Macrophage-derived reactive oxygen species suppress miR-328 targeting CD44 in cancer cells and promote redox adaptation

Takatsugu Ishimoto, Hidetaka Sugihara, Masayuki Watanabe, Hiroshi Sawayama, Masaaki Iwatsuki, Yoshifumi Baba, Hirohisa Okabe, Kosei Hidaka, Naomi Yokoyama, Keisuke Miyake, Momoko Yoshikawa, Osamu Nagano, Yoshihiro Komohara, Motohiro Takeya, Hideyuki Saya, Hideo Baba

Research output: Contribution to journalArticlepeer-review

71 Citations (Scopus)


CD44 is frequently overexpressed in a wide variety of epithelial malignancies including gastrointestinal cancer and causes resistance to currently available treatments. MicroRNAs (miRNAs) are non-coding RNAs that regulate molecular pathways in cancer by targeting various genes. The aim of this study was to investigate the regulation of CD44 expression by miRNAs and to develop new molecular targets in gastrointestinal cancer. We performed miRNA screening in six human gastrointestinal cancer cell lines and identified three candidate miRNAs that could regulate CD44 expression in gastrointestinal cancer. Among these, we focused on miR-328 and examined its functional relevance using growth assays and cytotoxicity assays. CD44 expression was reduced in gastrointestinal cancer cell lines forced to express miR-328, leading to inhibition of cancer cell growth in vitro and in vivo, and impaired resistance to chemotherapeutic drugs and reactive oxygen species (ROS). In contrast, induction of CD44 expression by miR-328 inhibitor led to promotion of cancer cell growth. Furthermore, we revealed that ROS produced by macrophages triggered CD44 expression through suppression of miR-328 in gastric cancer cells. Finally, tumor-infiltrating macrophages (CD68 and CD163) were closely related to both miR-328 downregulation and CD44 upregulation in 63 patients with surgically resected gastric cancer. These findings suggest that macrophages in the tumor microenvironment may cause increased CD44 expression through miR-328 suppression, resulting in tumor progression by enhancing ROS defense. miR-328-CD44 signaling mediated by macrophages may thus represent a potential target for the treatment of gastrointestinal cancer.

Original languageEnglish
Pages (from-to)1003-1011
Number of pages9
Issue number5
Publication statusPublished - 04-2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cancer Research


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