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. 2022 Feb 8:13:762514.
doi: 10.3389/fgene.2022.762514. eCollection 2022.

Immune ULBP1 is Elevated in Colon Adenocarcinoma and Predicts Prognosis

Guo-Tian Ruan  1   2 , Hai-Lun Xie  1   2 , Li-Chen Zhu  3 , Yi-Zhong Ge  1   2 , Lin Yan  4 , Cun Liao  5 , Yi-Zhen Gong  6 , Han-Ping Shi  1   2
Affiliations

Immune ULBP1 is Elevated in Colon Adenocarcinoma and Predicts Prognosis

Guo-Tian Ruan et al. Front Genet. .

Abstract

Background: Colon adenocarcinoma (COAD) is still the main cause of cancer deaths worldwide. Although immunotherapy has made progress in recent years, there is still a need to improve diagnosis, prognosis, and treatment tools. UL-16 binding protein 1 (ULBP1) is a ligand that activates the receptor natural killer cell group 2 receptor D (NKG2D) and plays an important immunomodulatory role. We aimed to investigate the clinical significance of ULBP1 in COAD. Methods: We obtained the relevant data from The Cancer Genome Atlas (TCGA). A total of 438 patients with COAD were included in this study, with a mean age of 67.1 ± 13.03 years old, of which 234 (53.42%) were male. The diagnostic value of COAD tumor tissues and adjacent tissues was analyzed by ROC curve. Univariate and multivariate survival analysis investigated the prognostic value of ULBP1 gene, and Gene Set Enrichment Analysis (GSEA) curve was performed to analyze the biological process and enriched enrichment pathway of ULBP1 in COAD. Combination survival analysis investigated the combined prognostic effect of prognostic genes. Results: ULBP1 gene had a high diagnostic value in COAD [AUC (TCGA) = 0.959; AUC (Guangxi) = 0.898]. Up-regulated ULBP1 gene of patients with COAD predicted a worse prognosis compared to those patients with down-regulated ULBP1 gene (Adjusted HR = 1.544, 95% CI = 1.020-2.337, p = 0.040). The GSEA showed that ULBP1 was involved in the apoptotic pathway and biological process of T cell mediated cytotoxicity, regulation of natural killer cell activation, and T cell mediated immunity of COAD. The combination survival analysis showed that the combination of high expression of ULBP1, AARS1, and DDIT3 would increase the 2.2-fold death risk of COAD when compared with those of low expression genes. Conclusion: The immune-related ULBP1 gene had diagnostic and prognostic value in COAD. The combination of ULBP1, AARS1, and DDIT3 genes could improve the prognostic prediction performance in COAD.

Keywords: COAD; GSEA; NKG2D; ULBP1; biomarker (BM).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
ULBP1’s immune infiltration in COAD and the relationship between ULBP1 and pan-cancer drug sensitivity tests based on GSCA. (A) immune infiltration; (B,C) GDSC and CTRP drug sensitivity test. Notes: COAD, colon adenocarcinoma; ULBP1, unique long 16 (UL16)-binding protein 1; GDSC, Genomics of Drug Sensitivity in Cancer; CTRP, The Cancer Therapeutics Response Portal; GSCA, Gene Set Cancer Analysis.
FIGURE 2
FIGURE 2
ULBP1 and ULBP1 methylation levels in tumor tissues and adjacent normal tissues, ULBP1 mutations, and protein expression in COAD. (A,B) GEPIA data: ULBP1 expression level in COAD and different COAD tumor stages; (C) ULBP1 methylation levels in COAD; (D) ULBP1 mutation; (E–G) immunohistochemistry. Notes: COAD, colon adenocarcinoma; ULBP1, unique long 16 (UL16)-binding protein 1; GEPIA, Gene Expression Profiling Interactive Analysis.
FIGURE 3
FIGURE 3
The expression level of ULBP1 gene in pan-carcinoma and the diagnostic ROC curve. (A) The expression level of ULBP1 gene in pan-cancers based on TIMER; (B,C) ROC curve of TCGA cohort and Guangxi validation cohort. Notes: COAD, colon adenocarcinoma; ULBP1, unique long 16 (UL16)-binding protein 1; ROC, receiver operating characteristic curve. *p < 0.05; ***p < 0.001; ****p < 0.0001.
FIGURE 4
FIGURE 4
Kaplan–Meier survival curves of genes in COAD. (A) ULBP1; (B) AARS1; (C) DDIT3; (D) ULBP1& AARS1 &DDIT3. Notes: COAD, colon adenocarcinoma; ULBP1, unique long 16 (UL16)-binding protein 1; AARS1, alanyl-tRNA synthetase 1; DDIT3, DNA damage inducible transcript 3.
FIGURE 5
FIGURE 5
Difference and enrichment analysis of high- and low- expressed ULBP1 groups in COAD. (A,B) differential expression analysis; (C) enrichment analysis. Notes: COAD, colon adenocarcinoma; ULBP1, unique long 16 (UL16)-binding protein 1.
FIGURE 6
FIGURE 6
GSEA of ULBP1 expression in COAD. Notes: COAD, colon adenocarcinoma; ULBP1, unique long 16 (UL16)-binding protein 1; GSEA, gene set enrichment analysis.
FIGURE 7
FIGURE 7
ULBP1 related co-expressed genes and enrichment analysis in COAD. (A) ULBP1 related co-expressed genes; (B) enrichmentanalysis. Notes: COAD, colon adenocarcinoma; ULBP1, unique long 16 (UL16)-binding protein 1.
FIGURE 8
FIGURE 8
Prognostic risk score model and time-dependent ROC curve of ULBP1 gene in COAD. (A) risk score developed by ULBP1, DDITS, and AARS; (B) kaplan–Meier survival curve of risk score; (C) time-dependent ROC curve. Notes: COAD, colon adenocarcinoma; ULBP1, unique long 16 (UL16)-bindingprotein 1; AARS1, alanyl-tRNA synthetase 1; DDIT3, DNA damage inducible transcript 3. ROC, receiver operating characteristic curve.
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