title: BMPR1B up-regulation via a miRNA binding site variation defines endometriosis susceptibility and CA125 levels.
abstract: BACKGROUND
  Bone morphogenetic protein receptor I B (BMPR1B) is a transmembrane receptor mediating TGF-β signal transduction. Recent studies indicate a tumor suppressor role for BMPR1B in ovarian cancer. Polymorphism at BMPR1B 3'UTR within the miR-125b binding site alters its binding affinity toward the miRNA, which may result in insufficient post-transcriptional repression.
  
  
  METHODS
  Single-nucleotide polymorphisms rs1970801, rs1434536, and rs11097457 near the miR-125b binding site in BMPR1B were genotyped by Taqman assay on 193 endometriosis patients and 202 healthy controls. BMPR1B and CA125 levels in ectopic endometrial tissues were evaluated by quantitative PCR and immunohistochemistry. Luciferase reporter assay was utilized to verify regulatory roles of BMPR1B 3'UTR with allelic variants of rs1434536 in a cell line model. Cell proliferation and migration were recorded, while expression of BMPR1B, CA125, glucocorticoid receptor (GCCR) and IL-1β were measured by quantitative PCR in endometrial cells transfected with wild-type or mutated miR-125b.
  
  
  RESULTS
  This study found two endometriosis-associated SNPs, rs1434536 (P = 0.010) and rs1970801 (P = 0.0087), located within and next to a miR-125b binding site on BMPR1B. Interestingly, patients with homozygous variant alleles at rs1434536 showed significantly lower serum CA125 levels. Immunohistochemistry staining further confirmed inverse correlation between BMPR1B and CA125 levels in three rs1434536 genotypes. Cell assays demonstrated the variant allele of rs1434536 up-regulating BMPR1B at both mRNA and protein levels, which negatively correlated with CA125 and IL-1β levels. Disruption of the binding between miR-125b and BMPR1B hampered abnormal cell proliferation.
  
  
  CONCLUSIONS
  SNPs of BMPR1B within and next to the miR-125b binding site manifested strong correlation with endometriosis development in a Taiwanese cohort. Disrupting the binding of miR-125b toward BMPR1B would increase protein expression, diminishing abnormal cell proliferation as well as serum and cellular CA125 levels. Genetic variation at the miR-125b binding site may play functional roles to protect against endometriosis progression.
authors: Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan ; Department of Public Health, China Medical University, Taichung, Taiwan ; School of Medicine, China Medical University, Taichung, Taiwan.
authors: Cherry Yin-Yi
authors: CY
authors: Chang
authors: Yi
authors: Y
authors: Chen
authors: Ming-Tsung
authors: MT
authors: Lai
authors: Hui-Wen
authors: HW
authors: Chang
authors: Jack
authors: J
authors: Cheng
authors: Carmen
authors: C
authors: Chan
authors: Chih-Mei
authors: CM
authors: Chen
authors: Shan-Chih
authors: SC
authors: Lee
authors: Ying-Ju
authors: YJ
authors: Lin
authors: Lei
authors: L
authors: Wan
authors: Pei-Wen
authors: PW
authors: Tsai
authors: Su-Han
authors: SH
authors: Yang
authors: Ching
authors: C
authors: Chung
authors: Jim Jinn-Chyuan
authors: JJ
authors: Sheu
authors: Fuu-Jen
authors: FJ
authors: Tsai
mesh_terms: D001665:Binding Sites; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics*; D018394:CA-125 Antigen / Q000097:blood / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D004715:Endometriosis / Q000097:blood / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015854:Up-Regulation
chemical_list: D018394:CA-125 Antigen; D053583:Interleukin-1beta; D035683:MicroRNAs; C498214:BMPR1B protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I