Expression and hormone regulation of Wnt2, 3, 4, 5a, 7a, 7b and 10b in normal human endometrium and endometrial carcinoma

Abstract

Summary Wnt genes are transforming to mouse breast epithelium and are hormonally regulated in vivo. To assess their role in another endocrine-responsive human cancer, the expression of seven Wnt genes (Wnt 2, 3, 4, 5a, 7a, 7b and 1 Ob) in normal human endometrium and endometrial cells, and endometrial carcinoma tissues and cell lines was investigated by ribonuclease protection analysis. Wnt2, 3, 4 and 5a mRNAs but not Wnt7a, 7b or 10b mRNAs were expressed in primary culture of normal endometrial epithelial (NEE) and stromal (NES) cells. In contrast, in four endometrial carcinoma cell lines (RL95-2, HEC-1 -A, AN3 CA and Ishikawa), Wnt2 and Wnt3 mRNAs were absent. Wnt4 was expressed in only one out of four cell lines (RL95-2), and Wnt5a was much lower. Wnt7a and Wnt7b mRNAs were expressed in three out of four cell lines (RL95-2, HEC-1 -A and Ishikawa). WntlOb mRNA was expressed in RL95-2 and AN3 CA. In fresh tissues, all Wnt genes apart from WntlOb were expressed in normal endometrium and endometrial carcinoma. Similar to the cell lines, the level of Wnt4 mRNA expression was significantly higher in the normal endometrium than endometrial carcinoma. Wnt2, 3 and 5a mRNAs were also lower in endometrial carcinoma compared with normal endometrium. There was no difference in the level of Wnt2, 3, 4 and 5a mRNA expression between proliferative phase and secretory phase of the menstrual cycle, or between either menstrual phase and the first trimester of pregnancy. In vitro, progesterone and/or 1 7,l-oestradiol had no effect on Wnt2, 3, 4, 5a and 7b mRNA expression in NES and all endometrial carcinoma cell lines. The data indicate that all Wnt genes were expressed in vitro, six out of seven Wnt genes (Wnt 2, 3, 4, 5a, 7a and 7b) were expressed endogenously in the human endometrium, their mRNA expression was hormonally independent and Wnt4 gene downregulation as well as down-regulation of Wnt 2, 3 and 5a may be associated with endometrial carcinoma.

Up-regulation of macrophage wnt gene expression in adenoma-carcinoma progression of human colorectal cancer

“…This contrasts with our studies of breast (Huguet et al, 1994) and endometrial (Bui et al, 1997a) cancer where wnts 5a, 7b and 10b, but not wnt 2, were up-regulated. It may be that several wnt genes are involved in the growth and development of individual organs and each cancer type may exhibit a deregulation in the expression of one or more wnt genes controlling normal development within that organ.…”

“…Wnt genes were initially isolated from mouse mammary carcinomas by insertional mutagenesis, but we have shown that they are also up-regulated in human hormone-dependent cancers of the breast (Huguet et al, 1994) and endometrium (Bui et al, 1997a). Wnts are members of a multigene family with over 14 genes in humans and most are conserved in Xenopus, suggesting specialized roles for each gene product.…”

Identification of molecular markers and signaling pathway in endometrial cancer in Hong Kong Chinese women by genome-wide gene expression profiling

“…Among them seven genes have been reported previously as differentially expressed in endometrial tumors. Lactotransferrin (LTF) was upregulated (Walmer et al, 1995), whereas six genes including SFRP4, DCN, IGFBP6, HGF, WT1 and WNT4 were downregulated in the endometrial tumors (Rutanen et al, 1994;Bui et al, 1997;Yoshida et al, 2002;Muller-Tidow et al, 2003;Smid-Koopman et al, 2004;Acs et al, 2004;Hrzenjak et al, 2004). Of these genes, only WT1 was been specifically associated with endometrioid cancer (Acs et al, 2004).…”

Differentiation of murine embryonic stem cells induces progesterone receptor gene expression

“…One model is that the primary role of PR during very early differentiation is to modulate expression levels of target gene transcription rather than act as an all or none regulator. Known target genes of PR in mature tissues that we examined in our study include Wnt4, Wnt5b and Areg, all of which are important developmental genes [50][51][52][53][54][55][56]. None of these known PR target genes are regulated by treatment with progesterone or the antiprogestin RU486 in mES cells.…”

“…We examined PR expression itself, since it has been reported to be down regulated by progesterone in some tissues [49]. We also examined the levels of expression of three genes that have been shown to be regulated by progesterone in mature tissues: Wnt4, Wnt5b, and amphiregulin (Areg) [50][51][52][53][54][55][56]. As can be seen in Figure 6, all four of these genes showed virtually no expression in undifferentiated mES cells (+LIF) and there was no effect of progesterone nor RU486 (a potent anti-progestin).…”