Reduced dermatopontin expression is a molecular link between uterine leiomyomas and keloids.
Uterine leiomyomas are prevalent estrogen-responsive clonal tumors, but the specific genetic alterations that contribute to their development have not been elucidated. To identify genes involved in the formation of leiomyomas, we used global expression profiling to compare clonal tumors with normal myometrium. Contrary to expectation, genes involved in estrogen action were not differentially expressed between leiomyoma and normal myometrium. Genes encoding extracellular-matrix proteins were prominently featured, suggesting their involvement in formation of a myofibroblast phenotype. Analysis of the extracellular matrix in the leiomyomas revealed a disordered collagen fibril orientation. Expression of the collagen-binding protein dermatopontin was found to be consistently decreased in leiomyoma by both reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time RT-PCR (mean underexpression = 9.41-fold) regardless of leiomyoma size, leiomyoma location, patient race, and patient age. This expression pattern was observed in 11 subjects and a total of 23 leiomyoma:myometrium pairs. Decreased expression of dermatopontin was also associated with keloid formation, a fibrotic disease that shares epidemiologic similarities with leiomyoma. Immunohistochemical studies of leiomyomas and keloids demonstrated reduced levels of dermatopontin in both tissues. In addition, ultrastructural analysis revealed that the orientation of the collagen fibrils in the keloid tissues strongly resembled that in the leiomyomas. Reduction in dermatopontin was associated with an increase in transforming growth factor-beta3 (TGFB3) mRNA levels in leiomyomas, whereas other genes involved in dermatopontin signaling were not differentially expressed. These findings suggest that leiomyoma development involves a myofibroblast cell phenotype characterized by dysregulation of genes encoding extracellular-matrix proteins. In particular, decreased expression of dermatopontin represents a molecular link between the leiomyoma and keloid phenotypes.
Catherino
William H
WH
Pediatric and Reproductive Endocrinology Branch, National Institutes of Health, Bethesda, Maryland 20892-1583, USA.
Leppert
Phyllis C
PC
Stenmark
Matthew H
MH
Payson
Mark
M
Potlog-Nahari
Clariss
C
Nieman
Lynnette K
LK
Segars
James H
JH
D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D011508:Chondroitin Sulfate Proteoglycans; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D052138:Genes, Neoplasm / Q000235:genetics; D006728:Hormones / Q000235:genetics; D006801:Humans; D007627:Keloid / Q000235:genetics* / Q000473:pathology; D007889:Leiomyoma / Q000235:genetics* / Q000473:pathology / Q000648:ultrastructure; D008854:Microscopy, Electron; D008875:Middle Aged; D008957:Models, Genetic; D009215:Myometrium / Q000473:pathology / Q000648:ultrastructure; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012313:RNA / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014594:Uterine Neoplasms / Q000235:genetics* / Q000473:pathology / Q000648:ultrastructure
D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D011508:Chondroitin Sulfate Proteoglycans; C082019:DPT protein, human; D016326:Extracellular Matrix Proteins; D006728:Hormones; D012334:RNA, Neoplasm; D012313:RNA