Dual Role of CRABP2 in Colorectal Cancer: Oncogenesis via Nuclear RB1 and Cytoplasmic AFG3L2/SLC25A39 Axis, While Limiting Liver Metastasis through Cytoplasmic AFG3L2/PINK1/Parkin‐Mediated Mitophagy
Abstract Colorectal cancer (CRC) progression and metastasis involve numerous regulatory factors. Among these, cellular retinoic acid‐binding protein 2 (CRABP2) has been implicated as both a tumor activator and suppressor. Here, it is aimed to clarify the role of CRABP2 in CRC growth and metastasis a...
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| Format: | Article |
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Wiley
2025-06-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202500552 |
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| author | Chuanxin Tian Sheng Yang Chuan Zhang Renzhong Zhu Chen Chen Xiaowei Wang Dongsheng Zhang Qingyang Sun Hengjie Xu Hongxu Nie Yue Zhang Dongjian Ji Junwei Tang Kangpeng Jin Yueming Sun |
| author_facet | Chuanxin Tian Sheng Yang Chuan Zhang Renzhong Zhu Chen Chen Xiaowei Wang Dongsheng Zhang Qingyang Sun Hengjie Xu Hongxu Nie Yue Zhang Dongjian Ji Junwei Tang Kangpeng Jin Yueming Sun |
| author_sort | Chuanxin Tian |
| collection | DOAJ |
| description | Abstract Colorectal cancer (CRC) progression and metastasis involve numerous regulatory factors. Among these, cellular retinoic acid‐binding protein 2 (CRABP2) has been implicated as both a tumor activator and suppressor. Here, it is aimed to clarify the role of CRABP2 in CRC growth and metastasis and explore the underlying molecular mechanisms mediating its cellular functions. Using both in vitro and in vivo models, including a colonocyte‐specific CRABP2 conditional knockout mouse model (Crabp2ΔIEC) and a subcutaneous tumorigenesis assay in BALB/c nude mice, it is shown that nuclear CRABP2 enhances tumor growth by interacting with and downregulating the tumor suppressor RB1, whereas cytoplasmic CRABP2 suppresses CRC liver metastasis by interacting with AFG3L2 and promoting mitophagy. In addition, the AFG3L2–SLC25A39 axis is identified as a distinct mechanism by which cytoplasmic CRABP2 increases mitochondrial glutathione stability to promote cell proliferation independent of the nuclear RB1 pathway. Notably, analysis of tissue from CRC patients reveals that CRABP2 protein has distinct prognostic implications and functional roles in the progression and metastasis of CRC dependent on its subcellular localization. Ultimately, by elucidating the role of CRABP2 in CRC, it is aimed to provide new insight into disease pathogenesis and inform the development of therapeutic interventions. |
| format | Article |
| id | doaj-art-7e4a85658c814d95b51fa41cfb3f7ded |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-7e4a85658c814d95b51fa41cfb3f7ded2025-08-20T03:31:26ZengWileyAdvanced Science2198-38442025-06-011223n/an/a10.1002/advs.202500552Dual Role of CRABP2 in Colorectal Cancer: Oncogenesis via Nuclear RB1 and Cytoplasmic AFG3L2/SLC25A39 Axis, While Limiting Liver Metastasis through Cytoplasmic AFG3L2/PINK1/Parkin‐Mediated MitophagyChuanxin Tian0Sheng Yang1Chuan Zhang2Renzhong Zhu3Chen Chen4Xiaowei Wang5Dongsheng Zhang6Qingyang Sun7Hengjie Xu8Hongxu Nie9Yue Zhang10Dongjian Ji11Junwei Tang12Kangpeng Jin13Yueming Sun14Department of General Surgery, Colorectal Institute of Nanjing Medical University The First Affiliated Hospital of Nanjing Medical University Nanjing 210029 ChinaDepartment of General Surgery, Colorectal Institute of Nanjing Medical University The First Affiliated Hospital of Nanjing Medical University Nanjing 210029 ChinaDepartment of General Surgery, Colorectal Institute of Nanjing Medical University The First Affiliated Hospital of Nanjing Medical University Nanjing 210029 ChinaInstitute of Translational Medicine Medical College Yangzhou University No.136 Jiangyang Road Yangzhou 210029 ChinaDepartment of General Surgery, Colorectal Institute of Nanjing Medical University The First Affiliated Hospital of Nanjing Medical University Nanjing 210029 ChinaDepartment of General Surgery, Colorectal Institute of Nanjing Medical University The First Affiliated Hospital of Nanjing Medical University Nanjing 210029 ChinaDepartment of General Surgery, Colorectal Institute of Nanjing Medical University The First Affiliated Hospital of Nanjing Medical University Nanjing 210029 ChinaDepartment of General Surgery, Colorectal Institute of Nanjing Medical University The First Affiliated Hospital of Nanjing Medical University Nanjing 210029 ChinaDepartment of General Surgery, Colorectal Institute of Nanjing Medical University The First