Analysis of m6A-Related lncRNAs for Prognosis Value and Response to Immune Checkpoint Inhibitors Therapy in Hepatocellular Carcinoma

Abstract

Introduction: N6-methyladenosine (m6A) modification and long non-coding RNAs (lncRNAs) play pivotal roles in the progression of hepatocellular carcinoma (HCC). However, how their interaction is involved in the prognostic value of HCC and immune checkpoint inhibitors (ICIs) therapy remains unclear. Methods: The RNA sequencing and clinical data of HCC patients were collected from TCGA database. The prognostic m6A-related lncRNAs were screened out with Pearson correlation test, univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) Cox regression. Patients with HCC were classified into 2 subtypes by consensus clustering. Survival analyses were performed to assess the prognostic value of different clusters and risk models. Potential tumor correlated biological pathways correlated with different clusters were explored through gene set enrichment analysis. We also identified the relationship of the risk model and clusters with response to immune checkpoint inhibitors (ICIs) therapy and tumor microenvironment (TME). Furthermore, the prognostic value of the 9 m6A-related lncRNAs was validated in the external cohort. Finally, the role of SNHG4 was explored by silencing and overexpression of SNHG4 through conducting proliferation, migration and invasion experiments. Results: Patients from 2 clusters and different risk groups based on m6A-related lncRNAs had significantly different clinicopathological characteristics and overall survival outcomes. Tumor-correlated biological pathways were found to be correlated with Cluster 2 through GSEA. Moreover, we found that patients from different clusters and risk groups expressed higher levels of immune checkpoint genes and had distinct TME and different responses for ICIs therapy. Prognostic value of this risk model was further confirmed in the external cohort. Finally, consistent with the discovery, SNHG4 played an oncogenic role in vitro. Conclusion:Our study demonstrated that the 9 m6A-related lncRNA signature may serve as a novel predictor in the prognosis of HCC and optimize (ICIs) therapy. SNHG4 plays an oncogenic role in HCC.

Comprehensive Analysis of the Correlation Between Pyroptosis-Related LncRNAs and Tumor Microenvironment, Prognosis, and Immune Infiltration in Hepatocellular Carcinoma

“…Consensus clustering analysis was performed to obtain two clusters. The role of N6-methyladenosine (m6A)-associated lncRNAs in immune infiltration and prognosis of HCC have been previously illustrated by Wang et al ( Wang et al, 2021a ), who similarly divided the TCGA liver cancer cohort into Clusters 1 ( n = 313) and 2 ( n = 57) based on consensus clustering analysis; Cluster 1 had a superior prognosis compared to Cluster 2 ( p < 0.001). This is consistent with our analysis, where Cluster 1 had a better prognosis than Cluster 2 in our cohort ( p < 0.001) ( Figure 4B ).…”

The Pyroptosis-Related Long Noncoding RNA Signature Predicts Prognosis and Indicates Immunotherapeutic Efficiency in Hepatocellular Carcinoma

“…In addition, the predictive accuracy of the risk score was assessed by the time-dependent ROC analysis at 1, 2, and 3 years, with area under the curve (AUC) values of 0.787, 0.761, and 0.739, respectively ( Figure 2H ), Furthermore, the AUC value of OS for the risk score was significantly higher than those for age, sex, tumor stage, tumor pathological grade, and tumor staging ( Figure 2I , Supplementary Figure S3 ). DCA curve and IDI were used to compare the discriminative ability between our model and the previously reported lncRNA prediction model for HCC ( Li et al, 2020 ; Guo et al, 2021a ; Guo et al, 2021b ; Huang et al, 2021b ; Wang et al, 2021b ; Lei et al, 2021 ; Li et al, 2021 ). DCA indicated that our pyroptosis-related lncRNA signature had positive net benefits and superiority compared with the previously reported lncRNA prediction signature for HCC ( Supplementary Figure S4 ).…”

Pyroptosis-Related LncRNA Signature Predicts Prognosis and Is Associated With Immune Infiltration in Hepatocellular Carcinoma

“…Zhang et al found that glioma patients with high risk had higher expression of immune checkpoint genes, including PDCD1LG2, TNFRSF14, and PDCD1 ( 46 ). Wang et al found increased expression of CD274, CTLA4, HAVCR2, and TIGIT in a high-risk group of HCC patients ( 47 ). Consistent with previous studies, PRlncSig score was positively correlated with the expression levels of immune checkpoint genes (HAVCR2, PDCD1, CD274, CTLA4, and TNFRSF14).…”