title: miRNA-708 control of CD44(+) prostate cancer-initiating cells.
abstract: Tumor recurrence in prostate cancer has been attributed to the presence of CD44-expressing tumor-initiating cells. In this study, we report that miR-708 is a key negative regulator of this CD44(+) subpopulation of prostate cancer cells, with important implications for diagnosis and prognosis of this disease. miR-708 was underexpressed in CD44(+) cells from prostate cancer xenografts. Reconstitution of miR-708 in prostate cancer cell lines or CD44(+) prostate cancer cells led to decreased tumorigenicity in vitro. Intratumoral delivery of synthetic miR-708 oligonucleotides triggered regression of established tumors in a murine xenograft model of human prostate cancer. Conversely, miR-708 silencing in a purified CD44(-) population of prostate cancer cells promoted tumor growth. Functional studies validated CD44 to be a direct target of miR-708 and also identified the serine/threonine kinase AKT2 as an additional target. Clinically, low miR-708 expression was associated significantly with poor survival outcome, tumor progression, and recurrence in patients with prostate cancer. Together, our findings suggest that reduced miR-708 expression leads to prostate cancer initiation, progression, and development by regulating the expression of CD44 as well as AKT2. miR-708 therefore may represent a novel therapeutic target or diagnostic and prognostic biomarker in prostate cancer.
authors.affiliation: Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, California 94121, USA.
authors.forename: Sharanjot
authors.initials: S
authors.lastname: Saini
authors.forename: Shahana
authors.initials: S
authors.lastname: Majid
authors.forename: Varahram
authors.initials: V
authors.lastname: Shahryari
authors.forename: Sumit
authors.initials: S
authors.lastname: Arora
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yamamura
authors.forename: Inik
authors.initials: I
authors.lastname: Chang
authors.forename: Mohd Saif
authors.initials: MS
authors.lastname: Zaman
authors.forename: Guoren
authors.initials: G
authors.lastname: Deng
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D018450:Disease Progression; D005786:Gene Expression Regulation; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000502:physiology*; D009361:Neoplasm Invasiveness / Q000235:genetics; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012008:Recurrence; D014183:Transplantation, Heterologous
chemical_list: D014408:Biomarkers, Tumor; D018960:Hyaluronan Receptors; C568528:MIRN708 microRNA, human; D035683:MicroRNAs; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt