title: A dosage-dependent pleiotropic role of Dicer in prostate cancer growth and metastasis.
abstract: Dicer is an RNase III enzyme essential for the maturation of the majority of microRNAs. Recent studies have revealed downregulation or hemizygous loss of Dicer in many tumor models and demonstrated that suppressing Dicer activity enhances tumorigenic activities of lung and breast cancer cells, which support Dicer as a haploinsufficient tumor suppressor in these cancer models. Surprisingly, we found that knocking down Dicer expression suppresses the growth and tumorigenic capacity of human prostate cancer cell lines, but enhances migratory capacities of some prostate cancer cell lines. Dicer is upregulated in human prostate cancer specimens, but lower Dicer expression portends a shorter time to recurrence. Complete ablation of Dicer activity in a Pten null mouse model for prostate cancer significantly halts tumor growth and progression, demonstrating that microRNAs have a critical role in maintaining cancer cell fitness. In comparison, hemizygous loss of Dicer in the same model also reduces primary tumor burden, but induces a more locally invasive phenotype and causes seminal vesicle obstruction at high penetrance. Disrupting Dicer activity leads to an increase in apoptosis and senescence in these models, presumably through upregulation of P16/INK4a and P27/Kip1. Collectively, these results highlight a pleotropic role of Dicer in tumorigenesis that is not only dosage-dependent but also tissue context-dependent.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: O
authors.initials: O
authors.lastname: Dakhova
authors.affiliation: Dan L. Duncan Cancer Center, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA [2] Dan L. Duncan Cancer Center, Houston, TX, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Lewis
authors.affiliation: Dan L. Duncan Cancer Center, Houston, TX, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: 1] Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA [2] Dan L. Duncan Cancer Center, Houston, TX, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Ittmann
authors.affiliation: 1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA [2] Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA [3] Dan L. Duncan Cancer Center, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Xin
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D016922:Cellular Senescence; D053487:DEAD-box RNA Helicases / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D053487:DEAD-box RNA Helicases