FTO downregulation-mediated m6A modification resulting in enhanced hepatocellular carcinoma invasion
Abstract Background Dysregulation of N6-methyladenosine (m6A) modifications has been implicated in various cancers, including hepatocellular carcinoma (HCC). This study aimed to elucidate the role of m6A modifications in HCC prognosis and the molecular mechanisms involved, particularly focusing on t...
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BMC
2025-05-01
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| Series: | Cell & Bioscience |
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| Online Access: | https://doi.org/10.1186/s13578-025-01395-w |
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| author | Cheng Zhou Yong Zhang Shi-Ming Shi Dan Yin Xue-Dong Li Ying-Hong Shi Jian Zhou Zheng Wang Qing Chen |
| author_facet | Cheng Zhou Yong Zhang Shi-Ming Shi Dan Yin Xue-Dong Li Ying-Hong Shi Jian Zhou Zheng Wang Qing Chen |
| author_sort | Cheng Zhou |
| collection | DOAJ |
| description | Abstract Background Dysregulation of N6-methyladenosine (m6A) modifications has been implicated in various cancers, including hepatocellular carcinoma (HCC). This study aimed to elucidate the role of m6A modifications in HCC prognosis and the molecular mechanisms involved, particularly focusing on the demethylase FTO. Methods We analyzed m6A expression in a cohort of 323 HCC patients using immunohistochemical (IHC) staining. The expression of m6A-related genes (FTO, ALKBH5, METTL3, METTL14) was evaluated by qRT-PCR in 120 paired HCC tissues. Further, we established HCC cell lines with altered FTO expression to assess its impact on cell proliferation, invasion, and metastasis through various in vitro assays and in vivo orthotopic HCC mouse models. Statistical analyses included Pearson chi-square test, Kaplan-Meier survival analysis, and both univariate and multivariate Cox regression analyses. Results IHC staining revealed elevated m6A levels in HCC tissues compared to adjacent non-tumorous tissues, with 57.3% of HCC patients showing increased m6A expression. High m6A levels were correlated with poorer overall survival (OS) and recurrence-free survival (RFS) rates. FTO, a demethylase, was significantly downregulated in HCC tissues and cell lines, particularly in highly metastatic lines. Overexpression of FTO in HCC cells reduced proliferation, migration, and invasion, whereas FTO knockdown had the opposite effect. In vivo, FTO overexpression decreased tumor growth and metastasis. RNA-Seq analysis identified VEGFA as a key gene downregulated by FTO, implicating its role in angiogenesis and tumor progression. Conclusions Our findings suggest that elevated m6A levels are associated with poor prognosis in HCC patients. FTO downregulation contributes to aberrant m6A modifications, promoting HCC progression and metastasis. FTO acts as a tumor suppressor by negatively regulating VEGFA expression, highlighting its potential as a therapeutic target for HCC treatment. These results highlight the significance of m6A modifications in HCC and provide a foundation for future research on targeted therapies. |
| format | Article |
| id | doaj-art-ba3b125eccc945ce967e056dde5f665a |
| institution | DOAJ |
| issn | 2045-3701 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | Cell & Bioscience |
| spelling | doaj-art-ba3b125eccc945ce967e056dde5f665a2025-08-20T02:55:24ZengBMCCell & Bioscience2045-37012025-05-0115111510.1186/s13578-025-01395-wFTO downregulation-mediated m6A modification resulting in enhanced hepatocellular carcinoma invasionCheng Zhou0Yong Zhang1Shi-Ming Shi2Dan Yin3Xue-Dong Li4Ying-Hong Shi5Jian Zhou6Zheng Wang7Qing Chen8Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan UniversityDepartment of General Surgery, Zhongshan Hospital, Fudan UniversityDepartment of Vascular, Thyroid, and Breast Surgery, Affiliated Hospital of Guangdong Medical UniversityDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan UniversityDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan UniversityDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan UniversityDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan UniversityDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan UniversityDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan UniversityAbstract Background Dysregulation of N6-methyladenosine (m6A) modifications has been implicated in various cancers, including hepatocellular carcinoma (HCC). This study aimed to elucidate the role of m6A modifications in HCC prognosis and the molecular mechanisms involved, particularly focusing on the demethylase FTO. Methods We analyzed m6A expression in a cohort of 323 HCC patients using immunohistochemical (IHC) staining. The expression of m6A-related genes (FTO, ALKBH5, METTL3, METTL14) was evaluated by qRT-PCR in 120 paired HCC tissues. Further, we established HCC cell lines with altered FTO expression to assess its impact on cell proliferation, invasion, and metastasis through various in vitro assays and in vivo orthotopic HCC mouse models. Statistical analyses included Pearson chi-square test, Kaplan-Meier survival analysis, and both univariate and multivariate Cox regression analyses. Results IHC staining revealed elevated m6A levels in HCC tissues compared to adjacent non-tumorous tissues, with 57.3% of HCC patients showing increased m6A expression. High m6A levels were correlated with poorer overall survival (OS) and recurrence-free survival (RFS) rates. FTO, a demethylase, was significantly downregulated in HCC tissues and cell lines, particularly in highly metastatic lines. Overexpression of FTO in HCC cells reduced proliferation, migration, and invasion, whereas FTO knockdown had the opposite effect. In vivo, FTO overexpression decreased tumor growth and metastasis. RNA-Seq analysis identified VEGFA as a key gene downregulated by FTO, implicating its role in angiogenesis and tumor progression. Conclusions Our findings suggest that elevated m6A levels are associated with poor prognosis in HCC patients. FTO downregulation contributes to aberrant m6A modifications, promoting HCC progression and metastasis. FTO acts as a tumor suppressor by negatively regulating VEGFA expression, highlighting its potential as a therapeutic target for HCC treatment. These results highlight the significance of m6A modifications in HCC and provide a foundation for future research on targeted therapies.https://doi.org/10.1186/s13578-025-01395-wHepatocellular carcinomaFat mass and obesity-associated proteinN6-methyladenosineVEGFA |
| spellingShingle | Cheng Zhou Yong Zhang Shi-Ming Shi Dan Yin Xue-Dong Li Ying-Hong Shi Jian Zhou Zheng Wang Qing Chen FTO downregulation-mediated m6A modification resulting in enhanced hepatocellular carcinoma invasion Cell & Bioscience Hepatocellular carcinoma Fat mass and obesity-associated protein N6-methyladenosine VEGFA |
| title | FTO downregulation-mediated m6A modification resulting in enhanced hepatocellular carcinoma invasion |
| title_full | FTO downregulation-mediated m6A modification resulting in enhanced hepatocellular carcinoma invasion |
| title_fullStr | FTO downregulation-mediated m6A modification resulting in enhanced hepatocellular carcinoma invasion |
| title_full_unstemmed | FTO downregulation-mediated m6A modification resulting in enhanced hepatocellular carcinoma invasion |
| title_short | FTO downregulation-mediated m6A modification resulting in enhanced hepatocellular carcinoma invasion |
| title_sort | fto downregulation mediated m6a modification resulting in enhanced hepatocellular carcinoma invasion |
| topic | Hepatocellular carcinoma Fat mass and obesity-associated protein N6-methyladenosine VEGFA |
| url | https://doi.org/10.1186/s13578-025-01395-w |
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