Tumor-Associated Macrophages Promote Epigenetic Silencing of Gelsolin through DNA Methyltransferase 1 in Gastric Cancer Cells

Abstract

Epigenetic repression of the tumor suppressor gelsolin (GSN) is frequently observed in cancers. Chronic inflammation can promote tumor progression via aberrant DNA methylation. In this study, we investigated the role of tumor-associated macrophages (TAMs) in DNA methylation of the <i>GSN</i> gene during gastric cancer progression. Immunofluorescence staining of 121 gastric cancer tissues showed aberrant localization of GSN and DNA methyltransferase 1 (DNMT1) and juxtaposition of DNMT1 and M2 TAMs. Decreased GSN protein and mRNA expression and increased DNA methylation in the <i>GSN</i> promoter were observed in gastric cancer cell lines and clinical specimens. To examine the effect of TAMs on DNA methylation in gastric cancer cells, we performed <i>in vitro</i> coculture assays and found increased DNMT1 expression but decreased GSN expression in gastric cancer cells after coculture with U937 cells. Knockdown of DNMT1 expression in gastric cancer cells could abort U937 coculture-mediated GSN downregulation. Meanwhile, CCL5 was the main chemokine upregulated in coculture medium. Treatment with CCL5 could induce DNMT1 expression in gastric cancer cells via STAT3 signaling. Inhibiting DNMT1 activity with procainamide, inhibiting DNA methylation with 5-AZA, or inhibiting CCL5/CCR5 signaling with maraviroc reduced tumor growth <i>in vivo</i> In conclusion, upregulation of DNMT1 by CCL5/CCR5/STAT3 signaling is critical for TAM-mediated <i>GSN</i> silencing in gastric cancer. This study identified potential targets for gastric cancer therapy. <i>Cancer Immunol Res; 5(10); 885-97. ©2017 AACR</i>.