Systematic multiomics analysis and in vitro experiments suggest that ITGA5 could serve as a promising therapeutic
Xiangxian Che1,2, Xi Tian1,3,2, Zhenda Wang1,3,2
1Department of Urology, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, 200032, People's Republic of China.
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.
Insights
High integrin alpha 5 (ITGA5) expression promotes clear cell renal cell carcinoma (ccRCC) progression, leading to an immunosuppressive tumor microenvironment. Combining ITGA5 inhibitors with anti-angiogenic drugs may offer a promising therapeutic strategy for ccRCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Integrin alpha 5 (ITGA5) is implicated in various cancers, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear.
- Understanding ITGA5's function in ccRCC is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the prognostic significance of ITGA5 in ccRCC.
- To elucidate the role of ITGA5 in ccRCC progression and its impact on the tumor microenvironment (TME).
- To explore potential therapeutic strategies targeting ITGA5.
Main Methods:
- Machine learning models were employed to assess ITGA5's prognostic value.
- In vitro experiments evaluated the biological effects of varying ITGA5 expression levels.
- Bioinformatic analyses explored ITGA5's comprehensive impact on the TME and drug sensitivity.
Main Results:
- ITGA5 upregulation was correlated with VHL mutations in ccRCC.
- ITGA5 promotes ccRCC cell proliferation, migration, and angiogenesis.
- High ITGA5 expression creates an immunosuppressive TME by reducing CD8+ T cell infiltration and recruiting macrophages.
- ITGA5 inhibition combined with VEGFR-targeted drugs showed potential therapeutic efficacy.
Conclusions:
- High ITGA5 expression is associated with adverse outcomes in ccRCC patients.
- ITGA5 drives ccRCC progression through proliferation, migration, angiogenesis, and macrophage recruitment.
- Targeting ITGA5 with inhibitors and anti-angiogenic agents presents a potential therapeutic strategy for ccRCC.
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