title: Curcumin modulates microRNA-203-mediated regulation of the Src-Akt axis in bladder cancer.
abstract: Bladder cancer is often associated with recurrence and progression to invasive metastatic disease that have palliative therapeutic options. The use of traditional chemotherapeutic agents for bladder cancer management often suffers from toxicity and resistance concerns. This emphasizes the need for development of safer, natural, nontoxic compounds as chemotherapeutic/chemopreventive agents. Curcumin (diferuloylmethane) is a natural compound that has been known to possess anticancer properties in various cancers, including bladder cancer. However, the biological targets of curcumin are not well defined. Recently, it has been proposed that curcumin may mediate epigenetic modulation of expression of microRNAs (miRNA). In this article, we define for the first time, that curcumin directly induces a tumor-suppressive miRNA, miR-203, in bladder cancer. miR-203 is frequently downregulated in bladder cancer due to DNA hypermethylation of its promoter. We studied the functional significance of miR-203 in bladder cancer cell lines and found that miR-203 has tumor suppressive properties. Also, we define Akt2 and Src as novel miR-203 targets in bladder cancer. Curcumin induces hypomethylation of the miR-203 promoter and subsequent upregulation of miR-203 expression. This leads to downregulation of miR-203 target genes Akt2 and Src that culminates in decreased proliferation and increased apoptosis of bladder cancer cells. This is the first report that shows a direct effect of curcumin on inducing epigenetic changes at a miRNA promoter with direct biological consequences. Our study suggests that curcumin may offer a therapeutic advantage in the clinical management of refractory bladder cancer over other standard treatment modalities.
authors.affiliation: Department of Urology, Veterans Affairs Medical Center, University of California, San Francisco, USA.
authors.forename: Sharanjot
authors.initials: S
authors.lastname: Saini
authors.forename: Sumit
authors.initials: S
authors.lastname: Arora
authors.forename: Shahana
authors.initials: S
authors.lastname: Majid
authors.forename: Varahram
authors.initials: V
authors.lastname: Shahryari
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Guoren
authors.initials: G
authors.lastname: Deng
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yamamura
authors.forename: Koji
authors.initials: K
authors.lastname: Ueno
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology*; D019175:DNA Methylation / Q000187:drug effects; D057890:Epigenomics; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D019459:Urothelium / Q000378:metabolism / Q000473:pathology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D003474:Curcumin