Inverse correlation of secreted frizzled-related protein 4 and beta-catenin expression in endometrial stromal sarcomas.
Endometrial stromal sarcomas are rare uterine tumours. Whereas the histology and immunohistochemistry of these tumours are well documented, almost nothing is known about the molecular mechanisms involved in their pathogenesis. To characterize the genes altered in these malignancies, a genome-wide cDNA library was generated by suppression subtractive hybridization and a set of differentially expressed clones was isolated. These were then used to produce custom-spotted cDNA arrays. Genes deregulated in endometrial stromal sarcomas were identified by cDNA array hybridization and were confirmed by quantitative real-time PCR analyses and in situ hybridization. Following cDNA array analysis, more than 300 genes deregulated in endometrial stromal sarcoma were selected and sequenced. Among the most significantly deregulated genes were those of secreted frizzled-related proteins (SFRPs), in particular secreted frizzled-related protein 4 (SFRP4). SFRPs are putative modulators of the Wnt-signalling pathway and play a role in different cellular events including cell proliferation. Compared with normal endometrium, the expression of SFRP4 was decreased in both low-grade endometrial stromal sarcoma (ESS; n = 10) and undifferentiated endometrial sarcoma (UES; n = 4), being lower in the latter more aggressive form. These results were verified on paraffin wax-embedded tissue by quantitative real-time PCR analysis and in situ hybridization. Furthermore, the expression of beta-catenin, an important component of the Wnt-signalling pathway, was regulated in an opposite manner to SFRP4, being particularly increased in undifferentiated sarcomas. The activation of the Wnt-signalling pathway was additionally supported by the immunohistochemical demonstration that beta-catenin was translocated to the nucleus in UES. SFRP4 may therefore be a putative tumour suppressor involved in deregulation of the Wnt pathway and in the pathogenesis of ESS and UES.
Hrzenjak
Andelko
A
Department of Pathology, Medical University, Graz, Austria. andelko.hrzenjak@klinikum-graz.at
Tippl
Michaela
M
Kremser
Marie-Luise
ML
Strohmeier
Bettina
B
Guelly
Christian
C
Neumeister
Doris
D
Lax
Sigurd
S
Moinfar
Farid
F
Tabrizi
Ali Dastranj
AD
Isadi-Moud
Narges
N
Zatloukal
Kurt
K
Denk
Helmut
H
D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D011506:Proteins; D015534:Trans-Activators; D051176:beta Catenin