title: The microRNA-23b/-27b cluster suppresses prostate cancer metastasis via Huntingtin-interacting protein 1-related.
abstract: Deregulation of microRNAs (miRs) contributes to progression and metastasis of prostate and other cancers. miR-23b and -27b, encoded in the same miR cluster (miR-23b/-27b), are downregulated in human metastatic prostate cancer compared with primary tumors and benign tissue. Expression of miR-23b/-27b decreases prostate cancer cell migration, invasion and results in anoikis resistance. Conversely, antagomiR-mediated miR-23b and -27b silencing produces the opposite result in a more indolent prostate cancer cell line. However, neither miR-23b/-27b expression or inhibition impacts prostate cancer cell proliferation suggesting that miR-23b/-27b selectively suppresses metastasis. To examine the effects of miR-23b/-27b on prostate cancer metastasis in vivo, orthotopic prostate xenografts were established using aggressive prostate cancer cells transduced with miR-23b/-27b or non-targeting control miRNA. Although primary tumor formation was similar between miR-23b/-27b-transduced cells and controls, miR-23b/-27b expression in prostate cancer cells decreased seminal vesicle invasion and distant metastases. Gene-expression profiling identified the endocytic adaptor, Huntingtin-interacting protein 1-related (HIP1R) as being downregulated by miR-23b/-27b. Increased HIP1R expression in prostate cancer cells inversely phenocopied the effects of miR-23b/-27b overexpression on migration, invasion and anchorage-independent growth. HIP1R rescued miR-23b/-27b-mediated repression of migration in prostate cancer cells. HIP1R mRNA levels were decreased in seminal vesicle tissue from mice bearing miR-23b/-27b-transduced prostate cancer cell xenografts compared with scrambled controls, suggesting HIP1R is a key functional target of miR-23b/-27b. In addition, depletion of HIP1R led to a more rounded, less mesenchymal-like cell morphology, consistent with decreased metastatic properties. Together, these data demonstrate that the miR-23b/-27b cluster functions as a metastasis-suppressor by decreasing HIP1R levels in pre-clinical models of prostate cancer.
authors.affiliation: Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Rice
authors.affiliation: Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Ishteiwy
authors.affiliation: Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: F
authors.initials: F
authors.lastname: Magani
authors.affiliation: Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Udayakumar
authors.affiliation: Department of Medicine, Division of Geriatrics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Reiner
authors.affiliation: Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Yates
authors.affiliation: Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: P
authors.initials: P
authors.lastname: Miller
authors.affiliation: Department of Medicine, Division of Geriatrics, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: C
authors.initials: C
authors.lastname: Perez-Stable
authors.affiliation: Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: P
authors.identifier: 0000-0001-7822-7553
authors.initials: P
authors.lastname: Rai
authors.affiliation: Department of Medicine, Division of Geriatrics, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: R
authors.initials: R
authors.lastname: Verdun
authors.affiliation: John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA.|John P Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Dykxhoorn
authors.affiliation: Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Burnstein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008840:Microfilament Proteins; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D033921:Vesicular Transport Proteins / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C489537:HIP1R protein, human; C552430:MIRN23a microRNA, human; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D008840:Microfilament Proteins; D033921:Vesicular Transport Proteins