Integrative multi-omics analysis reveals the LncRNA 60967.1–PLCD4–ATRA axis as a key regulator of colorectal cancer progression and immune response
Abstract Colorectal cancer (CRC) is a major global health concern, characterized by high morbidity and mortality rates. CRC progression involves intricate molecular networks that remain incompletely understood. In this study, we conducted an integrative multi-omics analysis of transcriptomic, proteo...
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BMC
2025-06-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-025-02359-x |
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| author | Yiyi Chen Ningning Zhao Lingna Xu Xiya Jia Fang Liu Jian Huang Xuhua Li Yunfei Wang Chuanxi Lai Yanbin Shen Fei Wang Yiming Lv Xuefeng Huang Fan Zhang Hongcang Gu Sheng Dai |
| author_facet | Yiyi Chen Ningning Zhao Lingna Xu Xiya Jia Fang Liu Jian Huang Xuhua Li Yunfei Wang Chuanxi Lai Yanbin Shen Fei Wang Yiming Lv Xuefeng Huang Fan Zhang Hongcang Gu Sheng Dai |
| author_sort | Yiyi Chen |
| collection | DOAJ |
| description | Abstract Colorectal cancer (CRC) is a major global health concern, characterized by high morbidity and mortality rates. CRC progression involves intricate molecular networks that remain incompletely understood. In this study, we conducted an integrative multi-omics analysis of transcriptomic, proteomic, and metabolomic profiles from CRC tissues and matched normal adjacent tissues (NATs). Our analysis revealed 1,394 differentially expressed long non-Coding RNAs (lncRNAs), 2,788 genes, 548 proteins, and 91 metabolites. A significant interaction network comprising 22 lncRNAs, 14 mRNAs/proteins, and 9 metabolites was identified, among which lncRNA 60967.1 emerged as a pivotal regulator. Functional validation demonstrated that lncRNA 60967.1 is markedly downregulated in CRC cell lines and patient tissues. Overexpression of lncRNA 60967.1 restored expression of the tumor suppressor PLCD4 and increased levels of all-trans retinoic acid (ATRA). This modulation enhanced IFN-γ-induced apoptosis and increased expression of the IFN-γ receptor subunit IFNGR1, thereby partially reversing IFN-γ resistance. In murine models, lncRNA 60967.1 overexpression promoted immune cell infiltration and synergized with anti–PD-1 therapy to inhibit tumor growth. Collectively, our findings uncover a novel lncRNA-mRNA/protein-metabolite network, the lncRNA 60967.1-PLCD4-ATRA axis, that plays a critical role in CRC progression and immune modulation, offering promising therapeutic targets for improved treatment efficacy. |
| format | Article |
| id | doaj-art-3674be1191f74481a8e8dfffc4946db7 |
| institution | DOAJ |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-3674be1191f74481a8e8dfffc4946db72025-08-20T03:10:28ZengBMCMolecular Cancer1476-45982025-06-0124112010.1186/s12943-025-02359-xIntegrative multi-omics analysis reveals the LncRNA 60967.1–PLCD4–ATRA axis as a key regulator of colorectal cancer progression and immune responseYiyi Chen0Ningning Zhao1Lingna Xu2Xiya Jia3Fang Liu4Jian Huang5Xuhua Li6Yunfei Wang7Chuanxi Lai8Yanbin Shen9Fei Wang10Yiming Lv11Xuefeng Huang12Fan Zhang13Hongcang Gu14Sheng Dai15Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityAnhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of SciencesDepartment of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityDepartment of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityAnhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of SciencesAnhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of SciencesAnhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of SciencesHangzhou ShengTing Medical Technology Co., LtdDepartment of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityDepartment of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityDepartment of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityDepartment of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityDepartment of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityAnhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of SciencesProvincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityDepartment of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityAbstract Colorectal cancer (CRC) is a major global health concern, characterized by high morbidity and mortality rates. CRC progression involves intricate molecular networks that remain incompletely understood. In this study, we conducted an integrative multi-omics analysis of transcriptomic, proteomic, and metabolomic profiles from CRC tissues and matched normal adjacent tissues (NATs). Our analysis revealed 1,394 differentially expressed long non-Coding RNAs (lncRNAs), 2,788 genes, 548 proteins, and 91 metabolites. A significant interaction network comprising 22 lncRNAs, 14 mRNAs/proteins, and 9 metabolites was identified, among which lncRNA 60967.1 emerged as a pivotal regulator. Functional validation demonstrated that lncRNA 60967.1 is markedly downregulated in CRC cell lines and patient tissues. Overexpression of lncRNA 60967.1 restored expression of the tumor suppressor PLCD4 and increased levels of all-trans retinoic acid (ATRA). This modulation enhanced IFN-γ-induced apoptosis and increased expression of the IFN-γ receptor subunit IFNGR1, thereby partially reversing IFN-γ resistance. In murine models, lncRNA 60967.1 overexpression promoted immune cell infiltration and synergized with anti–PD-1 therapy to inhibit tumor growth. Collectively, our findings uncover a novel lncRNA-mRNA/protein-metabolite network, the lncRNA 60967.1-PLCD4-ATRA axis, that plays a critical role in CRC progression and immune modulation, offering promising therapeutic targets for improved treatment efficacy.https://doi.org/10.1186/s12943-025-02359-xColorectal cancerMulti-omicsLncRNAsTumor microenvironmentImmunity |
| spellingShingle | Yiyi Chen Ningning Zhao Lingna Xu Xiya Jia Fang Liu Jian Huang Xuhua Li Yunfei Wang Chuanxi Lai Yanbin Shen Fei Wang Yiming Lv Xuefeng Huang Fan Zhang Hongcang Gu Sheng Dai Integrative multi-omics analysis reveals the LncRNA 60967.1–PLCD4–ATRA axis as a key regulator of colorectal cancer progression and immune response Molecular Cancer Colorectal cancer Multi-omics LncRNAs Tumor microenvironment Immunity |
| title | Integrative multi-omics analysis reveals the LncRNA 60967.1–PLCD4–ATRA axis as a key regulator of colorectal cancer progression and immune response |
| title_full | Integrative multi-omics analysis reveals the LncRNA 60967.1–PLCD4–ATRA axis as a key regulator of colorectal cancer progression and immune response |
| title_fullStr | Integrative multi-omics analysis reveals the LncRNA 60967.1–PLCD4–ATRA axis as a key regulator of colorectal cancer progression and immune response |
| title_full_unstemmed | Integrative multi-omics analysis reveals the LncRNA 60967.1–PLCD4–ATRA axis as a key regulator of colorectal cancer progression and immune response |
| title_short | Integrative multi-omics analysis reveals the LncRNA 60967.1–PLCD4–ATRA axis as a key regulator of colorectal cancer progression and immune response |
| title_sort | integrative multi omics analysis reveals the lncrna 60967 1 plcd4 atra axis as a key regulator of colorectal cancer progression and immune response |
| topic | Colorectal cancer Multi-omics LncRNAs Tumor microenvironment Immunity |
| url | https://doi.org/10.1186/s12943-025-02359-x |
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