J Cancer 2019; 10(19):4719-4730. doi:10.7150/jca.32456 This issue

Research Paper

Colorectal Cancer Is Associated with a Deficiency of Lipoxin A4, an Endogenous Anti-inflammatory Mediator

Haojing Liu1*, Ji Zeng2*, Wei Huang3, Qiang Xu3, Duyun Ye3, Rui Sun4✉, Dongxin Zhang2,3✉

1. Department of Internal Medicine, Wuhan Fourth Hospital; Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, People's Republic of China
2. Department of Clinical Laboratory, Wuhan Fourth Hospital; Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, People's Republic of China
3. Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
4. Department of Oncology, Wuhan Fourth Hospital; Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, People's Republic of China
*Haojing Liu and Ji Zeng contributed equally to this work.

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Citation:
Liu H, Zeng J, Huang W, Xu Q, Ye D, Sun R, Zhang D. Colorectal Cancer Is Associated with a Deficiency of Lipoxin A4, an Endogenous Anti-inflammatory Mediator. J Cancer 2019; 10(19):4719-4730. doi:10.7150/jca.32456. Available from https://www.jcancer.org/v10p4719.htm

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Abstract

Unresolved inflammation, due to insufficient production of proresolving anti-inflammatory lipid mediators, can lead to tumorigenesis. Among these mediators, lipoxin A4 (LXA4) has potent anti-carcinogenic properties, and may serve as key target for modulating inflammation-associated cancer like colorectal cancer. The purpose of present study was to clarify the roles of LXA4 in colorectal cancer. We investigated the effects and underlying mechanisms of LXA4 in colorectal cancer and its relationship with tumor-associated inflammation and immune microenvironment by employing clinical samples and mouse colorectal cancer cell line CT26-bearing tumor model as well as colorectal cancer cells. It was found that colorectal cancer is associated with dysregulation of immune microenvironment and deficiency of LXA4 that could play different roles at different stages of tumor growth: inhibiting early but promoting late tumor growth. Analysis of peripheral immune cells in subcutaneous xenograft mice model disclosed that early LXA4 treatment induced lymphocytes and inhibited neutrophils and monocytes, while late LXA4 treatment induced neutrophils but inhibited lymphocytes. Detailed analysis of tumor microenvironment revealed that early LXA4 treatment could inhibit inflammatory mediators expressions and leukocytes infiltration into tumor. Furthermore, LXA4 could suppress the expressions of p-ERK, p-P38 and NF-κB in subcutaneous xenograft. Additionally, LXA4 could inhibit the proliferation and migration of colorectal cancer cells, and, meanwhile, inhibit the proliferation and migration of colorectal cancer cells stimulated by activated macrophage-conditioned media. These findings suggest that colorectal cancer is associated with a deficiency of LXA4 that could suppress colorectal cancer via modulating tumor-associated inflammation and immune microenvironment as well as inhibiting colorectal cancer cell development.

Keywords: colorectal cancer, immune microenvironment, inflammation, lipoxin A4, subcutaneous xenograft