title: Dysregulation of miR-212 Promotes Castration Resistance through hnRNPH1-Mediated Regulation of AR and AR-V7: Implications for Racial Disparity of Prostate Cancer.
abstract: OBJECTIVE
  The causes of disproportionate incidence and mortality of prostate cancer among African Americans (AA) remain elusive. The purpose of this study was to investigate the mechanistic role and assess clinical utility of the splicing factor heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1) in prostate cancer progression among AA men.
  
  
  METHODS
  We employed an unbiased functional genomics approach coupled with suppressive subtractive hybridization (SSH) and custom cDNA microarrays to identify differentially expressed genes in microdissected tumors procured from age- and tumor grade-matched AA and Caucasian American (CA) men. Validation analysis was performed in independent cohorts and tissue microarrays. The underlying mechanisms of hnRNPH1 regulation and its impact on androgen receptor (AR) expression and tumor progression were explored.
  
  
  RESULTS
  Aberrant coexpression of AR and hnRNPH1 and downregulation of miR-212 were detected in prostate tumors and correlate with disease progression in AA men compared with CA men. Ectopic expression of miR-212 mimics downregulated hnRNPH1 transcripts, which in turn reduced expression of AR and its splice variant AR-V7 (or AR3) in prostate cancer cells. hnRNPH1 physically interacts with AR and steroid receptor coactivator-3 (SRC-3) and primes activation of androgen-regulated genes in a ligand-dependent and independent manner. siRNA silencing of hnRNPH1 sensitized prostate cancer cells to bicalutamide and inhibited prostate tumorigenesis in vivo
  
  
  CONCLUSIONS
  Our findings define novel roles for hnRNPH1 as a putative oncogene, splicing factor, and an auxiliary AR coregulator. Targeted disruption of the hnRNPH1-AR axis may have therapeutic implications to improve clinical outcomes in patients with advanced prostate cancer, especially among AA men.
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Dingwu
authors.initials: D
authors.lastname: Jia
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Hogyoung
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Zakaria Y
authors.initials: ZY
authors.lastname: Abd Elmageed
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Amrita
authors.initials: A
authors.lastname: Datta
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Rodney
authors.initials: R
authors.lastname: Davis
authors.affiliation: Department of Biostatistics, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana.
authors.forename: Sudesh
authors.initials: S
authors.lastname: Srivastav
authors.affiliation: Department of Pathology, Tulane University School of Medicine, New Orleans, Louisiana. Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Moroz
authors.affiliation: Department of Pathology, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Byron E
authors.initials: BE
authors.lastname: Crawford
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana. Division of Urology, Southeast Louisiana Veterans Health Care System, New Orleans, Louisiana.
authors.forename: Krishnarao
authors.initials: K
authors.lastname: Moparty
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana. Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Raju
authors.initials: R
authors.lastname: Thomas
authors.affiliation: Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Hudson
authors.affiliation: Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ambs
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana. Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana. Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana. amageed@tulane.edu.
authors.forename: Asim B
authors.initials: AB
authors.lastname: Abdel-Mageed
mesh_terms: D017398:Alternative Splicing; D000728:Androgens / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016000:Cluster Analysis; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009570:Nitriles / Q000494:pharmacology; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements; D014105:Tosyl Compounds / Q000494:pharmacology
chemical_list: D000728:Androgens; D000813:Anilides; D000970:Antineoplastic Agents; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H; C551411:MIRN212 microRNA, human; D035683:MicroRNAs; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide; D056921:Nuclear Receptor Coactivator 3