Identification and validation of a fatty acid metabolism-related lncRNA signature as a predictor for prognosis and immunotherapy in patients with liver cancer

Abstract

Background Fatty acid (FA) metabolism is considered the emerging cause of tumor development and metastasis, driving poor prognosis. Long non-coding RNAs (lncRNAs) are closely related to cancer progression and play important roles in FA metabolism. Thus, the discovery of FA metabolism-related lncRNA signatures to predict outcome and immunotherapy response is critical in improving the survival of patients with hepatocellular carcinoma (HCC). Methods FA metabolism scores and a FA metabolism-related lncRNA signature were constructed using a single-sample gene set enrichment analysis based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. “ConsensusClusterPlus” was used to screen molecular subtypes. Chi-squared test and Fisher’s exact test were applied to explore the relationship between clinical, genomic mutation characteristics and subtypes. Transcription factor (TF) activity scores, cellular distributions, immune cell infiltration, and immunotherapy response were employed to investigate the functions of FA metabolism-related lncRNA signatures. FA metabolism microarray and western blot were performed to detect the biological function of candidate lncRNAs. Results A total of 70 lncRNAs that highly correlated with FA metabolism scores in two cohorts were used to construct two distinct clusters. Patients in cluster 2 had lower FA metabolism scores and worse survival than those in cluster 1. Patients in cluster 2 exhibited a high frequency of DNA damage, gene mutations, oncogenic signaling such as epithelial-to-mesenchymal transition, and a high degree of immune cell infiltration. Moreover, the lncRNA signature could predict the effects of immunotherapy in patients with HCC. Furthermore, three lncRNAs (SNHG1, LINC00261, and SNHG7) were identified that were highly correlated with FA metabolism. Additionally, SNHG1 and SNHG7 were found to regulate various FA metabolism-related genes and ferroptosis-related genes in vitro experiments. GSEA analysis revealed that SNHG1 and SNHG7 promote fatty acid beta-oxidation. SNHG1 and SNHG7 silencing dramatically reduced lipid droplets in HCC cells. Many immune-infiltration genes and TFs were overexpressed in HCC tissues with SNHG1 and SNHG7 high expression. Conclusions A novel molecular model of FA metabolism-related lncRNAs was developed, which has significantly prognostic potential in HCC diagnosis and aids in clinical decision making.

Functional analysis of hepatic long non‐coding ribonucleic acids during liver transplantation in humans

“…Increasing evidence has confirmed that lncRNAs are essential in regulating various biological processes, including cell proliferation, differentiation, apoptosis, migration, invasion, and the cell cycle 31,32 . Recently, the role of lncRNAs in the diagnosis and treatment of liver diseases has also been recognized 33,34 . It has also been reported that lncRNAs participate in gene regulation during ischemia–reperfusion injury of important organs such as the brain 35,36 and the heart 37 …”

“…31,32 Recently, the role of lncRNAs in the diagnosis and treatment of liver diseases has also been recognized. 33,34 It has also been reported that lncRNAs participate in gene regulation during ischemia-reperfusion injury of important organs such as the brain 35,36 and the heart. 37 Nevertheless, research on lncRNAs expression profiles in liver transplantation is still limited and is mainly derived from animal or in vitro models of liver transplantation.…”

Revealing metastatic castration‐resistant prostate cancer master regulator through lncRNAs‐centered regulatory network

“…Our results showed exclusive MetNorm regulons were enriched to lipid metabolism, cholesterol/sterol homeostasis, and cell cycle signaling, suggesting their role in cell proliferation and castration resistance in mCRPC. Two of these MRs (HAND2‐AS1 and LINC00261) are described in the literature associated with the maintenance of intracellular cholesterol 52 and fatty acid metabolism, 53 respectively. Several findings have supported the involvement of cholesterol in cell proliferation by maintaining membrane integrity and signal transduction 54 .…”

Noncoding RNAs in Hepatocellular Carcinoma: Potential Applications in Combined Therapeutic Strategies and Promising Candidates of Treatment Response

“…An in silico study identified an FA metabolism-related lncRNA signature which categorized patients from two online datasets on the basis of a high or low FA metabolic score. Notably, patients with a lower FA metabolic score presented a higher immune cell infiltration score, an upregulation of critical immune checkpoint inhibitor genes, and a higher tumor immune dysfunction and exclusion (TIDE) score, suggesting that this patient subgroup may experience immune escape and may have a lower probability of benefit from immunotherapy [104]. Similarly, a signature based on the expression of the lncRNA SNHG1 and on its target genes FANCD2 (FA complementation group D2) and G6PD (glucose 6 phosphate dehydrogenase), the expression of which is increased due to miR-199a sponging activity, displayed an association with poorer OS in patients within the high-risk group.…”