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Systematic Analysis of the Clinical Significance, Molecular Characterization, and Potential Targeted Agents of Immune-Related Genes in Hepatocellular Carcinoma
40 Pages Posted: 12 Sep 2018
More...Abstract
Background: Hepatocellular carcinoma (HCC) has a profound effect on health, and current treatments are of limited effect. Recent advances in immunotherapy have allowed us to view HHC therapy in a new light.
Methods: To increase our understanding of immune-related genes (IRGs) in HCC, we combined RNA sequencing data and clinical information to identify HCC-specific IRGs. We developed an IRG-based prognostic index (IRGPI) to estimate the prognosis of HCC patients by using univariate and multivariate Cox regression model. Furthermore, weighted correlation network analysis and assessment of immune cells infiltration levels were conducted to explore the biological understanding of IRGPI. To explore the multidimensional molecular characteristics of IRGs, we also analyzed copy number alterations, transcription factor (TF) regulatory relationships, methylation status and alternative splicing events of IRGs with several bioinformatics tools, including cBioPortal, Cistrome Cancer, MethylMix and SpliceSeq. Connectivity Map (CMAP) combined with molecular docking analysis were conducted to explore and identify certain novel drugs with immunotherapeutic potential for HCC.
Findings: A total 35 HCC-specific IRGs could be promising clinical biomarkers for distinguishing among HCC types and monitoring disease progression. A prognostic predictor IRGPI we proposed was excellent in distributing HCC patients into different groups with distinct clinical outcome. This IRGPI was developed by correlating immune cell infiltration levels to functional enrichment analyses which may be associated with T cell activation and chemokine signaling pathways. Exploration into the immune transcription factor (TF) regulatory network uncovered several TFs playing regulatory roles on HCC-specific IRGs that could have significant clinical potential. Furthermore, methylations status and alternative splicing events of IRGs that could also have important implications for the prognostic landscape of HCC. With the help of the CMAP database, we proposed that several molecules (lycorine, amphotericin B, chloroquine, dobutamine, econazole, pralidoxime, and metixene) might be used for HCC immunotherapy.
Interpretation: Overall, this study provides a valuable prognostic biomarker resource, novel and multidimensional molecular insights into IRGs, and potential novel drugs for HCC treatment.
Funding Statement: This work was supported by the Guangxi Medical University Training Program for Distinguished Young Scholars (2017); Medical Excellence Award Funded by the Creative Research Development Grant from the First Affiliated Hospital of Guangxi Medical University; Innovation Project of Guangxi Graduate Education (YCSW2018104).
Declaration of Interests: The authors declare that they have no competing interests.
Keywords: Hepatocellular Carcinoma; Immune-Related Genes; Methylation; Alternative Splicing; Personalized Medicine
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