title: MicroRNA-205 inhibits Src-mediated oncogenic pathways in renal cancer.
abstract: The Src family of protein kinases (SFK) plays key roles in regulating fundamental cellular processes, including cell growth, differentiation, cell shape, migration, and survival, and specialized cell signals in various malignancies. The pleiotropic functions of SFKs in cancer make them promising targets for intervention. Here, we sought to investigate the role of microRNA-205 (miR-205) in inhibition of Src-mediated oncogenic pathways in renal cancer. We report that expression of miR-205 was significantly suppressed in renal cancer cell lines and tumors when compared with normal tissues and a nonmalignant cell line and is correlated inversely with the expression of SFKs. miR-205 significantly suppressed the luciferase activity of reporter plasmids containing the 3'-UTR (untranslated region) sequences complementary to either Src, Lyn, or Yes, which was abolished by mutations in these 3'-UTR regions. Overexpression of miR-205 in A498 cells reduced Src, Lyn, and Yes expression, both at mRNA and protein levels. Proliferation of renal cancer cells was suppressed by miR-205, mediated by the phospho-Src-regulated ERK1/2 pathway. Cell motility factor FAK (focal adhesion kinase) and STAT3 activation were also inhibited by miR-205. Transient and stable overexpression of miR-205 in A498 cells resulted in induction of G₀/G₁ cell-cycle arrest and apoptosis, as indicated by decreased levels of cyclin D1 and c-Myc, suppressed cell proliferation, colony formation, migration, and invasion in renal cancer cells. miR-205 also inhibited tumor cell growth in vivo. This is the first study showing that miR-205 inhibits proto-oncogenic SFKs, indicating a therapeutic potential of miR-205 in the treatment of renal cancer.
authors.affiliation: Department of Urology, VA Medical Center and University of California San Francisco, USA.
authors.forename: Shahana
authors.initials: S
authors.lastname: Majid
authors.forename: Sharanjot
authors.initials: S
authors.lastname: Saini
authors.forename: Altaf A
authors.initials: AA
authors.lastname: Dar
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirata
authors.forename: Varahram
authors.initials: V
authors.lastname: Shahryari
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yamamura
authors.forename: Koji
authors.initials: K
authors.lastname: Ueno
authors.forename: Mohd Saif
authors.initials: MS
authors.lastname: Zaman
authors.forename: Kamaldeep
authors.initials: K
authors.lastname: Singh
authors.forename: Inik
authors.initials: I
authors.lastname: Chang
authors.forename: Guoren
authors.initials: G
authors.lastname: Deng
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
mesh_terms: D017209:Apoptosis / Q000502:physiology; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D015536:Down-Regulation; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051575:Proto-Oncogene Proteins c-yes / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051575:Proto-Oncogene Proteins c-yes; D034741:RNA, Small Interfering; D048490:raf Kinases; D018631:ras Proteins; D019061:src-Family Kinases; C534425:MIR205, human; C489834:YES1 protein, human; C060902:lyn protein-tyrosine kinase