Abstract
Increasing evidence has suggested that long non-coding RNAs (lncRNAs) are critical regulators in the Toll-like receptors (TLR)-signaling network to modulate colorectal cancer (CRC) development and progression. However, the mechanism and clinical significance for lncRNAs regulating TLR signaling pathways in CRC remained largely unknown. In this study, we performed an integrative network analysis of transcriptomics by focusing on a lncRNA-perturbed TLR-signaling network, identifying 280 lncRNAs and 122 mRNAs. We found a profound phenomenon that abnormal expression of some lncRNAs can perturb the TLR-signaling network to contribute to CRC development and progression. Furthermore, we identified a novel TLR-related prognostic gene signature (TLRLncSig) composed of three lncRNAs (MCHR2, AC011472.4, and AC063944.1), and one mRNA (CDKN2B). Utilizing TLRLncSig could classify CRC patients of training set into two groups with significantly different overall survival. The prognostic value of the TLRLncSig was further validated in the other two independent CRC datasets with different platforms. Results of multivariate and stratification analysis indicated that the TLRLncSig is an independent prognostic factor, and our study underscores the clinical significance of TLR-related lncRNAs in CRC development and progression.
Highlights
Colorectal cancer (CRC) is the third most common form of cancer incidence and death in both men and women and ranked top 1 in digestive system cancers (Siegel et al, 2020a)
Unsupervised hierarchical clustering analysis showed that the expression pattern of these DETLRgenes clustered all samples in the The Cancer Genome Atlas (TCGA) dataset into two groups with a significant association with sample disease status (p < 0.001, chi-squared test; Figure 1B)
To identify long non-coding RNAs (lncRNAs) associated with colorectal cancer (CRC), we performed differential expression analysis for 14799 lncRNAs between 41 paired CRC and control samples and identified 2154 differentially expressed lncRNAs (DElncRNAs) with [|log2(fold change]| > 1 and false discovery rate (FDR)-adjusted p-value < 0.05 (Supplementary Table S1)
Summary
Colorectal cancer (CRC) is the third most common form of cancer incidence and death in both men and women and ranked top 1 in digestive system cancers (Siegel et al, 2020a). It is estimated that there are 147,950 estimated new cases and 42,170 estimated deaths in the United States according to cancer statistics, 2020 (Siegel et al, 2020b). Surgery followed by chemotherapy and radiotherapy is the most common treatment. Approximately 25–40% of patients develop tumor relapse (Walker et al, 2014). The classic staging system was commonly used, it is not sufficient for prognosis prediction because of intertumor and intratumor heterogeneity of cancer (Aziz et al, 2017). Molecular biomarkers were needed to identify for improving prognosis
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