An Autophagy-Related Long Noncoding RNA Signature Contributes to Poor Prognosis in Colorectal Cancer

Abstract

Purpose: Colorectal cancer is one of the most common malignant primary tumors, prone to metastasis, and associated with a poor prognosis. As autophagy is closely related to the development and treatment of colorectal cancer, we investigated the potential prognostic value of long noncoding RNA (lncRNA) associated with autophagy in colorectal cancer.

Methods: In this study, we acquired information on the expression of lncRNAs in colorectal cancer from the Cancer Genome Atlas (TCGA) database and found that 860 lncRNAs were associated with autophagy-related genes. Subsequently, univariate Cox regression analysis was used to investigate 32 autophagy-related lncRNAs linked to colon cancer prognosis. Subsequently, eight of the 32 autophagy-related lncRNAs (i.e., long intergenic nonprotein coding RNA 1503 [LINC01503], ZEB1 antisense RNA 1 [ZEB1-AS1], AC087481.3, AC008760.1, AC073896.3, AL138756.1, AL022323.1, and TNFRSF10A-AS1) were selected through multivariate Cox regression analysis. Based on these autophagy-related lncRNAs, a risk signature was constructed, and the patients were divided into high- and low-risk groups.

Results: The high-risk group's overall survival time was significantly shorter than that of the low-risk group (p < 0.0001). Receiver operating characteristic curve analysis was performed to further confirm the validity of the model (area under the curve: 0.689). Moreover, multivariate regression suggested that the risk score was a significant prognostic risk factor in colorectal cancer. Gene set enrichment analysis showed that these gene sets are significantly enriched in cancer-related pathways, such as Kirsten rat sarcoma viral oncogene homolog (KRAS) signaling.

Conclusion: The risk signature of eight autophagy-related lncRNAs has prognostic potential for colorectal cancer. These autophagy-related lncRNAs may play a vital role in the biology of colorectal cancer.

Figure 1

Co-expression network of autophagy genes and related prognostic lncRNAs. Red nodes represent autophagy-related lncRNAs. Blue nodes represent autophagy genes. LncRNA, long noncoding RNA.

Figure 2

Kaplan–Meier survival curve of the eight selected autophagy-related lncRNAs in colorectal cancer in TCGA database. The Kaplan–Meier survival analysis indicated that patients with high expression of AC008760.1, AC087481.3, AL138756.1, LINC01503, and ZEB1-AS1 had worse prognosis. In contrast, those with high expression of AC073896.3, AL022323.1, and TNFRSF10A-AS1 had better prognosis. LncRNA, long noncoding RNA; TCGA, the Cancer Genome Atlas; LINC01503, long intergenic nonprotein coding RNA 1503; AS1, antisense RNA 1.

Figure 3

The relationships among autophagy-related genes, autophagy-related lncRNAs, and risk types in the Sankey diagram. lncRNA, long noncoding RNA.

Figure 4

Risk analysis of autophagy-related lncRNAs in patients with colorectal cancer in TCGA database. (a) The risk score in the high- and low-risk groups for the risk signature in colorectal cancer. (b) Survival time of patients with colorectal cancer in high- and low-risk groups. (c) Expression of the eight selected autophagy-related lncRNAs in colorectal cancer. Red color represents increased expression. Blue color represents decreased expression. LncRNA, long noncoding RNA; TCGA, the Cancer Genome Atlas.

Figure 5

Prognostic value of the risk signature based on coefficients and HR. (a) Survival analysis of the high- and low-risk groups according to the risk model in TCGA database. (b) The accuracy of the model was verified using multi-indicator ROC analysis. HR, hazard ratio; TCGA, the Cancer Genome Atlas; ROC, receiver operating characteristic.

Figure 6

Analysis of the risk signature as an independent prognostic indicator through (a) univariate and (b) multivariate cox regression analyses.

Figure 7

Gene set enrichment analysis showing the enriched hallmark pathways in the two groups based on TCGA database. (a), (b) KRAS and myogenic gene sets were significantly enriched in the high-risk group. (c), (d) G2°M checkpoint and E2F targets gene sets were significantly enriched in the low-risk group. TCGA, the Cancer Genome Atlas; KRAS, Kirsten rat sarcoma viral oncogene homolog.

Figure 8

The expression levels of the eight autophagy-related lncRNAs in CRC cell lines. (a) The expression of the 8 lncRNAs in each cell lines. (b) The total expression levels of the eight autophagy-related lncRNAs in 7 cell lines. LncRNA, long noncoding RNA; CRC, colorectal cancer.