Role of TGF-β signaling in uterine carcinosarcoma.
Role of TGF-β signaling in uterine carcinosarcoma.
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DOI：
10.18632/oncotarget.3711
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发表时间：
2015-06-10
期刊：
影响因子：
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通讯作者：
Bhattacharya R
中科院分区：
文献类型：
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作者：
Dwivedi SK;McMeekin SD;Slaughter K;Bhattacharya R
子宫癌肉瘤 (UCS) 罕见（3-4%），但具有高度侵袭性，在子宫恶性肿瘤中死亡率极高（16.4%）。转化生长因子β (TGFβ) 是一种多功能细胞因子，可调节重要的细胞过程，包括上皮间质转化 (EMT)。双相元件的存在以及证明 19q13.1 处 TGFβ 扩增的报告促使我们研究 TGFβ 信号传导在 UCS 中的作用。在这里，我们证明了 TGFβ 途径的成分在 UCS 中表达并发挥功能。 TGFβ-I 在 UCS 细胞系中诱导显着的 Smad2/3 磷酸化、迁移和 EMT 反应，这种反应可以被礼来公司开发的 TGFβ 受体 I (TGFβR-I) 或 TGFβ 受体 I/II (TGFβR-I/II) 抑制剂减弱。重要的是，TGFβ-I 诱导的增殖是 c-Myc 依赖性的，可能是通过细胞周期的激活。 c-Myc 是由响应 TGFβ-I 的活化 T 细胞核因子 (NFAT-1) 的核转位诱导的。抑制 NFAT-1 或 TGFβR-I 可阻断 UCS 中的 c-Myc 诱导、细胞周期进展和增殖。与非复发性 UCS 患者样本相比，复发性 UCS 患者样本中 c-Myc mRNA 水平升高，这也证实了这一点。有趣的是，在没有外源 TGFβ 的情况下，TGFβR-I/II 抑制剂可能通过非 Smad 途径增强增殖。因此，抑制TGFβR-I可以有效治疗UCS。
Uterine carcinosarcomas (UCS) are rare (3-4%) but highly aggressive, accounting for a disproportionately high (16.4%) mortality among uterine malignancies. Transforming growth factor beta (TGFβ) is a multifunctional cytokine that regulates important cellular processes including epithelial-mesenchymal transition (EMT). Existence of biphasic elements and a report demonstrating amplification of TGFβ at 19q13.1 prompted us to investigate the role of TGFβ signaling in UCS. Here we demonstrated the components of TGFβ pathway are expressed and functional in UCS. TGFβ-I induced significant Smad2/3 phosphorylation, migration and EMT responses in UCS cell lines which could be attenuated by the TGFβ receptor I (TGFβR-I) or TGFβ receptor I/II (TGFβR-I/II) inhibitor developed by Eli Lilly and company. Importantly, TGFβ-I induced proliferation was c-Myc dependent, likely through activation of cell cycle. c-Myc was induced by nuclear translocation of nuclear factor of activated T cells (NFAT-1) in response to TGFβ-I. Inhibition of NFAT-1 or TGFβR-I blocked c-Myc induction, cell cycle progression and proliferation in UCS. In corroboration, mRNA levels of c-Myc were elevated in recurrent versus the non-recurrent UCS patient samples. Interestingly, in the absence of exogenous TGFβ the TGFβR-I/II inhibitor enhanced proliferation likely through non-Smad pathways. Thus, inhibition of TGFβR-I could be efficacious in treatment of UCS.