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

Zhiwen Luo; Zhong He; Haocheng Qin; Yisheng Chen; Beijie Qi; Jinrong Lin; Yaying Sun; Junming Sun; Xiaoping Su; Ziwen Long; Shiyi Chen

doi:10.3389/fphar.2022.1053137

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

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

Authors

Zhiwen Luo¹, Zhong He², Haocheng Qin², Yisheng Chen¹, Beijie Qi³, Jinrong Lin¹, Yaying Sun¹, Junming Sun⁴, Xiaoping Su⁵, Ziwen Long⁶, Shiyi Chen¹

Affiliations

¹ Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China.
² Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai, China.
³ Department of Orthopedics, Shanghai Pudong Hospital, Fudan University, Shanghai, China.
⁴ Laboratory Animal Center, Guangxi Medical University, Nanning, China.
⁵ Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, College & Hospital of Stomatology, Guangxi Medical University, Nanning, China.
⁶ Department of Gastric Cancer Sugery, Fudan University Shanghai Cancer Center, Shanghai, China.

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.