Decreased interleukin-17RA expression is associated with good prognosis in patients with colorectal cancer and inhibits tumor growth and vascularity in mice

Jeng-Kai Jiang; Chi-Hung Lin; Ting-An Chang; Liang-Chuan Lo; Chien-Ping Lin; Ruey-Hwa Lu; Chih-Yung Yang

doi:10.1002/cam4.7059

Decreased interleukin-17RA expression is associated with good prognosis in patients with colorectal cancer and inhibits tumor growth and vascularity in mice

Cancer Med. 2024 Mar;13(5):e7059. doi: 10.1002/cam4.7059.

Authors

Jeng-Kai Jiang^{1

2}, Chi-Hung Lin^{3

4

5}, Ting-An Chang⁶, Liang-Chuan Lo⁷, Chien-Ping Lin², Ruey-Hwa Lu⁸, Chih-Yung Yang^{9

10

11}

Affiliations

¹ School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
² Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
³ Institute of Microbiology and Immunology, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁴ Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
⁵ Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁶ Department of Pathology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan.
⁷ National Genomics Center for Clinical and Biotechnological Applications, Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁸ Department of Surgery, Zhongxing Branch, Taipei City Hospital, Taipei, Taiwan.
⁹ Commission for General Education, National United University, Miaoli, Taiwan.
¹⁰ General Education Center, University of Taipei, Taipei, Taiwan.
¹¹ Department of Education and Research, Taipei City Hospital, Taipei, Taiwan.

Abstract

Background: Interleukin-17 (IL-17) is a pro-inflammatory cytokine that plays a vital role in the promotion of tumorigenesis in various cancers, including colorectal cancer (CRC). Based on current evidence, IL-17 binds to interleukin-17 receptor A (IL-17RA); however, the role of IL-17RA has not been elucidated in previous studies on CRC. In this study, we explored the role of IL-17RA in human CRC tissues and the progression of CRC in humans and mice.

Methods: The expressions of IL-17RA and epithelial-mesenchymal transition (EMT)-related genes were examined in CRC cells and tissue samples by quantitative real-time polymerase chain reaction. The role of IL-17RA in pathogenesis and prognosis was evaluated using a Chi-squared test, Kaplan-Meier analysis, univariate, and multivariate Cox regression analysis in 133 CRC patients. A tumor-bearing mice model was executed to evaluate the role of IL-17RA in tumor growth, vascularity and population of infiltrating immune cells.

Results: IL-17RA expression was found to be significantly higher in CRC tissues than in adjacent normal tissues. The expression of IL-17RA in Stage IV patients was significantly higher than that in Stages I and II patients. Patients with high IL-17RA expression exhibited significantly worse overall and CRC-specific survival than those with low IL-17RA expression. Functional assessment suggested that the knockdown of IL-17RA expression distinctly suppressed cellular proliferation, migration, invasion, and EMT-related gene expression. In a tumor-bearing mouse model, decreased IL-17RA expression significantly repressed tumor growth and vascularity and reduced the population of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs).

Conclusion: Reduced IL-17RA expression also suppressed cellular proliferation, migration, and invasion, and the expression of EMT genes. Knockdown of IL-17RA inhibited tumor growth and vascularity and decreased the population of Tregs and MDSCs in mouse tumors. Overall, IL-17RA expression was identified to be independently associated with the prognosis of patients with CRC.

Keywords: colorectal cancer; interleukin-17 receptor A; prognosis; tumor growth.

MeSH terms

Animals
Cell Line, Tumor
Cell Movement
Cell Proliferation
Colorectal Neoplasms* / pathology
Cytokines / metabolism
Disease Models, Animal
Epithelial-Mesenchymal Transition / genetics
Gene Expression Regulation, Neoplastic
Humans
Interleukin-17* / genetics
Interleukin-17* / metabolism
Mice
Prognosis

Substances

Interleukin-17
Cytokines

Abstract

MeSH terms

Substances

Grants and funding