Molecular mechanisms of the progression of the pituitary tumor and the role of tissue remodeling factors

用17b -雌二醇（E2）或儿茶酚-雌激素（4-OH E2）治疗可增加GH3细胞植入动物的血清催乳素水平和肿瘤大小。肿瘤组织中VEGF、碱性FGF以及igf结合蛋白7 （IGFBP7）和调控微管动力学的胞质磷蛋白stathmin的表达增加。E2增加了培养的GH3细胞中VEGF和IGFBP7的表达。抑制IGFBP7表达可刺激肿瘤VEGF表达，抑制肿瘤细胞增殖。整合素B1簇和集落的形成受到抑制。生长抑素受体（SSTR）激动剂或IGFBP7抑制VEGF表达，提示IGFBP7可能是参与抑制肿瘤进展的靶分子。此外，生长抑素抑制ERK的磷酸化并诱导CDK抑制剂p27。E2通过雌激素受体a （ERα）诱导的MAP激酶激活被SSTR刺激抑制，E2处理下调SSTR1的表达。因此，SSTR1在ERα作用下抑制细胞增殖信号通路中起着至关重要的作用。

Treatment with 17B-estradiol (E2) or catechol-estrogen (4-OH E2) increased the serum levels of prolactin and the size of tumor in the animals implanted with GH3 cells. The expressions of VEGF and basic FGF as well as IGF-binding protein 7 (IGFBP7) and stathmin, a cytosolic phosphoprotein that regulates microtubule dynamics increased in the tumor tissues. E2 increased VEGF and IGFBP7 expression in cultured GH3 cells. Knocking down IGFBP7 expression stimulated tumor VEGF expression and decreased the proliferation of tumor cells. The formation of integrin B1 cluster and colonies was suppressed. Somatostatin receptor (SSTR) agonist or IGFBP7 inhibited VEGF expression, suggesting that IGFBP7 may be a target molecule that is involved in the suppression of tumor progression. Furthermore, Somatostatin inhibited the phosphorylation of ERK and induced a CDK inhibitor, p27. E2-induced MAP kinase activation via the estrogen receptor a (ERα) was suppressed by SSTR stimulation and E2 treatment down-regulates SSTR1 expression. Thus, SSTR1 is a crucial role for inhibiting the signaling pathway of proliferation under ERα.