Hypomethylation induced overexpression of PLOD3 facilitates colorectal cancer progression through TM9SF4-mediated autophagy
Abstract Colorectal cancer (CRC) ranks among the primary causes of human mortality globally. Numerous studies have highlighted the significant role of PLOD3 in the progression of various cancers. However, the exact function and underlying mechanisms of PLOD3 in CRC remains incompletely understood. T...
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Nature Publishing Group
2025-03-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07503-5 |
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| author | Renzhong Zhu Chuanxin Tian Nan Gao Zhiqiang Li Sheng Yang Yue Zhang Ming Zhou Kangpeng Jin Chuan Zhang Yueming Sun |
| author_facet | Renzhong Zhu Chuanxin Tian Nan Gao Zhiqiang Li Sheng Yang Yue Zhang Ming Zhou Kangpeng Jin Chuan Zhang Yueming Sun |
| author_sort | Renzhong Zhu |
| collection | DOAJ |
| description | Abstract Colorectal cancer (CRC) ranks among the primary causes of human mortality globally. Numerous studies have highlighted the significant role of PLOD3 in the progression of various cancers. However, the exact function and underlying mechanisms of PLOD3 in CRC remains incompletely understood. To investigate the expression of PLOD3, qRT‒PCR, immunohistochemistry and western blotting were utilized to analyze the expression of PLOD3 in CRC tissues and adjacent normal tissues. Functional assays were conducted to assess the roles of PLOD3 both in vitro and in vivo. To elucidate the potential mechanism of PLOD3 in CRC, a range of techniques, including coimmunoprecipitation, immunofluorescence, CHX pulse-chase, and ubiquitination assays were used. As the results indicated, hypomethylation of the PLOD3 promoter leads to its over- expression in CRC, and elevated PLOD3 levels are associated with a poor prognosis. Both in vitro and in vivo models demonstrated that PLOD3 enhances CRC cell proliferation, invasion, and migration. Furthermore, through mechanistic studies, TM9SF4 was identified as a protein that interacts with PLOD3 and contributes to CRC progression by promoting autophagy. Additionally, PLOD3 could be secreted by CRC cells and secreted PLOD3 could promote CRC cells migration and invasion. These results demonstrated that PLOD3 promotes CRC progression through the PLOD3/TM9SF4 axis and could be a potential biomarker and treatment target for CRC. |
| format | Article |
| id | doaj-art-aecc9191bcf54bd092b07bc7489e3e05 |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death and Disease |
| spelling | doaj-art-aecc9191bcf54bd092b07bc7489e3e052025-08-20T01:49:39ZengNature Publishing GroupCell Death and Disease2041-48892025-03-0116111510.1038/s41419-025-07503-5Hypomethylation induced overexpression of PLOD3 facilitates colorectal cancer progression through TM9SF4-mediated autophagyRenzhong Zhu0Chuanxin Tian1Nan Gao2Zhiqiang Li3Sheng Yang4Yue Zhang5Ming Zhou6Kangpeng Jin7Chuan Zhang8Yueming Sun9Institute of Translational Medicine, Medical College, Yangzhou UniversityDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical UniversityGeneral Surgery department of Dongtai People’s HospitalMOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua UniversityDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical UniversityInstitute of Translational Medicine, Medical College, Yangzhou UniversityDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical UniversityInstitute of Translational Medicine, Medical College, Yangzhou UniversityAbstract Colorectal cancer (CRC) ranks among the primary causes of human mortality globally. Numerous studies have highlighted the significant role of PLOD3 in the progression of various cancers. However, the exact function and underlying mechanisms of PLOD3 in CRC remains incompletely understood. To investigate the expression of PLOD3, qRT‒PCR, immunohistochemistry and western blotting were utilized to analyze the expression of PLOD3 in CRC tissues and adjacent normal tissues. Functional assays were conducted to assess the roles of PLOD3 both in vitro and in vivo. To elucidate the potential mechanism of PLOD3 in CRC, a range of techniques, including coimmunoprecipitation, immunofluorescence, CHX pulse-chase, and ubiquitination assays were used. As the results indicated, hypomethylation of the PLOD3 promoter leads to its over- expression in CRC, and elevated PLOD3 levels are associated with a poor prognosis. Both in vitro and in vivo models demonstrated that PLOD3 enhances CRC cell proliferation, invasion, and migration. Furthermore, through mechanistic studies, TM9SF4 was identified as a protein that interacts with PLOD3 and contributes to CRC progression by promoting autophagy. Additionally, PLOD3 could be secreted by CRC cells and secreted PLOD3 could promote CRC cells migration and invasion. These results demonstrated that PLOD3 promotes CRC progression through the PLOD3/TM9SF4 axis and could be a potential biomarker and treatment target for CRC.https://doi.org/10.1038/s41419-025-07503-5 |
| spellingShingle | Renzhong Zhu Chuanxin Tian Nan Gao Zhiqiang Li Sheng Yang Yue Zhang Ming Zhou Kangpeng Jin Chuan Zhang Yueming Sun Hypomethylation induced overexpression of PLOD3 facilitates colorectal cancer progression through TM9SF4-mediated autophagy Cell Death and Disease |
| title | Hypomethylation induced overexpression of PLOD3 facilitates colorectal cancer progression through TM9SF4-mediated autophagy |
| title_full | Hypomethylation induced overexpression of PLOD3 facilitates colorectal cancer progression through TM9SF4-mediated autophagy |
| title_fullStr | Hypomethylation induced overexpression of PLOD3 facilitates colorectal cancer progression through TM9SF4-mediated autophagy |
| title_full_unstemmed | Hypomethylation induced overexpression of PLOD3 facilitates colorectal cancer progression through TM9SF4-mediated autophagy |
| title_short | Hypomethylation induced overexpression of PLOD3 facilitates colorectal cancer progression through TM9SF4-mediated autophagy |
| title_sort | hypomethylation induced overexpression of plod3 facilitates colorectal cancer progression through tm9sf4 mediated autophagy |
| url | https://doi.org/10.1038/s41419-025-07503-5 |
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