Apatinib Suppressed Macrophage-Mediated Malignant Behavior of Hepatocellular Carcinoma Cells via Modulation of VEGFR2/STAT3/PD-L1 Signaling

Author:

Yin T.1,Fu C. B.1,Wu D. D.1,Nie L.1,Chen H.1,Wang Y.1

Affiliation:

1. Department of Hepatobiliary and Pancreatic Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan

Abstract

Hepatocellular carcinoma (HCC) is the most frequently diagnosed primary liver tumor worldwide. Tumor-associated macrophages (TAMs) usually have a similar phenotype to M2-like macrophages and can participate in tumor progression by secreting cytokines to suppress the immune response of tumor-infiltrating lymphocytes. We investigated the role of M2 macrophages in HCC progression and explored the effects of vascular endothelial growth factor receptor 2 inhibitor – apatinib . As a cellular model of HCC, Hepb3 cell line was used. M2 macrophages were obtained by differentiation of THP-1 cells. The Transwell chamber was used to co-culture M2 macrophages and Hepb3 cells. CCK-8 assay and EdU assay were conducted to measure cell viability and proliferation capacity. Transwell migration assay was conducted to estimate cellular metastatic potential. Cytokine expression levels were assessed by ELISA. Western blot was used to quantify the activation of the VEGFR2/STAT3/PD-L1 axis. It has been shown that co-culture with M2 macrophages increased, proliferation, viability, cytokine production, invasion, and migration of Hepb3 cells. The secretion of TGF-β1, IL-6, MMP-9, and VEGF was significantly increased after co-culture. Apatinib suppressed M2 macrophage-induced proliferation, cell viability, invasion, and migration of Hepb3 cells. Moreover, apatinib remarkedly decreased expression levels of p-VEGFR2, p-STAT3, and PD-L1 in Hepb3 cells under the co-culture conditions. In conclusion, apatinib treatment could suppress TAMs-mediated cancer cell behaviors of HCC cells via modulation of the VEGFR2/STAT3/PD-L1 signaling pathway.

Publisher

The Russian Academy of Sciences

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