastasis, while the WM_Score-low group was associated with a survival advantage, apoptosis, and cell cycle signaling pathways. WM_Score correlated highly with the regulation of transcription and post-transcriptional events contributing to the development of CRC. In response to anti-cancer drugs, WM_Score highly negatively correlated (drug sensitive) with drugs which targeted oncogenic related pathways, such as MAPK, EGFR, and mTOR signaling pathways, positively correlated (drug resistance) with drugs which targeted in apoptosis and cell cycle. Importantly, the WM_Score was associated with the therapeutic efficacy of PD-L1 blockade, suggesting that the development of potential drugs targeting these “writers” to aid the clinical benefits of immunotherapy. Conclusions Our study is the first to provide a comprehensive analysis of four RNA modifications in CRC. We revealed the potential function of these writers in TME, transcriptional and post-transcriptional events, and identified their therapeutic liability in targeted therapy and immunotherapy. This work highlights the cross-talk and potential clinical utility of RNA modification “writers” in cancer therapy.https://doi.org/10.1186/s12943-021-01322-wRNA modification “writer”Colorectal cancerTumor microenvironmentWM_ScoreDrug sensitivityImmunotherapy |
| spellingShingle | Huifang Chen Jiameng Yao Rujuan Bao Yu Dong Ting Zhang Yanhua Du Gaoyang Wang Duan Ni Zhenzhen Xun Xiaoyin Niu Youqiong Ye Hua-Bing Li Cross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer Molecular Cancer RNA modification “writer” Colorectal cancer Tumor microenvironment WM_Score Drug sensitivity Immunotherapy |
| title | Cross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer |
| title_full | Cross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer |
| title_fullStr | Cross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer |
| title_full_unstemmed | Cross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer |
| title_short | Cross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer |
| title_sort | cross talk of four types of rna modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer |
| topic | RNA modification “writer” Colorectal cancer Tumor microenvironment WM_Score Drug sensitivity Immunotherapy |
| url | https://doi.org/10.1186/s12943-021-01322-w |
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