title: MiR-221 promotes the development of androgen independence in prostate cancer cells via downregulation of HECTD2 and RAB1A.
abstract: Hormone-sensitive prostate cancer typically progresses to castration resistant prostate cancer (CRPC) after the androgen deprivation therapy. We investigated the impact of microRNAs (miRs) in the transition of prostate cancer to CRPC. MiR-221/-222 was highly expressed in bone metastatic CRPC tumor specimens. We previously demonstrated that transient overexpression of miR-221/-222 in LNCaP promoted the development of the CRPC phenotype. In current study, we show that stably overexpressing miR-221 confers androgen independent (AI) cell growth in LNCaP by rescuing LNCaP cells from growth arrest at G1 phase due to the lack of androgen. Overexpressing of miR-221 in LNCaP reduced the transcription of a subgroup of androgen-responsive genes without affecting the androgen receptor (AR) or AR-androgen integrity. By performing systematic biochemical and bioinformatical analyses, we identified two miR-221 targets, HECTD2 and RAB1A, which could mediate the development of CRPC phenotype in multiple prostate cancer cell lines. Downregulation of HECTD2 significantly affected the androgen-induced and AR-mediated transcription, and downregulation of HECTD2 or RAB1A enhances AI cell growth. As a result of the elevated expression of miR-221, expression of many cell cycle genes was altered and pathways promoting epithelial to mesenchymal transition/tumor metastasis were activated. We hypothesize that a major biological consequence of upregulation of miR-221 is reprogramming of AR signaling, which in turn may mediate the transition to the CRPC phenotype.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA [2] Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: H H
authors.initials: HH
authors.lastname: He
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Sweeney
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: S X
authors.initials: SX
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Brown
authors.affiliation: Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Balk
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: G-Sm
authors.initials: GS
authors.lastname: Lee
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: P W
authors.initials: PW
authors.lastname: Kantoff
mesh_terms: D000728:Androgens / Q000494:pharmacology; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D010641:Phenotype; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D020761:rab1 GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000728:Androgens; D035683:MicroRNAs; D011944:Receptors, Androgen; D044767:Ubiquitin-Protein Ligases; D020761:rab1 GTP-Binding Proteins; C525709:MIR221, human; C544073:HECTD2 protein, human