Expression of Wnt4 in Human Pituitary Adenomas Regulates Activation of the β-Catenin-Independent Pathway
Expression of Wnt4 in Human Pituitary Adenomas Regulates Activation of the β-Catenin-Independent Pathway
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DOI：
10.1007/s12022-008-9048-9
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发表时间：
2008-12-01
影响因子：
4.4
通讯作者：
Osamura, Robert Yoshiyuki
中科院分区：
文献类型：
--
作者：
Miyakoshi, Takashi;Takei, Mao;Osamura, Robert Yoshiyuki
Wnt 信号通路与多种人类癌症的发生有关。 Wnt4 是 Wnt 基因家族的一个成员，已知在胚胎发育过程中调节小鼠垂体前叶细胞类型的增殖。为了阐明 Wnt 信号在人垂体腺瘤中的作用，我们通过免疫组织化学检查了垂体腺瘤和正常垂体中 Wnt4 及其假定受体 Frizzled6 (Fzd6) 的表达。 Wnt4 在生长激素腺瘤 (GHomas)、催乳素腺瘤 (PRLomas) 和促甲状腺激素腺瘤 (TSHomas) 中的表达高于正常垂体。 Fzd6 在 GHomas、PRLomas、TSHomas 和促性腺激素亚基 (GnSU) 阳性腺瘤中广泛表达。在正常垂体中，Wnt4 和 Fzd6 主要共定位于糖蛋白激素阳性细胞的卵泡刺激素、黄体生成素和 α 亚基中。通过 β-连环蛋白免疫组织化学分析典型的 Wnt/β-连环蛋白信号通路。在所有垂体腺瘤中，β-连环蛋白都位于细胞膜上，但不在细胞核中。另一方面，Erk1/2 在 GHomas 和 TSHomas 中高度激活。这些结果表明，通过“β-连环蛋白独立”途径激活 Wnt4/Fzd6 信号传导在垂体腺瘤细胞的增殖和存活中发挥作用。包括 Pit-1 在内的转录因子的详细参与仍有待进一步研究。
The Wnt signaling pathway has been implicated in the genesis of numerous human cancers. A member of the Wnt family of genes, Wnt4, has been known to regulate proliferation of anterior pituitary cell types in the mouse during embryonic development. In order to elucidate the roles of Wnt signaling in human pituitary adenomas, we examined the expression of Wnt4 and its putative receptor Frizzled6 (Fzd6) by immunohistochemistry in pituitary adenomas and normal pituitaries. Expression of Wnt4 was higher in growth hormone-producing adenomas (GHomas), prolactin-producing adenomas (PRLomas), and thyroid-stimulating hormone-producing adenomas (TSHomas) than in the normal pituitary. Fzd6 was widely expressed in GHomas, PRLomas, TSHomas, and gonadotropin subunit (GnSU)-positive adenomas. In normal pituitary glands, Wnt4 and Fzd6 were colocalized predominantly in follicle-stimulating hormone-, luteinizing hormone-, and alpha-subunits of glycoprotein hormone-positive cells. The canonical Wnt/beta-catenin signaling pathway was analyzed by beta-catenin immunohistochemistry. beta-Catenin was localized at the cell membrane in all pituitary adenomas, but not in the nuclei. On the other hand, Erk1/2 was highly activated in GHomas and TSHomas. These results suggested that activation of Wnt4/Fzd6 signaling through a "beta-catenin-independent" pathway played a role in proliferation and survival of the pituitary adenoma cells. Detailed involvement of transcription factors including Pit-1 remains to be further investigated.