BMPR1B Up-Regulation via a miRNA Binding Site Variation Defines Endometriosis Susceptibility and CA125 Levels

Abstract

BackgroundBone 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.MethodsSingle-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.ResultsThis 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.ConclusionsSNPs 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.

Evaluation the susceptibility of five polymorphisms in microRNA-binding sites to female breast cancer risk in Chinese population

“…These three SNPs were reported in strong linkage disequilibrium (Saetrom et al, 2009), which were also observed in the present study (rs1434536-rs11097457: r 2 = 0.875; rs1434536-rs1970801: r 2 = 0.860; rs1970801-rs11097457: r 2 = 0.986) and another study based on Chinese population (Chang et al, 2013). Two functional studies revealed rs1434536 T allele disrupts miR-125b recognition of BMPR1B 3′UTR (Saetrom et al, 2009;Chang et al, 2013), leading to higher expression of BMPR1B. Rs1434536 TT and rs1970801 TT were reported to be associated with increased risk of breast cancer in most population from Caucasian ancestry (Saetrom et al, 2009).…”

“…However, in present study, the significant association was failed to obtain from Chinese population, which may be due to the genotype distribution of the two different ethnicities (results from Saetrom et al, 2009: T allele was 55.51% in controls and 53.1% in HapMap; this study: T allele was 38.15% in controls and 40.60% in HapMap). Moreover, the frequency of T allele was similar to that in another study in Chinese population with 38.83% T allele in 197 health controls (Chang et al, 2013). Although, it has been concluded that rs1434536 disrupts the regulation of miR-125b to BMPR1B expression, which leads to poor prognosis accompanying ER higher expression (Smith et al, 2008), in this study, the results of the subgroup analysis based ER expression shows no significant association of rs1434536 to breast cancer risk for ER(+) or ER(−) subgroup, which is inconsistent to the results of previous studies.…”

“…Previous studies (Saetrom et al, 2009;Chang et al, 2013) and this study have revealed that rs1970801 T allele was strong in linkage disequilibrium with rs1434536T allele, which was discussed to be associated with lower level of cancer antigen 125 (CA125) (Chang et al, 2013), and was regarded as a biomarker of breast cancer. In this study, sub-group analysis by first menstruation age (≤14/ N14) revealed that, in the sub-group of first menstruation age N14 years old, rs1970801 T allele (genotype TT/GT) carriers have lower breast cancer risk than those with GG genotype.…”

Up-regulation of ribosome biogenesis by MIR196A2 genetic variation promotes endometriosis development and progression

“…Microarray and functional studies revealed that miRNA levels are related to benign conditions, malignant diseases and fertility disorders of the female reproductive tract alike [15–18]. While no link has yet been established between miRNA gene polymorphisms and endometriosis, such polymorphisms might be crucial epigenetic factors influencing endometriosis susceptibility [8, 9, 19]. In this study, we identified an endometriosis-related SNP in MIR196A2 and demonstrated its novel function in regulating the expression of several small nucleolar RNAs (snoRNAs) and ribosomal proteins (RPs).…”

MicroRNA variants as genetic determinants of bone mass

“…A second study demonstrated a similar mechanism for the rs1434536-T variant and higher prostate cancer risk [117]. Remarkably, the rs1434536-T allele was shown to impart BMPR-IB mediated protection against endometriosis, due to diminished miR-125b directed repression [118]. SNP rs1434536-T is a common variant, and increased BMPRI-B levels in individuals carrying this allele might contribute to higher bone mass.…”