title: Macrophage-derived reactive oxygen species suppress miR-328 targeting CD44 in cancer cells and promote redox adaptation.
abstract: 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.
authors: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors: Takatsugu
authors: T
authors: Ishimoto
authors: Hidetaka
authors: H
authors: Sugihara
authors: Masayuki
authors: M
authors: Watanabe
authors: Hiroshi
authors: H
authors: Sawayama
authors: Masaaki
authors: M
authors: Iwatsuki
authors: Yoshifumi
authors: Y
authors: Baba
authors: Hirohisa
authors: H
authors: Okabe
authors: Kosei
authors: K
authors: Hidaka
authors: Naomi
authors: N
authors: Yokoyama
authors: Keisuke
authors: K
authors: Miyake
authors: Momoko
authors: M
authors: Yoshikawa
authors: Osamu
authors: O
authors: Nagano
authors: Yoshihiro
authors: Y
authors: Komohara
authors: Motohiro
authors: M
authors: Takeya
authors: Hideyuki
authors: H
authors: Saya
authors: Hideo
authors: H
authors: Baba
mesh_terms: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D018960:Hyaluronan Receptors; C548170:MIRN328 microRNA, human; D035683:MicroRNAs; D017382:Reactive Oxygen Species