TTLL4 mediates the PI3K/AKT/MDM2 pathway to promote hepatocellular carcinoma progression and predict patient prognosis
Hepatocellular carcinoma (HCC) is a highly lethal and heterogeneous tumor driven by the dysregulation of multiple genes. Tubulin tyrosine ligase-like 4 (TTLL4) has been linked to tumor progression, but its specific role in HCC pathogenesis remains unclear. RNA sequencing data, somatic mutation profi...
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| Format: | Article |
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AIP Publishing LLC
2025-06-01
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| Series: | APL Bioengineering |
| Online Access: | http://dx.doi.org/10.1063/5.0267938 |
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| author | Zeping He Desheng Chen Lei Li Shanbao Li Fangbin Song Jinfeng Cai Xueyan Guo Yaohao Luo Xinshuai Wang Zeping Chen Junming Xu |
| author_facet | Zeping He Desheng Chen Lei Li Shanbao Li Fangbin Song Jinfeng Cai Xueyan Guo Yaohao Luo Xinshuai Wang Zeping Chen Junming Xu |
| author_sort | Zeping He |
| collection | DOAJ |
| description | Hepatocellular carcinoma (HCC) is a highly lethal and heterogeneous tumor driven by the dysregulation of multiple genes. Tubulin tyrosine ligase-like 4 (TTLL4) has been linked to tumor progression, but its specific role in HCC pathogenesis remains unclear. RNA sequencing data, somatic mutation profiles, and clinical characteristics were analyzed from TCGA, GEO, and TIMER databases. The effects of TTLL4 on cell proliferation, migration, and apoptosis were studied using functional assays and flow cytometry. In vivo, tumor growth and metastasis were evaluated through subcutaneous implantation and tail vein injection. Immunohistochemistry assessed TTLL4 and Ki-67 expression. TTLL4 was upregulated in HCC and associated with poor prognosis, linking it to cancer progression and the PI3K–AKT signaling pathway. Knockdown of TTLL4 in HCC cells reduced proliferation, migration, and colony formation while increasing apoptosis. In vivo, TTLL4 knockdown slowed tumor growth and reduced lung metastasis. It also decreased the expression of proteins in the PI3K/AKT/MDM2 pathway, while overexpression upregulated these proteins. Rescue experiments further suggest that TTLL4 may exert its regulatory effects on this pathway by modulating PI3K expression levels. TTLL4 plays a significant role in HCC progression via the PI3K/AKT/MDM2 pathway and may serve as a novel therapeutic target for HCC diagnosis and treatment. |
| format | Article |
| id | doaj-art-0a2ae76199f5463ab1fbc8ab8a5ca6e7 |
| institution | Matheson Library |
| issn | 2473-2877 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | AIP Publishing LLC |
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| series | APL Bioengineering |
| spelling | doaj-art-0a2ae76199f5463ab1fbc8ab8a5ca6e72025-07-02T17:37:52ZengAIP Publishing LLCAPL Bioengineering2473-28772025-06-0192026128026128-1110.1063/5.0267938TTLL4 mediates the PI3K/AKT/MDM2 pathway to promote hepatocellular carcinoma progression and predict patient prognosisZeping He0Desheng Chen1Lei Li2Shanbao Li3Fangbin Song4Jinfeng Cai5Xueyan Guo6Yaohao Luo7Xinshuai Wang8Zeping Chen9Junming Xu10Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, ChinaDepartment of Hepatic Surgery and Liver Transplantation Center, Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, ChinaDepartment of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, ChinaDepartment of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, ChinaDepartment of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, ChinaDepartment of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, ChinaDepartment of Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, ChinaDepartment of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, ChinaDepartment of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, ChinaDepartment of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, ChinaDepartment of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, ChinaHepatocellular carcinoma (HCC) is a highly lethal and heterogeneous tumor driven by the dysregulation of multiple genes. Tubulin tyrosine ligase-like 4 (TTLL4) has been linked to tumor progression, but its specific role in HCC pathogenesis remains unclear. RNA sequencing data, somatic mutation profiles, and clinical characteristics were analyzed from TCGA, GEO, and TIMER databases. The effects of TTLL4 on cell proliferation, migration, and apoptosis were studied using functional assays and flow cytometry. In vivo, tumor growth and metastasis were evaluated through subcutaneous implantation and tail vein injection. Immunohistochemistry assessed TTLL4 and Ki-67 expression. TTLL4 was upregulated in HCC and associated with poor prognosis, linking it to cancer progression and the PI3K–AKT signaling pathway. Knockdown of TTLL4 in HCC cells reduced proliferation, migration, and colony formation while increasing apoptosis. In vivo, TTLL4 knockdown slowed tumor growth and reduced lung metastasis. It also decreased the expression of proteins in the PI3K/AKT/MDM2 pathway, while overexpression upregulated these proteins. Rescue experiments further suggest that TTLL4 may exert its regulatory effects on this pathway by modulating PI3K expression levels. TTLL4 plays a significant role in HCC progression via the PI3K/AKT/MDM2 pathway and may serve as a novel therapeutic target for HCC diagnosis and treatment.http://dx.doi.org/10.1063/5.0267938 |
| spellingShingle | Zeping He Desheng Chen Lei Li Shanbao Li Fangbin Song Jinfeng Cai Xueyan Guo Yaohao Luo Xinshuai Wang Zeping Chen Junming Xu TTLL4 mediates the PI3K/AKT/MDM2 pathway to promote hepatocellular carcinoma progression and predict patient prognosis APL Bioengineering |
| title | TTLL4 mediates the PI3K/AKT/MDM2 pathway to promote hepatocellular carcinoma progression and predict patient prognosis |
| title_full | TTLL4 mediates the PI3K/AKT/MDM2 pathway to promote hepatocellular carcinoma progression and predict patient prognosis |
| title_fullStr | TTLL4 mediates the PI3K/AKT/MDM2 pathway to promote hepatocellular carcinoma progression and predict patient prognosis |
| title_full_unstemmed | TTLL4 mediates the PI3K/AKT/MDM2 pathway to promote hepatocellular carcinoma progression and predict patient prognosis |
| title_short | TTLL4 mediates the PI3K/AKT/MDM2 pathway to promote hepatocellular carcinoma progression and predict patient prognosis |
| title_sort | ttll4 mediates the pi3k akt mdm2 pathway to promote hepatocellular carcinoma progression and predict patient prognosis |
| url | http://dx.doi.org/10.1063/5.0267938 |
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