Systematic multiomics analysis and in vitro experiments suggest that ITGA5 could serve as a promising therapeutic target for ccRCC
Abstract Background Integrin alpha 5 (ITGA5) was previously confirmed to be related to prognosis in several cancer types; however, its function in clear cell renal cell carcinoma (ccRCC) and how this molecule regulates tumor progression and the tumor microenvironment (TME) remain to be elucidated. M...
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BMC
2024-11-01
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| Series: | Cancer Cell International |
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| Online Access: | https://doi.org/10.1186/s12935-024-03546-4 |
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| author | Xiangxian Che Xi Tian Zhenda Wang Shuxuan Zhu Shiqi Ye Yue Wang Yihan Chen Yiyun Huang Aihetaimujiang Anwaier Peifeng Yao Yijia Chen Keting Wu Yifei Liu Wenhao Xu Hailiang Zhang Dingwei Ye |
| author_facet | Xiangxian Che Xi Tian Zhenda Wang Shuxuan Zhu Shiqi Ye Yue Wang Yihan Chen Yiyun Huang Aihetaimujiang Anwaier Peifeng Yao Yijia Chen Keting Wu Yifei Liu Wenhao Xu Hailiang Zhang Dingwei Ye |
| author_sort | Xiangxian Che |
| collection | DOAJ |
| description | Abstract Background Integrin alpha 5 (ITGA5) was previously confirmed to be related to prognosis in several cancer types; however, its function in clear cell renal cell carcinoma (ccRCC) and how this molecule regulates tumor progression and the tumor microenvironment (TME) remain to be elucidated. Methods We investigated the prognostic implications of ITGA5 with a machine learning model and evaluated biological behaviors of different levels of ITGA5 expression in vitro. Bioinformatic analysis was performed to explain the comprehensive effect of ITGA5 on the TME and drug sensitivity. Results We constructed a machine learning model to elaborate the prognostic implication of ITGA5. As tumorigenesis of ccRCC was tightly relevant with several mutant genes, we investigated the correlation between ITGA5 expression and frequent mutations and found ITGA5 upregulation in VHL mutant ccRCC (P = 0.016). Through overexpressing, silencing, and blocking ITGA5, we verified the role of ITGA5 in promoting ccRCC adverse biological activities; and the potential functions of ITGA5 in ccRCC were bioinformatically demonstrated, summarizing as cell proliferation, migration, and angiogenesis. The localization of ITGA5 primarily in endothelia and macrophages further verified its magnitude in angiogenesis and aroused our excavation in ITGA5 regulation of immune infiltration landscape. Generally, ITGA5-high ccRCC presented an immunosuppressive TME by inducing a lower level of CD8 + T cell infiltration. For the last part we predicted drug sensitivity relevant to ITGA5 and concluded that a joint medication of ITGA5 inhibitors and VEGFR-target drugs (including sunitinib, axitinib, pazopanib, and motesanib) might be a promising therapeutic strategy. Conclusion Our findings clarified the adverse outcome induced by high expression of ITGA5 in ccRCC patients. In vitro experiments and bioinformatical analysis identified ITGA5 function as predominantly cell proliferation, migration, angiogenesis, and macrophage recruitment. Further, we predicted immune infiltration and medication sensitivity regulation by ITGA5 and proposed a joint use of ITGA5 inhibitors and anti-angiogenetic drugs as a potential potent therapeutic strategy. |
| format | Article |
| id | doaj-art-74550581662841f7acbd39c4e2f6f98f |
| institution | Kabale University |
| issn | 1475-2867 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj-art-74550581662841f7acbd39c4e2f6f98f2025-01-12T12:40:43ZengBMCCancer Cell International1475-28672024-11-0124111810.1186/s12935-024-03546-4Systematic multiomics analysis and in vitro experiments suggest that ITGA5 could serve as a promising therapeutic target for ccRCCXiangxian Che0Xi Tian1Zhenda Wang2Shuxuan Zhu3Shiqi Ye4Yue Wang5Yihan Chen6Yiyun Huang7Aihetaimujiang Anwaier8Peifeng Yao9Yijia Chen10Keting Wu11Yifei Liu12Wenhao Xu13Hailiang Zhang14Dingwei Ye15Department of Urology, Fudan University Shanghai Cancer CenterDepartment of Urology, Fudan University Shanghai Cancer CenterDepartment of Urology, Fudan University Shanghai Cancer CenterDepartment of Urology, Fudan University Shanghai Cancer CenterDepartment of Urology, Fudan University Shanghai Cancer CenterDepartment of Urology, Fudan University Shanghai Cancer CenterDepartment of