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. 2022 Nov 17:13:1053137.
doi: 10.3389/fphar.2022.1053137. eCollection 2022.

Exercise-induced IL-15 acted as a positive prognostic implication and tumor-suppressed role in pan-cancer

Zhiwen Luo  1 , Zhong He  2 , Haocheng Qin  2 , Yisheng Chen  1 , Beijie Qi  3 , Jinrong Lin  1 , Yaying Sun  1 , Junming Sun  4 , Xiaoping Su  5 , Ziwen Long  6 , Shiyi Chen  1
Affiliations

Exercise-induced IL-15 acted as a positive prognostic implication and tumor-suppressed role in pan-cancer

Zhiwen Luo et al. Front Pharmacol. .

Abstract

Objective: Exercise can produce a large number of cytokines that may benefit cancer patients, including Interleukin 15 (IL-15). IL-15 is a cytokine that has multiple functions in regulating the adaptive and innate immune systems and tumorigenesis of lung and breast cancers. However, the roles of IL-15 in other types of cancer remain unknown. In this article, we try to systematically analyze if IL-15 is a potential molecular biomarker for predicting patient prognosis in pan-cancer and its connection with anti-cancer effects of exercise. Methods: The expression of IL-15 was detected by The Cancer Genome Atlas (TCGA) database, Human protein Atlas (HPA), and Genotype Tissue-Expression (GTEX) database. Analysis of IL-15 genomic alterations and protein expression in human organic tissues was analyzed by the cBioPortal database and HPA. The correlations between IL-15 expression and survival outcomes, clinical features, immune-associated cell infiltration, and ferroptosis/cuproptosis were analyzed using the TCGA, ESTIMATE algorithm, and TIMER databases. Gene Set Enrichment Analysis (GSEA) was performed to evaluate the biological functions of IL-15 in pan-cancer. Results: The differential analysis suggested that the level of IL-15 mRNA expression was significantly downregulated in 12 tumor types compared with normal tissues, which is similar to the protein expression in most cancer types. The high expression of IL-15 could predict the positive survival outcome of patients with LUAD (lung adenocarcinoma), COAD (colon adenocarcinoma), COADREAD (colon and rectum adenocarcinoma), ESCA (esophageal carcinoma), SKCM (skin cutaneous melanoma), UCS (uterine carcinosarcoma), and READ (rectum adenocarcinoma). Moreover, amplification was found to be the most frequent mutation type of IL-15 genomic. Furthermore, the expression of IL-15 was correlated to the infiltration levels of various immune-associated cells in pan-cancer assessed by the ESTIMATE algorithm and TIMER database. In addition, IL-15 is positively correlated with ferroptosis/cuproptosis-related genes (ACSL4 and LIPT1) in pan-cancer. Levels of IL-15 were reported to be elevated in humans for 10-120 min following an acute exercise. Therefore, we hypothesized that the better prognosis of pan-cancer patients with regular exercise may be achieved by regulating level of IL-15. Conclusion: Our results demonstrated that IL-15 is a potential molecular biomarker for predicting patient prognosis, immunoreaction, and ferroptosis/cuproptosis in pan-cancer and partly explained the anti-cancer effects of exercise.

Keywords: IL-15; exercise; ferroptosis/cuproptosis; immune; multi-analyses; pan-cancer; prognosis.

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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
Differential expression pattern of IL-15. (A) IL-15 mRNA expression in normal tissues from GTEX data. (B) Differential IL-15 mRNA expression between paired samples in TCGA cancers. The red dot represents cancer samples, and the blue dot represents paired normal samples. (C) Differential IL-15 mRNA expression between TCGA cancers and GTEX normal tissues. The red column represents cancer samples, and the blue column represents normal samples. The normal group was normal tissue in TCGA and GTEX databases. (D) IL-15 mRNA expression in different cancer types in TIMER. The normal group was normal tissue in the TCGA database. *p < 0.05, **p < 0.01, and ***p < 0.001.
FIGURE 2
FIGURE 2
The protein expression level of IL-15 in human multiple cancer tissues (A) LGG, (B) COADREAD, (C) SKCM, (D) LUAD, (E) BRCA, (F) BLCA, (G) THCA, and (H) PRAD. Representative images of IL-15 expression in pan-cancer tissues are shown. Original magnification, ×100 and ×400. Scare bar = 200 μm or 50 μm.
FIGURE 3
FIGURE 3
High expression of IL-15 promoted patient survival period. (A and G) Kaplan–Meier analysis of the association between IL-15 expression and DSS in LUAD and ESCA. (B–F,H) Kaplan–Meier analysis of the correlation between IL-15 expression and OS in COAD, COADREAD, SKCM, PCPG, READ, and UCS. The red line shows high IL-15 expression, and the blue line represents low IL-15 expression. OS, overall survival; DSS, disease-specific survival.
FIGURE 4
FIGURE 4
The genetic alterations of IL-15. (A) Alteration summary of IL-15 in TCGA pan-cancer datasets. (B) Summary of IL-15 structural variant, mutations, and copy-number alterations. (C) The mutation types, number, and sites of the IL-15 genetic alterations. (D) The alteration types of IL-15 in pan-cancer. (E)The related genes alteration frequency in the IL-15 altered group (Red) and unaltered group (blue).
FIGURE 5
FIGURE 5
Correlation between IL-15 gene expression and tumor immune microenvironment in TCGA database. (A–H) Analysis of immune-associated cells infiltration with IL-15 expression in pan-cancer using lollipop diagrams and box plots. *p < 0.05, **p < 0.01, and ***p < 0.001.
FIGURE 6
FIGURE 6
GSEA analysis in KEGG signature of IL-15 in LUAD (A), PCPG (B), COAD (C), READ (D), COADREAD (E), ESCA (F), SKCM (G), and UCS (H). The left panel: Different color curves show different functions or pathways (Top 5). The peak of the upward and downward curve represents the positive and negative regulation of IL-15, respectively. Score, enrichment score. The right panel: Summary of GSEA plots of representative data is presented. The horizontal axis is the degree of correlation, and the vertical axis is the corresponding pathway.
FIGURE 7
FIGURE 7
Correlation and survival analysis for IL-15 and ferroptosis-related genes in pan-cancers (A) Correlation between IL-15 and ferroptosis-related genes in LUAD. (B) Correlation between IL-15 and ACSL4 in pan-cancers. (C) Survival analysis for ACSL4 in pan-cancers. (D) Protein expression of ACSL4 in SKCM and normal skin tissue.
FIGURE 8
FIGURE 8
Correlation and survival analysis for IL-15 and cuproptosis-related genes in pan-cancers (A) Correlation between IL-15 and cuproptosis-related genes in LUAD. (B) Correlation between IL-15 and cuproptosis -related genes in SKCM. (C) Correlation between IL-15 and LIPT1 in pan-cancers. (D) Survival analysis for LIPT1 in pan-cancers. (E) Protein expression of LIPT1 in SKCM and normal skin tissue.
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