HOXB4/METTL7B cascade mediates malignant phenotypes of hepatocellular carcinoma through TKT m6A modification
Abstract Background Hepatocellular carcinoma is a fatal malignancy that lacking specific therapies. Homeobox B4 (HOXB4) was negatively correlated with poor prognosis in cancers, but its role in hepatocellular carcinoma has not been elucidated. Results We confirmed that HOXB4 was downregulated in hep...
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BMC
2025-03-01
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| Online Access: | https://doi.org/10.1186/s13062-025-00620-3 |
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| author | Enshuang Guo Lei Li Jiankun Yang Yongjian Zhou Lu Bai Weiwei Zhu Qiuyue Hu Huifen Wang Hongqiang Liu |
| author_facet | Enshuang Guo Lei Li Jiankun Yang Yongjian Zhou Lu Bai Weiwei Zhu Qiuyue Hu Huifen Wang Hongqiang Liu |
| author_sort | Enshuang Guo |
| collection | DOAJ |
| description | Abstract Background Hepatocellular carcinoma is a fatal malignancy that lacking specific therapies. Homeobox B4 (HOXB4) was negatively correlated with poor prognosis in cancers, but its role in hepatocellular carcinoma has not been elucidated. Results We confirmed that HOXB4 was downregulated in hepatocellular carcinoma tissues and lower HOXB4 expression associated with poor prognosis. Gain- and loss-of function experiments were performed to understand the functional consequences. We revealed that HOXB4 overexpression inhibited proliferation and metastasis of hepatocellular carcinoma cells, accompanied with the decrease in epithelial-mesenchymal transition and increase in cell apoptosis. Database analysis showed that HOXB4 was positively correlated with the immune infiltration. PD-L1 expression was decreased in HOXB4 overexpressed hepatocellular carcinoma cells. HOXB4 overexpression was confirmed to inhibit the progression of hepatocellular carcinoma and promote T cell infiltration in vivo. N6-methyladenosine (m6A) modification was implicated in the tumorigenesis. RNA-seq analysis showed that HOXB4 overexpression modulated METTL7B expression. With the performance of dual-luciferase reporter, ChIP, and DNA pulldown assays, we revealed that HOXB4 binding to METTL7B promoter and inhibited its mRNA expression. The increased aggressiveness of hepatocellular carcinoma cells and the enhanced immune escape, triggered by HOXB4 knockdown, were inhibited via METTL7B downregulation. Methylated RNA immunoprecipitation assay displayed that METTL7B controlled the mRNA decay of TKT in m6A methylation. METTL7B overexpression increase the expression of TKT, ultimately promoting hepatocellular carcinoma progression and immune evasion. Conclusions HOXB4 mediated the malignant phenotypes and modulated the immune evasion via METTL7B/TKT axis. The HOXB4/METTL7B cascade and its downstream changes might be novel targets for blocking hepatocellular carcinoma progression. Graphical Abstract |
| format | Article |
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| institution | DOAJ |
| issn | 1745-6150 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
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| series | Biology Direct |
| spelling | doaj-art-4bb8eabfdcd746e68ef589d96df7f94d2025-08-20T02:59:19ZengBMCBiology Direct1745-61502025-03-0120111710.1186/s13062-025-00620-3HOXB4/METTL7B cascade mediates malignant phenotypes of hepatocellular carcinoma through TKT m6A modificationEnshuang Guo0Lei Li1Jiankun Yang2Yongjian Zhou3Lu Bai4Weiwei Zhu5Qiuyue Hu6Huifen Wang7Hongqiang Liu8Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Osteology, Yellow River Central Hospital of the Yellow River Conservancy CommissionExperimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Infectious Diseases, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Infectious Diseases, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Infectious Diseases, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Infectious Diseases, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Infectious Diseases, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Emergency, Henan Province Hospital of Traditional Chinese MedicineAbstract Background Hepatocellular carcinoma is a fatal malignancy that lacking specific therapies. Homeobox B4 (HOXB4) was negatively correlated with poor prognosis in cancers, but its role in hepatocellular carcinoma has not been elucidated. Results We confirmed that HOXB4 was downregulated in hepatocellular carcinoma tissues and lower HOXB4 expression associated with poor prognosis. Gain- and loss-of function experiments were performed to understand the functional consequences. We revealed that HOXB4 overexpression inhibited proliferation and metastasis of hepatocellular carcinoma cells, accompanied with the decrease in epithelial-mesenchymal transition and increase in cell apoptosis. Database analysis showed that HOXB4 was positively correlated with the immune infiltration. PD-L1 expression was decreased in HOXB4 overexpressed hepatocellular carcinoma cells. HOXB4 overexpression was confirmed to inhibit the progression of hepatocellular carcinoma and promote T cell infiltration in vivo. N6-methyladenosine (m6A) modification was implicated in the tumorigenesis. RNA-seq analysis showed that HOXB4 overexpression modulated METTL7B expression. With the performance of dual-luciferase reporter, ChIP, and DNA pulldown assays, we revealed that HOXB4 binding to METTL7B promoter and inhibited its mRNA expression. The increased aggressiveness of hepatocellular carcinoma cells and the enhanced immune escape, triggered by HOXB4 knockdown, were inhibited via METTL7B downregulation. Methylated RNA immunoprecipitation assay displayed that METTL7B controlled the mRNA decay of TKT in m6A methylation. METTL7B overexpression increase the expression of TKT, ultimately promoting hepatocellular carcinoma progression and immune evasion. Conclusions HOXB4 mediated the malignant phenotypes and modulated the immune evasion via METTL7B/TKT axis. The HOXB4/METTL7B cascade and its downstream changes might be novel targets for blocking hepatocellular carcinoma progression. Graphical Abstracthttps://doi.org/10.1186/s13062-025-00620-3Hepatocellular carcinomaHomeobox B4Methyltransferase-like 7BMalignant progressionImmune evasion |
| spellingShingle | Enshuang Guo Lei Li Jiankun Yang Yongjian Zhou Lu Bai Weiwei Zhu Qiuyue Hu Huifen Wang Hongqiang Liu HOXB4/METTL7B cascade mediates malignant phenotypes of hepatocellular carcinoma through TKT m6A modification Biology Direct Hepatocellular carcinoma Homeobox B4 Methyltransferase-like 7B Malignant progression Immune evasion |
| title | HOXB4/METTL7B cascade mediates malignant phenotypes of hepatocellular carcinoma through TKT m6A modification |
| title_full | HOXB4/METTL7B cascade mediates malignant phenotypes of hepatocellular carcinoma through TKT m6A modification |
| title_fullStr | HOXB4/METTL7B cascade mediates malignant phenotypes of hepatocellular carcinoma through TKT m6A modification |
| title_full_unstemmed | HOXB4/METTL7B cascade mediates malignant phenotypes of hepatocellular carcinoma through TKT m6A modification |
| title_short | HOXB4/METTL7B cascade mediates malignant phenotypes of hepatocellular carcinoma through TKT m6A modification |
| title_sort | hoxb4 mettl7b cascade mediates malignant phenotypes of hepatocellular carcinoma through tkt m6a modification |
| topic | Hepatocellular carcinoma Homeobox B4 Methyltransferase-like 7B Malignant progression Immune evasion |
| url | https://doi.org/10.1186/s13062-025-00620-3 |
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