Oncology, Fudan University Shanghai Medical CollegeDepartment of Oncology, Fudan University Shanghai Medical CollegeDepartment of Urology, Fudan University Shanghai Cancer CenterSchool of Informatics, Xiamen UniversityDepartment of Oncology, Fudan University Shanghai Medical CollegeDepartment of Oncology, Fudan University Shanghai Medical CollegeDepartment of Oncology, Fudan University Shanghai Medical CollegeDepartment of Urology, Fudan University Shanghai Cancer CenterDepartment of Urology, Fudan University Shanghai Cancer CenterDepartment of Urology, Fudan University Shanghai Cancer CenterAbstract Background Integrin alpha 5 (ITGA5) was previously confirmed to be related to prognosis in several cancer types; however, its function in clear cell renal cell carcinoma (ccRCC) and how this molecule regulates tumor progression and the tumor microenvironment (TME) remain to be elucidated. Methods We investigated the prognostic implications of ITGA5 with a machine learning model and evaluated biological behaviors of different levels of ITGA5 expression in vitro. Bioinformatic analysis was performed to explain the comprehensive effect of ITGA5 on the TME and drug sensitivity. Results We constructed a machine learning model to elaborate the prognostic implication of ITGA5. As tumorigenesis of ccRCC was tightly relevant with several mutant genes, we investigated the correlation between ITGA5 expression and frequent mutations and found ITGA5 upregulation in VHL mutant ccRCC (P = 0.016). Through overexpressing, silencing, and blocking ITGA5, we verified the role of ITGA5 in promoting ccRCC adverse biological activities; and the potential functions of ITGA5 in ccRCC were bioinformatically demonstrated, summarizing as cell proliferation, migration, and angiogenesis. The localization of ITGA5 primarily in endothelia and macrophages further verified its magnitude in angiogenesis and aroused our excavation in ITGA5 regulation of immune infiltration landscape. Generally, ITGA5-high ccRCC presented an immunosuppressive TME by inducing a lower level of CD8 + T cell infiltration. For the last part we predicted drug sensitivity relevant to ITGA5 and concluded that a joint medication of ITGA5 inhibitors and VEGFR-target drugs (including sunitinib, axitinib, pazopanib, and motesanib) might be a promising therapeutic strategy. Conclusion Our findings clarified the adverse outcome induced by high expression of ITGA5 in ccRCC patients. In vitro experiments and bioinformatical analysis identified ITGA5 function as predominantly cell proliferation, migration, angiogenesis, and macrophage recruitment. Further, we predicted immune infiltration and medication sensitivity regulation by ITGA5 and proposed a joint use of ITGA5 inhibitors and anti-angiogenetic drugs as a potential potent therapeutic strategy.https://doi.org/10.1186/s12935-024-03546-4Clear cell renal cell carcinomaITGA5BiomarkerMachine learningTumor microenvironment |
| spellingShingle | Xiangxian Che Xi Tian Zhenda Wang Shuxuan Zhu Shiqi Ye Yue Wang Yihan Chen Yiyun Huang Aihetaimujiang Anwaier Peifeng Yao Yijia Chen Keting Wu Yifei Liu Wenhao Xu Hailiang Zhang Dingwei Ye Systematic multiomics analysis and in vitro experiments suggest that ITGA5 could serve as a promising therapeutic target for ccRCC Cancer Cell International Clear cell renal cell carcinoma ITGA5 Biomarker Machine learning Tumor microenvironment |
| title | Systematic multiomics analysis and in vitro experiments suggest that ITGA5 could serve as a promising therapeutic target for ccRCC |
| title_full | Systematic multiomics analysis and in vitro experiments suggest that ITGA5 could serve as a promising therapeutic target for ccRCC |
| title_fullStr | Systematic multiomics analysis and in vitro experiments suggest that ITGA5 could serve as a promising therapeutic target for ccRCC |
| title_full_unstemmed | Systematic multiomics analysis and in vitro experiments suggest that ITGA5 could serve as a promising therapeutic target for ccRCC |
| title_short | Systematic multiomics analysis and in vitro experiments suggest that ITGA5 could serve as a promising therapeutic target for ccRCC |
| title_sort | systematic multiomics analysis and in vitro experiments suggest that itga5 could serve as a promising therapeutic target for ccrcc |
| topic | Clear cell renal cell carcinoma ITGA5 Biomarker Machine learning Tumor microenvironment |
| url | https://doi.org/10.1186/s12935-024-03546-4 |
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