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已发表论文
整合空间转录组学及实验验证揭示了肝细胞癌中与免疫逃逸相关的 UBC 介导的上皮间质转化
Authors Li X, Qin X, Shi K, Lu G, Tian G, Chen Y, Yao R
Received 15 September 2025
Accepted for publication 11 December 2025
Published 19 December 2025 Volume 2025:14 Pages 1437—1454
DOI https://doi.org/10.2147/ITT.S567643
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Michael Shurin
Xiaosong Li,1,2,* Xian Qin,3,4,* Kezhi Shi,5 Guangrui Lu,1,2 Guodong Tian,1,2 Yue Chen,1,2 Rucheng Yao1,2
1The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei, People’s Republic of China; 2Hepatopancreatobiliary Surgery, Yichang Central People’s Hospital, Yichang, Hubei, People’s Republic of China; 3Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 4Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, Hubei, People’s Republic of China; 5Oncology Department, Yichang Central People’s Hospital, Yichang, Hubei, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Rucheng Yao, The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei, People’s Republic of China, Email yaorucheng@163.com
Background: Hepatocellular carcinoma (HCC) exhibits pronounced spatial heterogeneity that limits therapeutic efficacy. The contribution of epithelial–mesenchymal transition (EMT) to regional tumor progression and immune evasion remains incompletely understood.
Methods: We integrated bulk transcriptomic datasets (TCGA, GSE14520), 34 single-cell RNA-seq samples, and 15 spatial transcriptomic datasets to delineate EMT activity across distinct HCC regions. Immune infiltration profiling, pathway enrichment, and multi-model machine learning were used to identify candidate EMT regulators. Functional validation was performed in Hep3B cells through wound healing, Transwell migration/invasion, and immunofluorescence assays.
Results: EMT activity was significantly elevated at tumor margins (fold change = 2.7, p < 0.001) and was associated with poorer overall survival (HR = 2.15, 95% CI: 1.41– 3.27, p < 0.001). Regions with high EMT signatures showed reduced CD8⁺ T-cell infiltration and increased immunosuppressive cells, including MDSCs, M2 macrophages, and Tregs, along with elevated expression of immune checkpoints (PDCD1, CTLA4, LAG3). Among candidate regulators, UBC was consistently ranked as a top EMT-associated gene across all models. Functional assays confirmed that UBC overexpression enhanced migration, invasion, and vimentin expression, whereas UBC knockdown reversed these effects.
Conclusion: Through integrative spatial multi-omics and experimental validation, we identify UBC as a key mediator of EMT and immune suppression at HCC margins. These findings provide mechanistic insight into spatial heterogeneity and suggest that targeting UBC could have translational potential for overcoming immune evasion in HCC.
Keywords: hepatocellular carcinoma, epithelial–mesenchymal transition, UBC, multi-omics integration, tumor microenvironment
1The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei, People’s Republic of China; 2Hepatopancreatobiliary Surgery, Yichang Central People’s Hospital, Yichang, Hubei, People’s Republic of China; 3Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 4Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, Hubei, People’s Republic of China; 5Oncology Department, Yichang Central People’s Hospital, Yichang, Hubei, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Rucheng Yao, The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei, People’s Republic of China, Email yaorucheng@163.com
Background: Hepatocellular carcinoma (HCC) exhibits pronounced spatial heterogeneity that limits therapeutic efficacy. The contribution of epithelial–mesenchymal transition (EMT) to regional tumor progression and immune evasion remains incompletely understood.
Methods: We integrated bulk transcriptomic datasets (TCGA, GSE14520), 34 single-cell RNA-seq samples, and 15 spatial transcriptomic datasets to delineate EMT activity across distinct HCC regions. Immune infiltration profiling, pathway enrichment, and multi-model machine learning were used to identify candidate EMT regulators. Functional validation was performed in Hep3B cells through wound healing, Transwell migration/invasion, and immunofluorescence assays.
Results: EMT activity was significantly elevated at tumor margins (fold change = 2.7, p < 0.001) and was associated with poorer overall survival (HR = 2.15, 95% CI: 1.41– 3.27, p < 0.001). Regions with high EMT signatures showed reduced CD8⁺ T-cell infiltration and increased immunosuppressive cells, including MDSCs, M2 macrophages, and Tregs, along with elevated expression of immune checkpoints (PDCD1, CTLA4, LAG3). Among candidate regulators, UBC was consistently ranked as a top EMT-associated gene across all models. Functional assays confirmed that UBC overexpression enhanced migration, invasion, and vimentin expression, whereas UBC knockdown reversed these effects.
Conclusion: Through integrative spatial multi-omics and experimental validation, we identify UBC as a key mediator of EMT and immune suppression at HCC margins. These findings provide mechanistic insight into spatial heterogeneity and suggest that targeting UBC could have translational potential for overcoming immune evasion in HCC.
Keywords: hepatocellular carcinoma, epithelial–mesenchymal transition, UBC, multi-omics integration, tumor microenvironment