title: The onset of human ectopic pregnancy demonstrates a differential expression of miRNAs and their cognate targets in the Fallopian tube.
abstract: Human ectopic pregnancy (EP) is a leading cause of pregnancy-related death, but the molecular basis underlying the onset of tubal EP is largely unknown. Female Dicer1 conditional knockout mice are infertile with dysfunctional Fallopian tube and have a different miRNA expression profile compared to wild-type mice, and we speculated that Dicer-mediated regulation of miRNA expression and specific miRNA-controlled targets might contribute to the onset of tubal EP. In the present study, we used microarray analysis and quantitative RT-PCR to examine the expression of miRNAs and core miRNA regulatory components in Fallopian tube tissues from women with EP. We found that the levels of DICER1, four miRNAs (let-7i, miR-149, miR-182, and miR-424), and estrogen receptor α distinguished the tubal implantation site from the non-implantation site. Computational algorithms and screening for interactions with the estrogen and progesterone receptor signaling pathways showed that the four miRNAs were predicted to target ten genes, including NEDD4, TAF15, and SPEN. Subsequent experiments showed differences in NEDD4 mRNA and protein levels between the implantation and non-implantation sites. Finally, we revealed that increases in smooth muscle cell NEDD4 and stromal cell TAF15, in parallel with a decrease in epithelial cell SPEN, were associated with tubal implantation. Our study suggests that changes in miRNA levels by the DICER-mediated miRNA-processing machinery result in aberrant expression of cell type-specific proteins that are potentially involved in the onset of tubal EP.
authors.affiliation: Department of Integrative Medicine and Neurobiology, State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University Shanghai 200032, China ; Institute of Acupuncture Research (WHO Collaborating Center for Traditional Medicine), Fudan University Shanghai 200032, China ; Institutes of Brain Science, Fudan University Shanghai 200032, China ; Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg Gothenburg 40530, Sweden.
authors.forename: Yi
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University Shanghai 200011, China.
authors.forename: Shien
authors.initials: S
authors.lastname: Zou
authors.affiliation: Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg Gothenburg 40530, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Weijdegård
authors.affiliation: Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University Shanghai 200011, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University Shanghai 200011, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Cong
authors.affiliation: Centre for Cellular Imaging, Core Facilities, The Sahlgrenska Academy at University of Gothenburg 40530 Gothenburg, Sweden.
authors.forename: Julia
authors.initials: J
authors.lastname: Fernandez-Rodriguez
authors.affiliation: Institutes of Biomedical Sciences at Fudan University Shanghai 200032, China ; Bio-X Center, Key Laboratory for The Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University Shanghai 200032, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg Gothenburg 40530, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Billig
authors.affiliation: Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg Gothenburg 40530, Sweden.
authors.forename: Ruijin
authors.initials: R
authors.lastname: Shao
mesh_terms: D000328:Adult; D015153:Blotting, Western; D053487:DEAD-box RNA Helicases; D005187:Fallopian Tubes / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D011274:Pregnancy, Tubal / Q000235:genetics* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D043244:Ribonuclease III; D059467:Transcriptome
chemical_list: D035683:MicroRNAs; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: Dicer; infertility; microRNAs; target genes; tubal ectopic pregnancy