title: Quercetin Decreases Claudin-2 Expression Mediated by Up-Regulation of microRNA miR-16 in Lung Adenocarcinoma A549 Cells.
abstract: Claudin-2 is highly expressed in human lung adenocarcinoma tissues and cells. Knockdown of claudin-2 decreases cell proliferation and migration. Claudin-2 may be a novel target for lung adenocarcinoma. However, there are no physiologically active substances of foods which decrease claudin-2 expression. We here found that quercetin, a flavonoid present in fruits and vegetables, time- and concentration-dependently decreases claudin-2 expression in lung adenocarcinoma A549 cells. In the present study, we examined what regulatory mechanism is involved in the decrease in claudin-2 expression by quercetin. Claudin-2 expression was decreased by LY-294002, a phosphatidylinositol 3-kinase (PI3-K) inhibitor, and U0126, a MEK inhibitor. These drugs inhibited the phosphorylation of Akt and ERK1/2, which are downstream targets of PI3-K and MEK, respectively. In contrast, quercetin did not inhibit the phosphorylation. Both LY-294002 and U0126 inhibited promoter activity of claudin-2, but quercetin did not. The stability of claudin-2 mRNA was decreased by quercetin. Quercetin increased the expression of microRNA miR-16. An inhibitor of miR-16 rescued quercetin-induced decrease in the claudin-2 expression. These results suggest that quercetin decreases claudin-2 expression mediated by up-regulation of miR-16 expression and instability of claudin-2 mRNA in lung adenocarcinoma cells.
authors.affiliation: Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan. 116023@gifu-pu.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sonoki
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan. final-detective-l@ezweb.ne.jp.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Sato
authors.affiliation: Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan. sendo@gifu-pu.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.affiliation: Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan. matsunagat@gifu-pu.ac.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsunaga
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan. masahiko-y@u-shizuoka-ken.ac.jp.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Yamaguchi
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan. y-yamaza@u-shizuoka-ken.ac.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan. sugatani@u-shizuoka-ken.ac.jp.
authors.forename: Junko
authors.initials: J
authors.lastname: Sugatani
authors.affiliation: Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan. ikari@gifu-pu.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Ikari
mesh_terms: D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002867:Chromones / Q000494:pharmacology; D057167:Claudins / Q000235:genetics / Q000378:metabolism*; D005638:Fruit; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011794:Quercetin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014675:Vegetables
chemical_list: D002070:Butadienes; D002867:Chromones; D057167:Claudins; D035683:MicroRNAs; D009025:Morpholines; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011794:Quercetin; D012333:RNA, Messenger; C491875:CLDN2 protein, human; C505362:MIRN16 microRNA, human; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
keywords: claudin-2; lung adenocarcinoma; miR-16; quercetin