RTN4IP1 Contributes to ESCC via Regulation of Amino Acid Transporters
Abstract Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of esophageal cancer cases. The lack of effective therapeutic targets makes it difficult to improve the overall survival of patients with ESCC. Reticulon 4 Interacting Protein 1 (RTN4IP1) is a novel mitochondrial oxidoreductas...
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| Format: | Article |
| Language: | English |
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Wiley
2025-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202406220 |
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| author | Huifang Wei Dengyun Zhao Yafei Zhi Qiong Wu Jing Ma Jialuo Xu Tingting Liu Jing Zhang Penglei Wang Yamei Hu Xinyu He Fangqin Guo Ming Jiang Dandan Zhang Wenna Nie Ran Yang Tongjin Zhao Zigang Dong Kangdong Liu |
| author_facet | Huifang Wei Dengyun Zhao Yafei Zhi Qiong Wu Jing Ma Jialuo Xu Tingting Liu Jing Zhang Penglei Wang Yamei Hu Xinyu He Fangqin Guo Ming Jiang Dandan Zhang Wenna Nie Ran Yang Tongjin Zhao Zigang Dong Kangdong Liu |
| author_sort | Huifang Wei |
| collection | DOAJ |
| description | Abstract Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of esophageal cancer cases. The lack of effective therapeutic targets makes it difficult to improve the overall survival of patients with ESCC. Reticulon 4 Interacting Protein 1 (RTN4IP1) is a novel mitochondrial oxidoreductase. Here, a notable upregulation of RTN4IP1 is demonstrated, which is associated with poor survival in patients with ESCC. RTN4IP1 depletion impairs cell proliferation and induces apoptosis of ESCC cells. Furthermore, c‐Myc regulates RTN4IP1 expression via iron regulatory protein 2 (IRP2) at the post‐transcriptional level. Mechanistically, RTN4IP1 mRNA harbors functional iron‐responsive elements (IREs) in the 3′ UTR, which can be targeted by IRP2, resulting in increased mRNA stability. Finally, RTN4IP1 depletion abrogates amino acid uptake and induces amino acid starvation via downregulation of the amino acid transporters SLC1A5, SLC3A2, and SLC7A5, indicating a possible pathway through which RTN4IP1 contributes to ESCC carcinogenesis and progression. In vivo studies using cell‐derived xenograft and patient‐derived xenograft mouse models as well as a 4‐nitroquinoline 1‐oxide‐induced ESCC model in esophageal‐specific Rtn4ip1 knockout mice demonstrate the essential role of RTN4IP1 in ESCC development. Thus, RTN4IP1 emerges as a key cancer‐promoting protein in ESCC, suggesting therapeutic RTN4IP1 suppression as a promising strategy for ESCC treatment. |
| format | Article |
| id | doaj-art-7b3d1db5abc9411e8083ac9555403fc5 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-7b3d1db5abc9411e8083ac9555403fc52025-08-20T02:30:35ZengWileyAdvanced Science2198-38442025-02-01128n/an/a10.1002/advs.202406220RTN4IP1 Contributes to ESCC via Regulation of Amino Acid TransportersHuifang Wei0Dengyun Zhao1Yafei Zhi2Qiong Wu3Jing Ma4Jialuo Xu5Tingting Liu6Jing Zhang7Penglei Wang8Yamei Hu9Xinyu He10Fangqin Guo11Ming Jiang12Dandan Zhang13Wenna Nie14Ran Yang15Tongjin Zhao16Zigang Dong17Kangdong Liu18Department of Pathophysiology School of Basic Medical Sciences Zhengzhou University, China‐US (Henan) Hormel Cancer Institute Zhengzhou 450000 ChinaDepartment of Pathophysiology School of Basic Medical Sciences, Zhengzhou University China‐US (Henan) Hormel Cancer Institute Chest Hospital of Zhengzhou University Zhengzhou 450000 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Zhengzhou University, China‐US (Henan) Hormel Cancer Institute Zhengzhou 450000 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Zhengzhou University, China‐US (Henan) Hormel Cancer Institute Zhengzhou 450000 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Zhengzhou University Zhengzhou 450000 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Zhengzhou University Zhengzhou 450000 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Zhengzhou University, China‐US (Henan) Hormel Cancer Institute Zhengzhou 450000 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Zhengzhou University, China‐US (Henan) Hormel Cancer Institute Zhengzhou 450000 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Zhengzhou University, China‐US (Henan) Hormel Cancer Institute Zhengzhou 