A Novel Ferroptosis-Related Long Non-Coding RNA Prognostic Signature Correlates With Genomic Heterogeneity, Immunosuppressive Phenotype, and Drug Sensitivity in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) with high heterogeneity is a common malignancy worldwide, but effective treatments are limited. Ferroptosis plays a critical role in tumors as a novel iron-dependent and reactive oxygen species-reliant type of cell death. Several studies have shown that long non-coding RNAs (lncRNAs) can drive HCC initiation and progression. However, the prognostic value of ferroptosis-related lncRNAs in patients with HCC has not been explored comprehensively. Gene set variation analysis (GSVA) based on gene set and RNA-seq profiles obtained from public databases indicated that ferroptosis is suppressed in HCC patients. Ferroptosis-related differentially expressed lncRNAs were screened by Pearson’s test. Univariate Cox regression, least absolute shrinkage and selection operator (LASSO) regression, and multivariate Cox regression were performed to establish a novel five ferroptosis-related lncRNA signature in the training cohort with 60% patients, which was further verified in the testing cohort with 40% patients. Dimensionality reduction analysis, Kaplan–Meier curve, receiver operating characteristic (ROC) curve, independent prognostic analysis, and stratification analysis confirmed that our signature had a high clinical application value in predicting the overall survival of HCC patients. Compared to the clinicopathological factors and the other four published HCC prognostic signatures, the current risk model had a better predictive value. The comparison results of functional enrichment, tumor immune microenvironment, genomic heterogeneity, and drug sensitivity between the high- and low-risk groups showed that the risk score is associated with extensive genomic alterations, immunosuppressive tumor microenvironment, and clinical treatment response. Finally, cell experiments showed that silencing LNCSRLR expression inhibited the growth, proliferation, migration, and invasion of the HCC cell line. Thus, the model can function as an efficient indicator for predicting clinical prognosis and treatment of anticancer drugs in HCC patients.

Ferroptosis-related lncRNA NRAV affects the prognosis of hepatocellular carcinoma via miR-375-3P/SLC7A11 axis

“…Finally, 6 lncRNA characteristic models related to ferroptosis were established, most of which have been reported to affect the progression of liver cancer and are associated with poor prognosis, including NRAV [27]. He et al found that ZFPM2-AS1 acts as a miRNA sponge and promotes cell invasion through regulation of miR-139/GDF10 in hepatocellular carcinoma [28], Ma et al Found that DANCR was upregulated in tumor tissues and plasma of patients with HCC, and its expression was highly correlated with microvascular, and liver capsule invasion of HCC [29], MKLN1-AS[30], LNCSRLR [31] and AL137186.2[32] also be associated with the prognosis of patients with HCC, which are consistent with our ndings. Moreover, after correcting for traditional clinical risk indicators, the six-FRLs signature model was shown to be an independent predictive factor for HCC.…”

Ferroptosis-related lncRNA NRAV affects the prognosis of hepatocellular carcinoma via miR-375-3P/SLC7A11 axis

“…In this study, we rst identi ed 84 genes and then identi ed 52 signi cant lncRNA associated with ferroptosis. Finally, 6 lncRNA characteristic models related to ferroptosis were established, most of which have been reported to affect the progression of liver cancer and associated with poor prognosis, including NRAV [27], He et al found that ZFPM2-AS1 acts as a miRNA sponge and promotes cell invasion through regulation of miR-139/GDF10 in hepatocellular carcinoma [28], Ma et al Found that DANCR was up-regulated in tumor tissues and plasma of patients with HCC, and its expression was highly correlated with microvascular and liver capsule invasion of HCC [29], MKLN1-AS [30], LNCSRLR [31] and AL137186.2 [32] also have been shown to be associated with the prognosis of patients with HCC, which are consistent with our ndings. Moreover, after correcting for traditional clinical risk indicators, the six-FRLs signature model was shown to be an independent predictive factor for HCC.…”

Regulation of ncRNAs involved with ferroptosis in various cancers

“…LINC01134 can promote Nrf2 recruitment to the GPX4 promoter region via the interaction of the RNA-DNA sequence to increase the transcripts of GPX4, and while LINC01134 silencing leads to oxaliplatin sensitivity by inhibiting the total ROS, lipid ROS, and MDA levels and decreasing the GSH/GSSG ratio ( Kang et al, 2022 ). Guanghao Li et al predicted some ferroptosis-related lncRNAs associating with immunosuppressive phenotype and drug sensitivity ( Li et al, 2022b ). Moreover, in Liu, Z. et al’s research, circRNA cIARS were found to be upregulated in sorafenib-induced HCC cells, which can promote ferroptosis via ferritinophagy by repressing the anti-autophagy effect of ALKBH5 ( Liu et al, 2020 ).…”