STAMBPL1/TRIM21 Balances AXL Stability Impacting Mesenchymal Phenotype and Immune Response in KIRC
Abstract Kidney renal clear cell carcinoma (KIRC) is recognized as an immunogenic tumor, and immunotherapy is incorporated into its treatment landscape for decades. The acquisition of a tumor mesenchymal phenotype through epithelial‐to‐mesenchymal transition (EMT) is associated with immune evasion a...
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202405083 |
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| author | Shiyu Huang Xuke Qin Shujie Fu Juncheng Hu Zhengyu Jiang Min Hu Banghua Zhang Jiachen Liu Yujie Chen Minghui Wang Xiuheng Liu Zhiyuan Chen Lei Wang |
| author_facet | Shiyu Huang Xuke Qin Shujie Fu Juncheng Hu Zhengyu Jiang Min Hu Banghua Zhang Jiachen Liu Yujie Chen Minghui Wang Xiuheng Liu Zhiyuan Chen Lei Wang |
| author_sort | Shiyu Huang |
| collection | DOAJ |
| description | Abstract Kidney renal clear cell carcinoma (KIRC) is recognized as an immunogenic tumor, and immunotherapy is incorporated into its treatment landscape for decades. The acquisition of a tumor mesenchymal phenotype through epithelial‐to‐mesenchymal transition (EMT) is associated with immune evasion and can contribute to immunotherapy resistance. Here, the involvement of STAM Binding Protein Like 1 (STAMBPL1) is reported in the development of mesenchymal and immune evasion phenotypes in KIRC cells. Mechanistically, STAMBPL1 elevated protein abundance and surface accumulation of TAM Receptor AXL through diminishing the TRIM21‐mediated K63‐linked ubiquitination and subsequent lysosomal degradation of AXL, thereby enhancing the expression of mesenchymal genes while suppressing chemokines CXCL9/10 and HLA/B/C. In addition, STAMBPL1 enhanced PD‐L1 transcription via facilitating nuclear translocation of p65, and knockdown (KD) of STAMBPL1 augmented antitumor effects of PD‐1 blockade. Furthermore, STAMBPL1 silencing and the tyrosine kinase inhibitor (TKI) sunitinib also exhibited a synergistic effect on the suppression of KIRC. Collectively, targeting the STAMBPL1/TRIM21/AXL axis can decrease mesenchymal phenotype and potentiate anti‐tumor efficacy of cancer therapy. |
| format | Article |
| id | doaj-art-ae1c584a21b046b58ee18a2566313123 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-ae1c584a21b046b58ee18a25663131232025-01-09T11:44:45ZengWileyAdvanced Science2198-38442025-01-01121n/an/a10.1002/advs.202405083STAMBPL1/TRIM21 Balances AXL Stability Impacting Mesenchymal Phenotype and Immune Response in KIRCShiyu Huang0Xuke Qin1Shujie Fu2Juncheng Hu3Zhengyu Jiang4Min Hu5Banghua Zhang6Jiachen Liu7Yujie Chen8Minghui Wang9Xiuheng Liu10Zhiyuan Chen11Lei Wang12Department of Urology Renmin Hospital of Wuhan University Wuhan Hubei 430060 ChinaDepartment of Urology Renmin Hospital of Wuhan University Wuhan Hubei 430060 ChinaDepartment of Urology Renmin Hospital of Wuhan University Wuhan Hubei 430060 ChinaDepartment of Urology Renmin Hospital of Wuhan University Wuhan Hubei 430060 ChinaDepartment of Urology Renmin Hospital of Wuhan University Wuhan Hubei 430060 ChinaDepartment of Cardiology Renmin Hospital of Wuhan University Wuhan Hubei 430060 ChinaDepartment of Urology Renmin Hospital of Wuhan University Wuhan Hubei 430060 ChinaDepartment of Urology Renmin Hospital of Wuhan University Wuhan Hubei 430060 ChinaDepartment of Urology Renmin Hospital of Wuhan University Wuhan Hubei 430060 ChinaDepartment of Urology Renmin Hospital of Wuhan University Wuhan Hubei 430060 ChinaDepartment of Urology Renmin Hospital of Wuhan University Wuhan Hubei 430060 ChinaDepartment of Urology Renmin Hospital of Wuhan University Wuhan Hubei 430060 ChinaDepartment of Urology Renmin Hospital of Wuhan University Wuhan Hubei 430060 ChinaAbstract Kidney renal clear cell carcinoma (KIRC) is recognized as an immunogenic tumor, and immunotherapy is incorporated into its treatment landscape for decades. The acquisition of a tumor mesenchymal phenotype through epithelial‐to‐mesenchymal transition (EMT) is associated with immune evasion and can contribute to immunotherapy resistance. Here, the involvement of STAM Binding Protein Like 1 (STAMBPL1) is reported in the development of mesenchymal and immune evasion phenotypes in KIRC cells. Mechanistically, STAMBPL1 elevated protein abundance and surface accumulation of TAM Receptor AXL through diminishing the TRIM21‐mediated K63‐linked ubiquitination and subsequent lysosomal degradation of AXL, thereby enhancing the expression of mesenchymal genes while suppressing chemokines CXCL9/10 and HLA/B/C. In addition, STAMBPL1 enhanced PD‐L1 transcription via facilitating nuclear translocation of p65, and knockdown (KD) of STAMBPL1 augmented antitumor effects of PD‐1 blockade. Furthermore, STAMBPL1 silencing and the tyrosine kinase inhibitor (TKI) sunitinib also exhibited a synergistic effect on the suppression of KIRC. Collectively, targeting the STAMBPL1/TRIM21/AXL axis can decrease mesenchymal phenotype and potentiate anti‐tumor efficacy of cancer therapy.https://doi.org/10.1002/advs.202405083immunotherapy resistancekidney renal clear cell carcinomamesenchymal phenotypeSTAM binding protein like 1ubiquitination |
| spellingShingle | Shiyu Huang Xuke Qin Shujie Fu Juncheng Hu Zhengyu Jiang Min Hu Banghua Zhang Jiachen Liu Yujie Chen Minghui Wang Xiuheng Liu Zhiyuan Chen Lei Wang STAMBPL1/TRIM21 Balances AXL Stability Impacting Mesenchymal Phenotype and Immune Response in KIRC Advanced Science immunotherapy resistance kidney renal clear cell carcinoma mesenchymal phenotype STAM binding protein like 1 ubiquitination |
| title | STAMBPL1/TRIM21 Balances AXL Stability Impacting Mesenchymal Phenotype and Immune Response in KIRC |
| title_full | STAMBPL1/TRIM21 Balances AXL Stability Impacting Mesenchymal Phenotype and Immune Response in KIRC |
| title_fullStr | STAMBPL1/TRIM21 Balances AXL Stability Impacting Mesenchymal Phenotype and Immune Response in KIRC |
| title_full_unstemmed | STAMBPL1/TRIM21 Balances AXL Stability Impacting Mesenchymal Phenotype and Immune Response in KIRC |
| title_short | STAMBPL1/TRIM21 Balances AXL Stability Impacting Mesenchymal Phenotype and Immune Response in KIRC |
| title_sort | stambpl1 trim21 balances axl stability impacting mesenchymal phenotype and immune response in kirc |
| topic | immunotherapy resistance kidney renal clear cell carcinoma mesenchymal phenotype STAM binding protein like 1 ubiquitination |
| url | https://doi.org/10.1002/advs.202405083 |
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