Downregulation of triggering receptor expressed on myeloid cells 1 inhibits invasion and migration of liver cancer cells by mediating macrophage polarization.

Abstract

Triggering receptor expressed on myeloid cells‑1 (TREM1) is a cell‑surface protein expressed on tumor‑associated macrophages (TAMs), the predominant inflammatory cells in the tumor microenvironment; however, the mechanisms for the influence of TREM1 on TAM polarization during liver cancer progression have not been investigated. In the present study, 20\xa0patients diagnosed with hepatocellular carcinoma\xa0(HCC) who underwent surgery were enrolled, and TREM1 expression on M1/M2\xa0macrophages and on M2\xa0macrophages was assessed by immunohistochemical staining. Human leukemia monocytic cells\xa0(THP‑1) were differentiated into M2\xa0macrophages using phorbol 12‑myristate 13‑acetate, IL‑4 and IL‑13. A specific short hairpin RNA was used to knockdown TREM1 expression. To investigate the effects of TREM1 downregulation in macrophages on the migration and invasion of liver cancer cells, HepG2 and MHCC97H cell lines were co‑cultured with specific conditioned media. Reverse transcription‑quantitative PCR and western blot analyses were used to detect M1 and M2\xa0macrophage marker expression. The expression levels of proteins of the PI3K/AKT/mTOR signaling pathway were analyzed by western blotting, revealing that TREM1 expression in HCC tissues was significantly elevated compared with that in adjacent normal tissues, and TREM1 was highly expressed on the cell membranes of M2\xa0macrophages in tumor tissues compared with in adjacent normal tissues. The present results demonstrated that TREM1 downregulation in macrophages shifted M2\xa0macrophages towards an M1 phenotype, as defined by higher expression levels of M1‑associated markers and decreased expression levels of M2‑associated markers. In addition, TREM1 downregulation in macrophages suppressed migration and invasion of HepG2 and MHCC97H cells. Furthermore, TREM1‑knockdown in macrophages inhibited PI3K/AKT/mTOR activation in the polarization of M2\xa0macrophages. In conclusion, downregulation of TREM1 expression in macrophages shifted M2\xa0macrophages towards a M1 phenotype via inhibiting PI3K/AKT signaling. In addition, migration and invasion of HepG2 and MHCC97H cells were inhibited when this signaling pathway was blocked. The present findings suggest TREM1 as a novel potential therapeutic target for liver cancer management.