title: MicroRNA-106b-25 cluster expression is associated with early disease recurrence and targets caspase-7 and focal adhesion in human prostate cancer.
abstract: The miR-106b-25 microRNA (miRNA) cluster is a candidate oncogene in human prostate cancer. Here, we report that miRNAs encoded by miR-106b-25 are upregulated in both primary tumors and distant metastasis. Moreover, increased tumor miR-106b expression was associated with disease recurrence and the combination of high miR-106b and low CASP7 (caspase-7) expressions in primary tumors was an independent predictor of early disease recurrence (adjusted hazard ratio=4.1; 95% confidence interval: 1.6-12.3). To identify yet unknown oncogenic functions of miR-106b, we overexpressed it in LNCaP human prostate cancer cells to examine miR-106b-induced global expression changes among protein-coding genes. The approach revealed that CASP7 is a direct target of miR-106b, which was confirmed by western blot analysis and a 3'-untranslated region reporter assay. Moreover, selected phenotypes induced by miR-106b knockdown in DU145 human prostate cancer cells did not develop when both miR-106b and CASP7 expression were inhibited. Further analyses showed that CASP7 is downregulated in primary prostate tumors and metastatic lesions across multiple data sets and is by itself associated with disease recurrence and disease-specific survival. Using bioinformatics, we also observed that miR-106b-25 may specifically influence focal adhesion-related pathways. This observation was experimentally examined using miR-106b-25-transduced 22Rv1 human prostate cancer cells. After infection with a miR-106b-25 lentiviral expression construct, 22Rv1 cells showed increased adhesion to basement membrane- and bone matrix-related filaments and enhanced soft agar growth. In summary, miR-106b-25 was found to be associated with prostate cancer progression and disease outcome and may do so by altering apoptosis- and focal adhesion-related pathways.
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD 20892-4258, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Hudson
authors.forename: M
authors.initials: M
authors.lastname: Yi
authors.forename: D
authors.initials: D
authors.lastname: Esposito
authors.forename: S A
authors.initials: SA
authors.lastname: Glynn
authors.forename: A M
authors.initials: AM
authors.lastname: Starks
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: A J
authors.initials: AJ
authors.lastname: Schetter
authors.forename: S K
authors.initials: SK
authors.lastname: Watkins
authors.forename: A A
authors.initials: AA
authors.lastname: Hurwitz
authors.forename: T H
authors.initials: TH
authors.lastname: Dorsey
authors.forename: R M
authors.initials: RM
authors.lastname: Stephens
authors.forename: C M
authors.initials: CM
authors.lastname: Croce
authors.forename: S
authors.initials: S
authors.lastname: Ambs
mesh_terms: D020413:3' Untranslated Regions; D053179:Caspase 7 / Q000235:genetics*; D045744:Cell Line, Tumor; D005109:Extracellular Matrix / Q000378:metabolism; D022001:Focal Adhesions; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000209:etiology*; D011471:Prostatic Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology
chemical_list: D020413:3' Untranslated Regions; C542541:MIRN106 microRNA, human; C568529:MIRN32 microRNA, human; D035683:MicroRNAs; C505520:CASP7 protein, human; D053179:Caspase 7