Abstract
Long non-coding RNAs (lncRNAs) as important regulators of gene expression also have critical functions in immune regulation. This study identified lncRNA modulators of immune-related pathways as biomarkers for hepatocellular carcinoma (HCC). The profile of lncRNA regulation in immune pathways in HCC was comprehensively mapped. To determine lncRNAs with immunomodulatory functions specific to HCC, the enrichment of lncRNAs in a collection of 17 immune functions was calculated applying gene set enrichment analysis (GSEA). Unsupervised clustering of samples were performed in the R package ConsensusClusterPlus to analyze subtype survival and immunological characteristics. The enrichment of 3,134 lncRNA–immune pathway pairs in both diseased and normal samples showed a total of 1,984 immunoregulatory functional lncRNAs specific to HCC only. In addition, 18 immune-related lncRNAs were disordered in HCC and were significantly associated with immune cell infiltration. Functional enrichment analysis indicated that the 18 dysregulated immune lncRNAs were enriched in cytokines, cytokine receptors, TGFb family members, TNF family members, and TNF family member receptor pathways. Two molecular subtypes of hepatocellular carcinoma were identified based on 18 dysregulated immune lncRNAs. Immunological profiling showed that subtype 1 samples with higher levels of cytokine response had a better survival, but subtype 2 samples with higher levels of tumor proliferation had poorer survival. This study identified 18 HCC-specific dysregulated immune lncRNAs and two HCC molecular subtypes with significant prognostic differences and immune characteristics. The current findings help understand the function of lncRNAs and promote the identification of immunotherapy targets.
Highlights
Hepatocellular carcinoma (HCC) as a highly aggressive malignancy is the third leading cause of cancer-related death (Siegel et al, 2013)
We identified 13,810 significant long non-coding RNAs (lncRNAs)–immune function pathway pairs in hepatocellular carcinoma (HCC) samples, and there were 3,732 lncRNA regulators enriched to different immune function sets
14,129 significant lncRNA–immune function pathway pairs were detected in the normal samples; here, 5,322 lncRNAs were found to be enriched to different immune functions
Summary
Hepatocellular carcinoma (HCC) as a highly aggressive malignancy is the third leading cause of cancer-related death (Siegel et al, 2013). A number of important driver genes have been discovered for HCC management, the mechanisms through which HCC occur, metastasize, and relapse are unclear Studies have primarily shown that lncRNAs are associated with a variety of cellular responses, for example, cell proliferation, apoptosis, and differentiation (Kretz et al, 2012; Wang et al, 2014). LncRNA NeST is associated with T cell activation and has critical functions in immune response regulation. Oncogenic lncRNA LINK-A down-regulates antigen presentation and intrinsic tumor suppression of cancer cells (Hu et al, 2019). Only a few functional immunerelated lncRNAs in HCC have been discovered (Jiang et al, 2017; Hu et al, 2019; Yang et al, 2019; Yu et al, 2019)
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