450000 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Zhengzhou University, China‐US (Henan) Hormel Cancer Institute Zhengzhou 450000 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Zhengzhou University, China‐US (Henan) Hormel Cancer Institute Zhengzhou 450000 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Zhengzhou University, China‐US (Henan) Hormel Cancer Institute Zhengzhou 450000 ChinaChina‐US (Henan) Hormel Cancer Institute Zhengzhou 450000 ChinaChina‐US (Henan) Hormel Cancer Institute Zhengzhou 450000 ChinaChina‐US (Henan) Hormel Cancer Institute Zhengzhou 450000 ChinaChina‐US (Henan) Hormel Cancer Institute Zhengzhou 450000 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Tianjian Laboratory of Advanced Biomedical Sciences Zhengzhou University Zhengzhou 450000 ChinaDepartment of Pathophysiology School of Basic Medical Sciences The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, State Key Laboratory of Esophageal Cancer Prevention and Treatment Provincial Cooperative Innovation Center for Cancer Chemoprevention China‐US (Henan) Hormel Cancer Institute, Tianjian Laboratory of Advanced Biomedical Sciences Zhengzhou University Zhengzhou 450000 ChinaDepartment of Pathophysiology School of Basic Medical Sciences The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, State Key Laboratory of Esophageal Cancer Prevention and Treatment Provincial Cooperative Innovation Center for Cancer Chemoprevention China‐US (Henan) Hormel Cancer Institute, Tianjian Laboratory of Advanced Biomedical Sciences Zhengzhou University Zhengzhou 450000 ChinaAbstract Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of esophageal cancer cases. The lack of effective therapeutic targets makes it difficult to improve the overall survival of patients with ESCC. Reticulon 4 Interacting Protein 1 (RTN4IP1) is a novel mitochondrial oxidoreductase. Here, a notable upregulation of RTN4IP1 is demonstrated, which is associated with poor survival in patients with ESCC. RTN4IP1 depletion impairs cell proliferation and induces apoptosis of ESCC cells. Furthermore, c‐Myc regulates RTN4IP1 expression via iron regulatory protein 2 (IRP2) at the post‐transcriptional level. Mechanistically, RTN4IP1 mRNA harbors functional iron‐responsive elements (IREs) in the 3′ UTR, which can be targeted by IRP2, resulting in increased mRNA stability. Finally, RTN4IP1 depletion abrogates amino acid uptake and induces amino acid starvation via downregulation of the amino acid transporters SLC1A5, SLC3A2, and SLC7A5, indicating a possible pathway through which RTN4IP1 contributes to ESCC carcinogenesis and progression. In vivo studies using cell‐derived xenograft and patient‐derived xenograft mouse models as well as a 4‐nitroquinoline 1‐oxide‐induced ESCC model in esophageal‐specific Rtn4ip1 knockout mice demonstrate the essential role of RTN4IP1 in ESCC development. Thus, RTN4IP1 emerges as a key cancer‐promoting protein in ESCC, suggesting therapeutic RTN4IP1 suppression as a promising strategy for ESCC treatment.https://doi.org/10.1002/advs.202406220Amino acid transportersc‐MycESCCIron regulatory proteinsIron responsive elementRTN4IP1 |
| spellingShingle | Huifang Wei Dengyun Zhao Yafei Zhi Qiong Wu Jing Ma Jialuo Xu Tingting Liu Jing Zhang Penglei Wang Yamei Hu Xinyu He Fangqin Guo Ming Jiang Dandan Zhang Wenna Nie Ran Yang Tongjin Zhao Zigang Dong Kangdong Liu RTN4IP1 Contributes to ESCC via Regulation of Amino Acid Transporters Advanced Science Amino acid transporters c‐Myc ESCC Iron regulatory proteins Iron responsive element RTN4IP1 |
| title | RTN4IP1 Contributes to ESCC via Regulation of Amino Acid Transporters |
| title_full | RTN4IP1 Contributes to ESCC via Regulation of Amino Acid Transporters |
| title_fullStr | RTN4IP1 Contributes to ESCC via Regulation of Amino Acid Transporters |
| title_full_unstemmed | RTN4IP1 Contributes to ESCC via Regulation of Amino Acid Transporters |
| title_short | RTN4IP1 Contributes to ESCC via Regulation of Amino Acid Transporters |
| title_sort | rtn4ip1 contributes to escc via regulation of amino acid transporters |
| topic | Amino acid transporters c‐Myc ESCC Iron regulatory proteins Iron responsive element RTN4IP1 |
| url | https://doi.org/10.1002/advs.202406220 |
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