Baba Tsukasa, Kang Hyun Sook, Hosoe Yuko, Kharma Budiman, Abiko Kaoru, Matsumura Noriomi, Hamanishi Junzo, Yamaguchi Ken, Yoshioka Yumiko, Koshiyama Masafumi, Mandai Masaki, Murphy Susan K, Konishi Ikuo
Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan,
Med Mol Morphol. 2015 Jun;48(2):76-84. doi: 10.1007/s00795-014-0081-0. Epub 2014 Jun 8.
Metastin/kisspeptin is encoded by KISS1 and functions as an endogenous ligand of GPR54. Interaction of metastin with GPR54 suppresses metastasis and also regulates release of gonadotropin-releasing hormone, which promotes secretion of estradiol (E2) and progesterone (P4). We have previously demonstrated epigenetic regulation of GPR54 in endometrial cancer and the potent role of metastin peptides in inhibiting metastasis in endometrial cancer. However, little is known about how the metastin-GPR54 axis is regulated in the endometrium, the precursor tissue of endometrial cancer. Endometrial stromal cells (ESCs) and endometrial glandular cells (EGCs) within the endometrium show morphological changes when exposed to E2 and P4. In this study, we show that metastin expression is induced in ESCs through decidualization, but is repressed in glandular components of atypical endometrial hyperplasia (AEH) and endometrial cancer relative to EGCs. The promoter of GPR54 is unmethylated in normal endometrium and in AEH. These results indicate metastin may function in decidualized endometrium to prepare for adequate placentation but this autocrine secretion of metastin is deregulated during oncogenesis to enable tumor cells to spread.
转移抑制素/亲吻素由KISS1编码，作为GPR54的内源性配体发挥作用。转移抑制素与GPR54的相互作用可抑制转移，还可调节促性腺激素释放激素的释放，促性腺激素释放激素可促进雌二醇（E2）和孕酮（P4）的分泌。我们之前已经证明了子宫内膜癌中GPR54的表观遗传调控以及转移抑制素肽在抑制子宫内膜癌转移中的重要作用。然而，关于转移抑制素 - GPR54轴在子宫内膜癌的前体组织子宫内膜中是如何调控的，我们知之甚少。当暴露于E2和P4时，子宫内膜内的子宫内膜基质细胞（ESC）和子宫内膜腺细胞（EGC）会出现形态变化。在本研究中，我们发现转移抑制素的表达通过蜕膜化在ESC中被诱导，但相对于EGC，在非典型子宫内膜增生（AEH）和子宫内膜癌的腺体成分中受到抑制。GPR54的启动子在正常子宫内膜和AEH中未甲基化。这些结果表明，转移抑制素可能在蜕膜化的子宫内膜中发挥作用，为适当的胎盘形成做准备，但在肿瘤发生过程中，这种转移抑制素的自分泌分泌失调，从而使肿瘤细胞得以扩散。
