SLAMF6/Ly108 promotes the development of hepatocellular carcinoma via facilitating macrophage M2 polarization

Qi Meng; Xiuyun Duan; Qingchao Yang; Dewen Xue; Zihao Liu; Yuanyuan Li; Qingyan Jin; Fang Guo; Shijie Jia; Zhaofeng Wang; Wenjiang Yan; Xu Chang; Peng Sun

doi:10.3892/ol.2022.13203

SLAMF6/Ly108 promotes the development of hepatocellular carcinoma via facilitating macrophage M2 polarization

Oncol Lett. 2022 Mar;23(3):83. doi: 10.3892/ol.2022.13203. Epub 2022 Jan 17.

Authors

Qi Meng¹, Xiuyun Duan¹, Qingchao Yang¹, Dewen Xue², Zihao Liu², Yuanyuan Li³, Qingyan Jin², Fang Guo², Shijie Jia², Zhaofeng Wang⁴, Wenjiang Yan⁵, Xu Chang², Peng Sun²

Affiliations

¹ School of Cheeloo Clinical Medicine, Shandong University, Jinan, Shandong 250102, P.R. China.
² Department of Intervention Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China.
³ Head and Neck Radiation Oncology Ward II, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China.
⁴ Surgical Department, Jinan Jiyang District Hospital of Traditional Chinese Medicine, Jinan, Shandong 251499, P.R. China.
⁵ The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.

Abstract

Tumor-associated macrophages (TAMs) are capable of worsening hepatocellular carcinoma (HCC) prognosis by accelerating tumor growth and progression. Signaling lymphocyte activation molecule family member 6 (SLAMF6; Ly108 in mice) is an immune regulator that is involved in numerous diseases. However, whether SLAMF6 might affect macrophage function in HCC has not yet been reported. Therefore, the present study aimed to determine the relationship between SLAMF6 expression on macrophages and HCC progression. In the present study, the expression of SLAMF6 in human blood samples and mice was analyzed by flow cytometry. Furthermore, macrophage-related polarization markers were detected via reverse transcription quantitative PCR. Clonogenic formation and Transwell assay were performed to determine the proliferation, migration and invasion of HCC cells. In addition, a murine HCC model was established to detect the function of SLAMF6 in vivo. The results demonstrated that SLAMF6 expression was increased in CD14⁺ cells obtained from patients with HCC. It was also determined that this increase was associated with a positive hepatitis B virus DNA status and high levels of α-fetoprotein. Polarized TAMs from THP-1 cells, murine peritoneal macrophages and murine bone marrow-derived macrophages all exhibited higher levels of SLAMF6 compared with M1 cells. Furthermore, an increased expression of Ly108 was detected in macrophages obtained from mice tumor tissues, indicating that the tumor microenvironment may promote Ly108 expression and macrophage M2 polarization. Ly108 small interfering RNA was applied to macrophages, which resulted in the suppression of M2 polarization. Ly108-silenced macrophages attenuated HCC cell migration and invasion and prevented tumor growth by inhibiting the nuclear factor-κB pathway. Altogether, the results from the present study suggested that SLAMF6/Ly108 was upregulated in TAMs, which may in turn accelerate the development of HCC.

Keywords: M2 macrophage; hepatocellular carcinoma; signaling lymphocyte activation molecule family member 6/Ly108.

Grants and funding

This study was supported by the Shandong Provincial Natural Science Foundation, China (grant no. ZR2020QH177) and the Key Research & Development Plan of Shandong Province (grant no. 2019GSF108013).