Molecular subtypes based on DNA sensors predict prognosis and tumor immunophenotype in hepatocellular carcinoma.

DNA sensors play crucial roles in inflammation and have been indicated to be involved in antitumor or tumorigenesis, while it is still unclear whether DNA sensors have potential roles in the prognosis and immunotherapy of hepatocellular carcinoma (HCC). Herein, The Cancer Genome Atlas and Gene Expression Omnibus databases were used to analyze RNA sequencing data and clinical information. A total of 14 DNA sensors were collected and performed consensus clustering to determine their molecular mechanisms in HCC. Two distinct molecular subtypes (Clusters C1 and C2) were identified and were associated with different overall survival (OS). Immune subtype analysis revealed that C1 was mainly characterized by inflammation, while C2 was characterized by lymphocyte depletion. Immune scoring and immunomodulatory function analysis confirmed the different immune microenvironment of C1 and C2. Notably, significant differences in "Hot Tumor" Immunophenotype were observed between the two subtypes. Moreover, the prognostic model based on DNA sensors is capable of effectively predicting the OS of HCC patients. Besides, the chemotherapeutic drug analysis showed the different sensitivity of two subtypes. Taken together, our study shows that the proposed DNA sensors were a reliable signature to predict the prognosis and immunotherapy response with potential application in the clinical decision and treatment of HCC.

LINC00839 promotes malignancy of liver cancer via binding FMNL2 under hypoxia.

Liver cancer is one of the most common malignant tumors in the world and metastasis is the leading cause of death associated with liver cancer. Hypoxia is a common feature of solid tumors and enhances malignant character of cancer cells. However, the exact mechanisms involved in hypoxia-driven liver cancer progression and metastasis have not been well clarified so far. The aim of this study was to investigate the contribution of long non-coding RNA (lncRNA) in hypoxia promoting liver cancer progression. We screened and revealed LINC00839 as a novel hypoxia-responsive lncRNA in liver cancer. LINC00839 expression was up-regulated in liver cancer tissues and cell lines, and the patients with high LINC00839 expression had shortened overall survival. LINC00839 further overexpressed under hypoxia and promoted liver cancer cell proliferation, migration, and invasion. Mechanistically, LINC00839 bound multiple proteins that were primarily associated with the metabolism and RNA transport, and positively regulated the expression of Formin-like protein 2 (FMNL2). LINC00839 could promote hypoxia-mediated liver cancer progression, suggesting it may be a clinically valuable biomarker and serve as a molecular target for the diagnosis, prognosis, and therapy of liver cancer.

Identification of Two Molecular Subtypes of Hepatocellular Carcinoma Based on Dysregulated Immune LncRNAs.

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.

Identification of molecular subtypes and prognostic signature for hepatocellular carcinoma based on genes associated with homologous recombination deficiency.

Hepatocellular carcinoma (HCC) is a rapidly developing digestive tract carcinoma. The prognosis of patients and side effects caused by clinical treatment should be better improved. Nonnegative matrix factorization (NMF) clustering was performed using 109 homologous recombination deficiency (HRD)-related of HCC genes from The Cancer Genome Atlas (TCGA) database. Limma was applied to analyze subtype differences. Immune scores and clinical characteristics of different subtypes were compared. An HRD signature were built with least absolute shrinkage operator (LASSO) and multivariate Cox analysis. Performance of the signature system was then assessed by Kaplan-Meier curves and receiver operating characteristic (ROC) curves. We identified two molecular subtypes (C1 and C2), with C2 showing a significantly better prognosis than C1. C1 contained 3623 differentially expressed genes. A 4-gene prognostic signature for HCC was established, and showed a high predicting accuracy in validation sets, entire TCGA data set, HCCDB18 and GSE14520 queues. Moreover, the risk score was validated as an independent prognostic marker for HCC. Our research identified two molecular subtypes of HCC, and proposed a novel scoring system for evaluating the prognosis of HCC in clinical practice.