Differential expression of secreted frizzled-related protein 4 in decidual cells during pregnancy

Abstract

During pregnancy, the uterus shows marked morphological and physiological changes under the regulation of ovarian steroid. To elucidate the molecular cues of these changes, we tried to identify the transcripts differentially expressed in the pregnant rat uterus by using the suppression subtractive hybridization method. Seven independent clones were isolated and one of the up-regulated genes was secreted frizzled-related protein 4 (sFRP4). sFRP4 contains a Wnt-binding domain and belongs to the secreted frizzled protein family whose members are assumed to function as modulators of the Wnt signal. The expression level of sFRP4 mRNA reached a peak in the pregnant uterus on day 12, when uterine decidualization was almost complete in the rat. In situ hybridization histochemistry revealed that sFRP4 transcripts were observed in the decidual cells. In addition, proliferating cell nuclear antigen (PCNA)-positive cells were shown to be overlapped in decidua, suggesting that sFRP4 mRNA expression was accompanied by the late phase of decidual cell proliferation. Moreover, sFRP4 and estrogen receptor-α transcripts were co-localized. Furthermore, we analyzed the regulation of sFRP4 by estrogen using 17β-estradiol-treated ovariectomized rats. sFRP4 mRNA was detected in the uterus at 48 h after estrogen treatment, especially in endometrial stroma where PCNA-positive cells were also observed. The results in this study led us to the notion that sFRP4 mRNA may be up-regulated after estrogen treatment in the late phase of uterine cell proliferation.

Membranous Expression of Secreted Frizzled-Related Protein 4 Predicts for Good Prognosis in Localized Prostate Cancer and Inhibits PC3 Cellular Proliferation in Vitro

“…Similarly, James et al (36) found sFRP4 protein expression in human osteoarthritic articular cartilage coincided with the presence of terminal deoxynucleotidyl transferase-mediated nick end labeling-positive chondrocyte nuclei, suggesting a role for sFRP4 in chondrocyte apoptosis (36). On the other hand, sFRP4 mRNA expression was up-regulated in human endometrial carcinoma compared with normal endometrium (33), and, in the decidual cells of rats, sFRP4 expression correlates with the expression of proliferating cell nuclear antigen (37), suggesting a role in cellular proliferation. Despite abundant evidence for the role of Wnt signaling in development (8 -10), only one study has demonstrated sFRP4 expression in this process, i.e., in the developing murine lung (38).…”

“…sFRP4 has been implicated in apoptosis (34 -36), proliferation (33,37), organ differentiation (38), and carcinogenesis (7,33,39). DDC-4, the rat homologue of sFRP4, was identified in involuted mammary glands, ovarian corpus luteum, and prostate, suggesting it is associated with apoptosis (34).…”

Bmp2 Is Critical for the Murine Uterine Decidual Response

“…In addition, a clear deregulation of secreted frizzled related protein 4 (Sfrp4), a Wnt antagonist, is observed. This protein has been found to be differentially regulated in rodents, primates, and human myometrium (1,11,18,47). Upon implantation, Sfrp4 expression is restricted to the undifferentiated stromal cells forming a dividing zone between the circular muscle layer and the forming decidua.…”

Secreted Frizzled-Related Protein 4 Regulates Two Wnt7a Signaling Pathways and Inhibits Proliferation in Endometrial Cancer Cells

“…Quantitative reverse transcription-PCR (RT-PCR) studies done in our laboratory found that in postmenopausal women treated with estrogen for 3 months SFRP4 expression in the endometrium increased 9-fold. 1 SFRP4 expression levels are significantly decreased in endometrial cancer (26)(27)(28)(29). Downregulation of SFRP4 and associated promoter hypermethylation has been reported in several other cancers, including mesothelioma, chronic lymphocytic leukemia, and esophageal adenocarcinoma (30)(31)(32).…”