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• W4386003480 abstract "Integrin αv (ITGAV, CD51) is regarded as a key component in multiple stages of tumor progression. However, the clinical failure of cilengitide, a specific inhibitor targeting surface CD51, suggests the importance of yet-unknown mechanisms by which CD51 promotes tumor progression.In this study, we used several hepatocellular carcinoma (HCC) cell lines and murine hepatoma cell lines. To investigate the role of CD51 on HCC progression, we used 3D invasion assay, in vivo bioluminescence imaging, etc. We used periostin-knockout transgenic mice to uncover the role of tumor microenvironment on CD51 cleavage. Moreover, we used several clinical-relevant HCC models, including patient-derived organoids, patient-derived xenografts etc, to evaluate the therapeutic efficacy.We found that CD51 could undergo transmembrane cleavage by γ-secretase to produce a functional intracellular domain (CD51-ICD). The cleaved CD51-ICD facilitated HCC invasion and metastasis by promoting the transcription of oxidative phosphorylation (OXPHOS)-related genes. Furthermore, we identified cancer-associated fibroblast (CAF)-derived periostin as the major driver for CD51 cleavage. Lastly, we showed that cilengitide-based therapy displayed a dramatic improvement in both patient-derived xenograft (PDX) and mouse xenograft models when supplemented with the γ-secretase inhibitor, LY3039478.To sum up, we revealed previously unrecognized action mechanisms of CD51 on HCC progression and uncovered the underlying cause of cilengitide treatment failure and supported the translational prospects of combined CD51-targeted therapy in the clinic.Integrin αv (CD51) is a widely recognized pro-tumoral molecule that plays a crucial role in various stages of tumor progression, making it a promising therapeutic target. However, despite early promising results, cilengitide, a specific antagonist of CD51, surprisingly failed in the phase 3 clinical trial. This prompted further investigation into the underlying mechanisms. This study reveals that the γ-secretase complex directly cleaves CD51 to produce an intracellular domain (CD51-ICD), which functions as a pro-tumoral transcriptional regulator and can bypass the inhibitory effects of cilengitide by entering the nucleus. Furthermore, the localization of CD51 in the nucleus is significantly associated with the prognosis of patients with HCC. These findings provide a theoretical basis for re-evaluating cilengitide in clinical settings and highlight the importance of identifying a more precise patient subpopulation for future clinical trials targeting CD51." @default.
• W4386003480 created "2023-08-20" @default.
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• W4386003480 date "2023-08-01" @default.
• W4386003480 modified "2023-10-12" @default.
• W4386003480 title "Combined inhibition of surface CD51 and γ-secretase-mediated CD51 cleavage improves therapeutic efficacy in experimental metastatic hepatocellular carcinoma" @default.
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• W4386003480 doi "https://doi.org/10.1016/j.jhep.2023.08.007" @default.
• W4386003480 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37604269" @default.
• W4386003480 hasPublicationYear "2023" @default.
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