LINC02257, an Enhancer RNA of Prognostic Value in Colon Adenocarcinoma, Correlates With Multi-Omics Immunotherapy-Related Analysis in 33 Cancers

Abstract

Accumulated evidence supports that long non-coding RNAs (lncRNAs) are involved significantly in the development of human cancers. Enhancer RNAs (eRNAs), a subtype of lncRNAs, have recently attracted much attention about their roles in carcinogenesis. Colon adenocarcinoma is one of the most commonly diagnosed tumors with unfavorable prognosis. It highlights the great significance of screening and identifying novel biomarkers. More importantly, it remains to be elucidated with respect to the function of eRNAs in colon adenocarcinoma, as is in pan-cancers. The expression of LINC02257 was determined based on the data obtained from The Cancer Genome Atlas (TCGA). Further evaluation was performed on the basis of the following analyses: clinicopathology and survival analysis, gene ontology (GO) terms, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, as well as multi-omics immunotherapy-related analysis and co-expression analysis. The statistical analysis was conducted in R software, and immune cell infiltration of LINC02257 expression in cancers was investigated by using the CIBERSORT algorithm. By large-scale data mining, our study highlighted that a total of 39 eRNA genes were associated with colon adenocarcinoma prognosis, among which 25 eRNAs showed significant associations with their predicted target genes. LINC02257 was identified as the most significant survival-associated eRNA, with DUSP10 as its target gene. Besides, the high expression of LINC02257 in colon adenocarcinoma was more vulnerable to unfavorable prognosis and correlated with various clinical characteristics. GO and KEGG analyses revealed that LINC02257 was closely correlated with extracellular matrix organization via the PI3K-Akt signaling pathway. Besides, LINC02257 expression correlated with a multi-omics analysis of 33 cancer types, such as survival analysis [overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI)] and immunotherapy-related analysis [tumor microenvironment (TME), tumor mutational burden (TMB), and microsatellite instability (MSI)]. Finally, we investigated the co-expression genes of LINC02257 and its potential signaling pathways across different cancer types. LINC02257 is screened and can function as an independent prognostic biomarker through the PI3K-Akt signaling pathway for colon adenocarcinoma. Simultaneously, LINC02257 may be a multifaceted and significant immunotherapy-related eRNA in different cancers.

Keywords: LINC02257; bioinformatic analysis; enhancer; immune-related multi-omics analysis; pan-cancers.

FIGURE 1

Flowchart of the study.

FIGURE 2

LINC02257 is correlated with multiple Clinicopathological variables in COAD (A) LINC02257 expression in 39 normal tissues and 398 tumor tissues via Wilcox test in a swarm plot, (B) LINC02257 expression between the paired tumor tissues and the normal tissues in the same sample. (C–H) High expression of LINC02257 is related to the patients age, T, N and stages I–IV and shows no significant correlation with gender and M (p < 0.05 was considered significant).

FIGURE 3

Survival analysis of LINC02257 and GO term and KEGG pathway analysis in COAD (A) LINC02257 related to the survival time of patients, and with the increase of LINC02257 expression, the prognosis of colon cancer patients was worse. (B) Multivariate COX regression analysis suggests that age and expression of LINC02257 could be independent factors for the prognosis survival of colon cancer patients. (C) GO enrichment analysis shows that the biological processes and molecular functions are strongly associated with LINC02257 in extracellular structure organization, ossification, collagen fibril organization and connective tissue development. (D) KEGG pathway analysis shows five pathways of the significant correlation with LINC02257 expression: PI3K-Akt signaling pathway. Focal adhesion, Phagosome, Regulation of actin cytoskeleton and MAPK signaling pathway (p < 0.05 was considered significant).

FIGURE 4

LINC02257 expression in 33 cancer types and its correlation with various clinicopathology features (A) LINC02257 in 33 tumor tissues and normal tissues; (*P < 0.001, *P < 0.01, *P < 0.05, no *P > 0.05) (B) In terms of age, COAD, ESCA, KIRP, UCEC, LAML show significant differences with LINC02257 expression. (C) As for gender, LINC02257 expression significantly correlates with ESCA and BRCA. (D) The stage of THCA, STAD, SKCM, READ, PAAD, LUAD, KIRC, HNSC, ESCA, COAD, BLCAexerts significant correlations with LINC02257 expression (p < 0.05 was considered significant).

FIGURE 5

Integrated survival analysis of LINC02257 expression in 33 cancer types (A) The expression of LINC02257 is significant related to OS in BLCA, BRCA, CHOL, COAD, GBM, KIRC, LAML, LUAD, PAAD, UCEC. (B) In respect to DSS, BLCA, CHOL, COAD, GBM, KICH, KIRC, KIRP, LUSC, PAAD, THCA, UCEC show significant correlation to LINC02257. (C) As for DFI, CHOL, ESCA, KIRP, PAAD is significantly related to LINC02257 expression. (D) PFI of COAD, GBM, KICH, KIRC, KIRP, LUSC, MESO, PAAD, READ, THCA, UCEC is significantly related to LINC02257 expression. P < 0.05 indicates that the expression of LINC02257 is significantly correlated with the prognosis and survival of the patients. HR > 1, with the increase of LINC02257 expression, the risk of poor prognosis is higher).

FIGURE 6

Correlation of LINC02257 expression with TMB and MSI in multiple cancer. (A) Correlation between TMB and LINC02257 expression. (B) Correlation between MSI and LINC02257 expression. Spearman’s correlation coefficients are shown above the bar graphs. (Spearman Correlation test, p < 0.05 was considered significant, *p < 0.05, **p < 0.0l, ***p < 0.001).

FIGURE 7

The relationship of LINC02257 expression in cancers and stromal and immune cells scores.

FIGURE 8

The expression of LINC02257 and the infiltrations of 22 immune cells in 33 different types of tumors (the type and content of immune cells on the X-axis, the gene expression distribution on the Y-axis; P-value < 0.001 and R > 0, indicates positive correlation and the existence of statistically significance difference).

FIGURE 9

Analysis of the co-expression of LINC02257 in 33 tumors and its correlation (The deeper the blue, the higher the P-value and the lower the correlation. Yellow represents a negative correlation and red represents a positive correlation. White indicates no correlation. ***P < 0.001, **P < 0.01, *P < 0.05, no *P > 0.05).