三氧化二砷靶向阻断calcineurin-NFAT-DSCR1通路抑制肺癌生长与转移的机制研究

Calcineurin-NFAT是VEGF下游介导血管内皮激活的效应分子。新近研究报道，上调calcineurin的内源性抑制剂DSCR1可抑制肿瘤生长和转移。我们前期研究发现，三氧化二砷(As2O3)能够阻断VEGF介导的血管内皮增殖，抑制肺癌移植瘤生长及胸膜转移引起的恶性胸腔积液，但其确切机制尚未明确。基于calcineurin-NFAT-DSCR1通路是VEGF的下游效应者，我们开展预实验发现calcineurin在肺癌高表达，而As2O3恰能上调内皮细胞DSCR1水平，抑制NFAT及其下游因子。我们推测As2O3正是通过上调DSCR1，从而阻断calcineurin-NFAT通路引起的内皮激活。我们拟以DSCR1基因缺陷小鼠构建肺癌模型，在体外和体内水平研究As2O3对calcineurin-NFAT-DSCR1通路的靶向阻断机制，为阐明As2O3抑制肺癌的作用机理提供实验证据。

Calcineurin-NFAT is the downstream effector of VEGF, which induces the activation and proliferation of endothelial cells. Recent research reports that the up-regulation of DSCR1, the endogenous inhibitor of calcineurin, could inhibit tumor growth and metastasis. We previously reported that arsenic trioxide (As2O3) could inhibit lung cancer growth and metastasis by inhibiting tumor angiogenesis via VEGF pathway suppression. However, the exact effect of As2O3 on vascular endothelial cells is still unclear. Based on the fact that calcineurin-NFAT-DSCR1 pathway is the downstream effector of VEGF, we carried out preliminary experiments and found a high expression of calcineurin in lung cancer, and that As2O3 could upregulate DSCR1, inhibit the expression of NFAT and its downstream factor Ang-2. Thus we hypothesized that As2O3 inhibits the calcineurin-NFAT pathway by up-regulating DSCR1, thereby inhibits tumor growth and metastasis. For this purpose, we will take vascular endothelial cells and DSCR1-/- mice with lung cancer as research objects, and carry out experiments in vivo and in vitro to verify our conjecture. This research will provide evidences for the mechanism of the inhibitory effect of As2O3 on lung cancer.