Research Paper Volume 13, Issue 3 pp 3969—3993
Transcriptomic characterization reveals prognostic molecular signatures of sorafenib resistance in hepatocellular carcinoma
- 1 Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- 2 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Received: June 4, 2020 Accepted: August 25, 2020 Published: January 20, 2021
https://doi.org/10.18632/aging.202365How to Cite
Copyright: © 2021 Yuan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Sorafenib is the first-line treatment for patients with advanced unresectable hepatocellular carcinoma (HCC); however, only a small number of patients benefit from sorafenib, and many develop sorafenib resistance (SR) and severe side effects. To identify biomarkers for SR, we systematically analyzed the molecular alterations in both sorafenib-resistant HCC specimens and cultured cells. By combining bioinformatics tools and experimental validation, four genes (C2orf27A, insulin-like growth factor 2 receptor, complement factor B, and paraoxonase 1) were identified as key genes related to SR in HCC and as independent prognostic factors significantly associated with clinical cancer stages and pathological tumor grades of liver cancer. These genes can affect the cytotoxicity of sorafenib to regulate the proliferation and invasion of Huh7 cells in vitro. Additionally, immune-cell infiltration according to tumor immune dysfunction and exclusion, a biomarker integrating the mechanisms of dysfunction and exclusion of T cells showed good predictive power for SR, with an AUC of 0.869. These findings suggest that immunotherapy may be a potential strategy for treating sorafenib-resistant HCC. Furthermore, the results enhance the understanding of the underlying molecular mechanisms of SR in HCC and will facilitate the development of precision therapy for patients with liver cancer.
Abbreviations
HCC: Hepatocellular Carcinoma; SR: sorafenib resistance; ICIs: immune checkpoint inhibitors; TME: tumor microenvironment; GEO: Gene Expression Omnibus; TCGA: the Cancer Genome Atlas; DEGs: differentially expressed genes; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; PPI: protein–protein interaction; ssGSEA: single-sample gene set enrichment analysis; APS: antigen processing and presenting machinery scores; TIS: T cell-infiltration score; IIS: immune infiltration score; IFNγ.GS: the ratio of IFN signaling in immune cells; TIDE: tumor immune dysfunction and exclusion (TIDE); GSVA: gene set variation analysis.