title: The oncogenic roles of DICER1 RNase IIIb domain mutations in ovarian Sertoli-Leydig cell tumors.
abstract: DICER1, an endoribonuclease required for microRNA (miRNA) biogenesis, is essential for embryogenesis and the development of many organs including ovaries. We have recently identified somatic hotspot mutations in RNase IIIb domain of DICER1 in half of ovarian Sertoli-Leydig cell tumors, a rare class of sex-cord stromal cell tumors in young women. These hotspot mutations lost IIIb cleavage activity of DICER1 in vitro and failed to produce 5p-derived miRNAs in mouse Dicer1-null ES cells. However, the oncogenic potential of these hotspot DICER1 mutations has not been studied. Here, we further revealed that the global expression of 5p-derived miRNAs was dramatically reduced in ovarian Sertoli-Leydig cell tumors carrying DICER1 hotspot mutations compared with those without DICER1 hotspot mutation. The miRNA production defect was associated with the deregulation of genes controlling cell proliferation and the cell fate. Using an immortalized human granulosa cell line, SVOG3e, we determined that the D1709N-DICER1 hotspot mutation failed to produce 5p-derived miRNAs, deregulated the expression of several genes that control gonadal differentiation and cell proliferation, and promoted cell growth. Re-expression of let-7 significantly inhibited the growth of D1709N-DICER1 SVOG3e cells, accompanied by the suppression of key regulators of cell cycle control and ovarian gonad differentiation. Taken together, our data revealed that DICER1 hotspot mutations cause systemic loss of 5p-miRNAs that can both drive pseudodifferentiation of testicular elements and cause oncogenic transformation in the ovary.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada; Department of Molecular Oncology, British Columbia Cancer Agency Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: Yemin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jiamin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Agency Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: Winnie
authors.initials: W
authors.lastname: Yang
authors.affiliation: Vancouver Prostate Cancer Centre, Vancouver, BC, Canada.
authors.forename: Fan
authors.initials: F
authors.lastname: Mo
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Agency Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: Janine
authors.initials: J
authors.lastname: Senz
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Molecular Oncology, British Columbia Cancer Agency Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: Damian
authors.initials: D
authors.lastname: Yap
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada; Department of Molecular Oncology, British Columbia Cancer Agency Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Anglesio
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Blake
authors.initials: B
authors.lastname: Gilks
authors.affiliation: Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. Electronic address: gmorin@bcgsc.ca.
authors.forename: Gregg B
authors.initials: GB
authors.lastname: Morin
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada; Department of Molecular Oncology, British Columbia Cancer Agency Cancer Research Centre, Vancouver, BC, Canada. Electronic address: dhuntsman@bccancer.bc.ca.
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
mesh_terms: D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006107:Granulosa Cells / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000235:genetics* / Q000378:metabolism; D018310:Sertoli-Leydig Cell Tumor / Q000235:genetics* / Q000378:metabolism
chemical_list: D035683:MicroRNAs; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases