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Decoding tumor heterogeneity in uveal melanoma: basement membrane genes as novel biomarkers and therapeutic targets revealed by multi-omics approaches for cancer immunotherapy

Affiliation
Queen Mary College ,Medical School of Nanchang University ,Nanchang ,China
Li, Yunyue;
Affiliation
Department of Neurosurgery ,First Affiliated Hospital of Anhui Medical University ,Hefei ,China
Cai, Huabao;
Affiliation
School of Stomatology ,Southwest Medical University ,Luzhou ,China
Yang, Jinyan;
Affiliation
School of Stomatology ,Southwest Medical University ,Luzhou ,China
Xie, Xixi;
Affiliation
Department of Breast Surgery ,The First Affiliated Hospital of Nanjing Medical University ,Nanjing ,China
Pei, Shengbin;
Affiliation
Department of Breast Surgery ,The First Affiliated Hospital of Nanjing Medical University ,Nanjing ,China
Wu, Yifan;
Affiliation
School of Stomatology ,Southwest Medical University ,Luzhou ,China
Zhang, Jinhao;
Affiliation
School of Stomatology ,Southwest Medical University ,Luzhou ,China
Song, Guobin;
Affiliation
First Teaching Hospital of Tianjin University of Traditional Chinese Medicine ,Tianjin ,China
Zhang, Jieying;
Affiliation
Heilongjiang University of Chinese Medicine ,Harbin ,China
Zhang, Qinhong;
Affiliation
Clinical Medical College ,Southwest Medical University ,Luzhou ,China
Chi, Hao;
Affiliation
Department of Specialty Medicine ,Ohio University ,Athens ,OH ,United States
Yang, Guanhu

Background: Uveal melanoma (UVM) is a primary intraocular malignancy that poses a significant threat to patients’ visual function and life. The basement membrane (BM) is critical for establishing and maintaining cell polarity, adult function, embryonic and organ morphogenesis, and many other biological processes. Some basement membrane protein genes have been proven to be prognostic biomarkers for various cancers. This research aimed to develop a novel risk assessment system based on BMRGs that would serve as a theoretical foundation for tailored and accurate treatment. Methods: We used gene expression profiles and clinical data from the TCGA-UVM cohort of 80 UVM patients as a training set. 56 UVM patients from the combined cohort of GSE84976 and GSE22138 were employed as an external validation dataset. Prognostic characteristics of basement membrane protein-related genes (BMRGs) were characterized by Lasso, stepwise multifactorial Cox. Multivariate analysis revealed BMRGs to be independent predictors of UVM. The TISCH database probes the crosstalk of BMEGs in the tumor microenvironment at the single-cell level. Finally, we investigated the function of ITGA5 in UVM using multiple experimental techniques, including CCK8, transwell, wound healing assay, and colony formation assay. Results: There are three genes in the prognostic risk model (ADAMTS10, ADAMTS14, and ITGA5). After validation, we determined that the model is quite reliable and accurately forecasts the prognosis of UVM patients. Immunotherapy is more likely to be beneficial for UVM patients in the high-risk group, whereas the survival advantage may be greater for UVM patients in the low-risk group. Knockdown of ITGA5 expression was shown to inhibit the proliferation, migration, and invasive ability of UVM cells in vitro experiments. Conclusion: The 3-BMRGs feature model we constructed has excellent predictive performance which plays a key role in the prognosis, informing the individualized treatment of UVM patients. It also provides a new perspective for assessing pre-immune efficacy.

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License Holder: Copyright © 2023 Li, Cai, Yang, Xie, Pei, Wu, Zhang, Song, Zhang, Zhang, Chi and Yang.

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