SIRT1 inhibits hepatocellular carcinoma metastasis by promoting M1 macrophage polarization via NF-κB pathway

Abstract

Background: Tumor-associated macrophages (TAMs) serve as crucial modulators of the complicated interaction between cancer cells and immune microenvironment. Sirtuin 1 (SIRT1) has an impact on immune reactions in cancer progression. Current knowledge of the role of SIRT1 in the regulation of M1-like macrophages as well as in hepatocellular carcinoma (HCC) is insufficient. Methods: SIRT1 expression in HCC tissues was detected using quantitative reverse transcriptase PCR (qRT-PCR) and Western blot. M1 markers were detected by qRT-PCR and flow cytometry assay. Moreover, the influence of SIRT1 on HCC cell apoptosis, migration, and invasion was studied using transwell assay, flow cytometry assay, and TUNEL assays, respectively. Results: In this study, it was revealed that SIRT1 was upregulated in patients suffering from HCC; these patients were also shown to have elevated levels of M1-like TAM infiltration. SIRT1 was able to reinforce M1-like macrophage infiltration and inhibit HCC metastasis. Furthermore, SIRT1 enhanced NF-κB stimulation, promoting phosphorylation of p65, IκB, and IκB kinase. It was further demonstrated in our study that SIRT1 had an impact on polarization of M1 through the NF-κB pathway. NF-κB repression downregulated M1 markers in macrophages, which excessively expressed SIRT1 and counteracted the influence of SIRT1 on migration of HCC cells. Conclusion: Taken together, these results offer proof that SIRT1 is an essential regulator of the immune reaction that counteracts malignant HCC cell migration as well as growth, indicating that macrophage SIRT1 could serve as an innovative target to treat HCC.