Affiliated Hospital of Nanjing Medical University Nanjing 210029 ChinaDepartment of General Surgery, Colorectal Institute of Nanjing Medical University The First Affiliated Hospital of Nanjing Medical University Nanjing 210029 ChinaDepartment of General Surgery, Colorectal Institute of Nanjing Medical University The First Affiliated Hospital of Nanjing Medical University Nanjing 210029 ChinaDepartment of General Surgery, Colorectal Institute of Nanjing Medical University The First Affiliated Hospital of Nanjing Medical University Nanjing 210029 ChinaDepartment of General Surgery, Colorectal Institute of Nanjing Medical University The First Affiliated Hospital of Nanjing Medical University Nanjing 210029 ChinaDepartment of General Surgery, Colorectal Institute of Nanjing Medical University The First Affiliated Hospital of Nanjing Medical University Nanjing 210029 ChinaDepartment of General Surgery, Colorectal Institute of Nanjing Medical University The First Affiliated Hospital of Nanjing Medical University Nanjing 210029 ChinaAbstract Colorectal cancer (CRC) progression and metastasis involve numerous regulatory factors. Among these, cellular retinoic acid‐binding protein 2 (CRABP2) has been implicated as both a tumor activator and suppressor. Here, it is aimed to clarify the role of CRABP2 in CRC growth and metastasis and explore the underlying molecular mechanisms mediating its cellular functions. Using both in vitro and in vivo models, including a colonocyte‐specific CRABP2 conditional knockout mouse model (Crabp2ΔIEC) and a subcutaneous tumorigenesis assay in BALB/c nude mice, it is shown that nuclear CRABP2 enhances tumor growth by interacting with and downregulating the tumor suppressor RB1, whereas cytoplasmic CRABP2 suppresses CRC liver metastasis by interacting with AFG3L2 and promoting mitophagy. In addition, the AFG3L2–SLC25A39 axis is identified as a distinct mechanism by which cytoplasmic CRABP2 increases mitochondrial glutathione stability to promote cell proliferation independent of the nuclear RB1 pathway. Notably, analysis of tissue from CRC patients reveals that CRABP2 protein has distinct prognostic implications and functional roles in the progression and metastasis of CRC dependent on its subcellular localization. Ultimately, by elucidating the role of CRABP2 in CRC, it is aimed to provide new insight into disease pathogenesis and inform the development of therapeutic interventions.https://doi.org/10.1002/advs.202500552AFG3L2cellular retinoic acid–binding proteinscolorectal cancerCRABP2liver metastasismitophagy |
| spellingShingle | Chuanxin Tian Sheng Yang Chuan Zhang Renzhong Zhu Chen Chen Xiaowei Wang Dongsheng Zhang Qingyang Sun Hengjie Xu Hongxu Nie Yue Zhang Dongjian Ji Junwei Tang Kangpeng Jin Yueming Sun Dual Role of CRABP2 in Colorectal Cancer: Oncogenesis via Nuclear RB1 and Cytoplasmic AFG3L2/SLC25A39 Axis, While Limiting Liver Metastasis through Cytoplasmic AFG3L2/PINK1/Parkin‐Mediated Mitophagy Advanced Science AFG3L2 cellular retinoic acid–binding proteins colorectal cancer CRABP2 liver metastasis mitophagy |
| title | Dual Role of CRABP2 in Colorectal Cancer: Oncogenesis via Nuclear RB1 and Cytoplasmic AFG3L2/SLC25A39 Axis, While Limiting Liver Metastasis through Cytoplasmic AFG3L2/PINK1/Parkin‐Mediated Mitophagy |
| title_full | Dual Role of CRABP2 in Colorectal Cancer: Oncogenesis via Nuclear RB1 and Cytoplasmic AFG3L2/SLC25A39 Axis, While Limiting Liver Metastasis through Cytoplasmic AFG3L2/PINK1/Parkin‐Mediated Mitophagy |
| title_fullStr | Dual Role of CRABP2 in Colorectal Cancer: Oncogenesis via Nuclear RB1 and Cytoplasmic AFG3L2/SLC25A39 Axis, While Limiting Liver Metastasis through Cytoplasmic AFG3L2/PINK1/Parkin‐Mediated Mitophagy |
| title_full_unstemmed | Dual Role of CRABP2 in Colorectal Cancer: Oncogenesis via Nuclear RB1 and Cytoplasmic AFG3L2/SLC25A39 Axis, While Limiting Liver Metastasis through Cytoplasmic AFG3L2/PINK1/Parkin‐Mediated Mitophagy |
| title_short | Dual Role of CRABP2 in Colorectal Cancer: Oncogenesis via Nuclear RB1 and Cytoplasmic AFG3L2/SLC25A39 Axis, While Limiting Liver Metastasis through Cytoplasmic AFG3L2/PINK1/Parkin‐Mediated Mitophagy |
| title_sort | dual role of crabp2 in colorectal cancer oncogenesis via nuclear rb1 and cytoplasmic afg3l2 slc25a39 axis while limiting liver metastasis through cytoplasmic afg3l2 pink1 parkin mediated mitophagy |
| topic | AFG3L2 cellular retinoic acid–binding proteins colorectal cancer CRABP2 liver metastasis mitophagy |
| url | https://doi.org/10.1002/advs.202500552 |
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