MicroRNA-668-3p Mediates Macrophage M2 Polarization by Targeting NFKBIA to Affect Gastric Cancer Cell Proliferation and Migration

MicroRNA-668-3p Mediates Macrophage M2 Polarization by Targeting NFKBIA to Affect Gastric Cancer Cell Proliferation and Migration

Chenghao Chu,^1,2 Bin Liu,^1,2 Yongwei Zhang,^1,2 Zhangxuan Xu,¹ Bin Wang,¹ and Kai Ling Chin^2,3

¹Department of General Surgery, Anqing First People’s Hospital, Anqing, Anhui Province, China
²Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Sabah, Malaysia
³Borneo Medical and Health Research Centre, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia

Macrophage polarization is implicated in the pathological mechanism of gastric cancer (GC). This study investigated how the miR-668-3p/ Nuclear factor kappa B inhibitor alpha (NFKBIA) axis drives macrophage polarization to contribute to GC progression. Inhibitors or shRNA were used to interfere with the expression of miR-668-3p or NFKBIA in the GC cell line. Subsequently, CCK-8, EdU, wound healing, and transwell assays were used to assess the biological behavior of the GC cells. Bioinformatics analysis predicted the target connection between miR-668-3p and NFKBIA, and a dual luciferase reporter gene experiment confirmed this relationship. After THP-1 macrophages were co-cultured with the supernatant of transfected GC cells, the M1 and M2 macrophage phenotypes were determined. Subsequently, these THP-1 macrophages were co-cultured with GC cells using the Transwell, and the biological behaviors of the GC cells were determiend. miR-668-3p inhibitor suppressed proliferation, invasion and migration of GC cells. The phenotype of M1 macrophage (IL-1β, TNF-α and IL-6) was boosted yet the phenotype of M2 macrophage (CD206, Fizz1 and IL-10) was declined by miR-668-3p inhibitor. NFKBIA was the target gene of miR-668-3p and it reversed the effects of miR-668-3p inhibitor on macrophage polarization and biological behaviors of the GC cells.miR-668-3p suppressed NFKBIA in GC cells to mediate M2 polarization of macrophages, thereby facilitating the tumorigenesis of GC.

Key words —— gastric cancer; macrophage polarization; metastasis; miR-668-3p; nuclear factor kappa B inhibitor alpha

===============================

Tohoku J. Exp. Med., 2025 March, 265(3), 173-182.

Correspondence: Kai Ling Chin, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Sabah, Malaysia; Borneo Medical and Health Research Centre, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu 88400, Malaysia.

e-mail: chinkl@ums.edu.my