Tumor-associated macrophages promote epigenetic silencing of gelsolin through DNA methyltransferase 1 in gastric cancer cells

Hao Chen Wang, Chin Wang Chen, Chia Lung Yang, I. Min Tsai, Ya Chin Hou, Chang Jung Chen, Yan Shen Shan

研究成果: Article同行評審

29 引文 斯高帕斯(Scopus)

摘要

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 GSN 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 GSN 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 in vitro 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 in vivo. In conclusion, upregulation of DNMT1 by CCL5/CCR5/STAT3 signaling is critical for TAM-mediated GSN silencing in gastric cancer. This study identified potential targets for gastric cancer therapy.

原文English
頁(從 - 到)885-897
頁數13
期刊Cancer Immunology Research
5
發行號10
DOIs
出版狀態Published - 2017 十月

All Science Journal Classification (ASJC) codes

  • 免疫學
  • 癌症研究

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