Study for physiological function of metastin/kisspeptin with special reference to reproduction.

我们以前发现metastin/kisspeptin在前腹侧室周核（AVPV）和弓状核（Arc.）在下丘脑AVPV中metastin基因（kiss-1）的表达受雌激素的负调节，Arc的表达受雌激素的负调节，可能通过GnRH/LH的峰式或脉冲式释放参与排卵和性腺发育。在本研究中，我们发现了一个时钟基因，调节metastin基因的表达。时钟基因（Dbp）不仅与E2及其核受体ER α对metastin的表达具有累加效应，而且二者的表达模式具有时空相关性。本研究还对metastin和GnRH神经元进行了免疫细胞化学研究，发现metastin和GnRH神经纤维在正中隆起处紧密接触，这强烈提示metastin可能对正中隆起的GnRH神经元有调节作用。另一方面，发现metastin是一种抑制癌细胞转移的肽，然而，metastin对转移的作用还没有很好的研究。本研究发现metastin在多种肿瘤细胞中激活ERK 1/2基因。我们还发现metastin对癌细胞的增殖和凋亡没有影响，但它抑制了乳腺癌和肺癌细胞的迁移。

We previously found that metastin/kisspeptin is produced in anteroventral periventricular nucleus(AVPV) and arcuate nucleus(Arc.) in the hypothalamus. It is also revealed that metastin gene (kiss-1) expression in AVPV is positively and Arc is negatively regulated by estrogen and may be involved in ovulation and gonadal development through the surge or pulse mode release of GnRH/LH. In this study we found a clock gene which regulates metastin gene expression. The clock gene (Dbp) shows not only additive effects with E2 and it's nuclear receptor ERa on the expression of metastin, but correlation of spatio-temporal expression pattern between Dbp and metastin. These results strongly suggest Dbp is key regulator, which set a time of LH surge.In this study we also performed immunocytochemical study for metastin and GnRH neurons and found that metastin and GnRH nerve fibers closely contacted at median eminence, which strongly suggest that metastin may regulate GnRH neurons in median eminence. On the other hand, metastin is found as a peptide which suppresses metastasis of cancer cells however, the effect of metastin on metastasis is not well studied. In this study we found that metastin activates ERK1/2 gene in many kind of cancer cells. We also found that metastin has no effect on the cancer cell proliferation and apoptosis however, it inhibited migration of a mammary carcinoma and a lung carcinoma cells.