Role of MTF1 in ovarian cancer

卵巢癌是女性最致命的妇科恶性肿瘤。然而，卵巢的治疗选择 癌症由于化疗耐药、频繁复发和转移而受到限制。然而， 涉及卵巢癌转移和化疗耐药的潜在分子机制在很大程度上尚不清楚。 金属反应转录因子1(MTF1)是一种锌指转录调节因子，它显著地 在卵巢癌中扩增或上调，这与无病生存率降低有关。然而， MTF1在卵巢癌中的作用完全未知。这项提议是为了测试MTF1如何贡献于 卵巢癌转移和化疗耐药及FDA批准的白血病I期药物APTO-253的检测 作为MTF1小分子抑制物在卵巢癌治疗中的应用。我们发现MTF1是细胞的关键调节因子 卵巢癌细胞周期及其小分子抑制剂APTO-253对MTF1的抑制作用 减少卵巢癌细胞的增殖、迁移和侵袭。CDK6细胞周期蛋白的表达 抑制p21的表达，上调p21的表达。特别是，APTO-253抑制cMyc的表达并诱导P53 表情。此外，我们还发现APTO-253抑制卵巢上皮细胞向间充质转化(EMT)。 癌症。我们的初步研究表明，MTF1是治疗卵巢癌的潜在药物靶点。至 为了明确MTF1的作用及其在治疗卵巢癌中的潜力，我们提出了两个具体的目标：1)测试 假设MTF1的表达被转录因子转录激活，并决定了 MTF1在卵巢癌中的调控网络。2)验证抑制MTF1抑制肿瘤的假设 细胞生长和肿瘤转移，并克服化疗耐药。这是一项具有创新性和重大意义的 利用功能得失研究MTF1调控网络的翻译研究项目 接近了。特别是，测试一种MTF1小分子抑制剂APTO-253，这是FDA批准的一期药物 在卵巢癌小鼠模型中，将为卵巢癌的治疗提供实验依据。

Ovarian cancer is the deadliest gynecological malignancy in women. However, therapeutic options for ovarian cancer are limited due to chemotherapeutic resistance, frequent recurrence, and metastasis. However, the underlying molecular mechanisms involving in ovarian cancer metastasis and chemoresistance is largely elusive. Metal responsive transcriptional factor 1 (MTF1) is a zinc finger transcriptional regulator and is significantly amplified or upregulated in ovarian cancer, which is associated with diminished disease-free survival. However, the role of MTF1 in ovarian cancer is completely unknown. This proposal is to test how MTF1 contributes to ovarian cancer metastasis and chemoresistance and test an FDA approved phase I drug APTO-253 for leukemia as a MTF1 small inhibitor in ovarian cancer treatment. We have found that MTF1 is a key regulator of the cell cycle in ovarian cancer cells and that inhibition of MTF1 using its small molecular inhibitor APTO-253 leads to reduced ovarian cancer cell proliferation, migration, and invasion. The expression of the CDK6 cell cycle protein was inhibited while p21 upregulated. In particular, APTO-253 inhibits cMyc expression and induces p53 expression. Moreover, we found that APTO-253 inhibits epithelia to mesenchymal transition (EMT) in ovarian cancer. Our preliminary studies implicated that MTF1 is a potential drug target in treating ovarian cancer. To define the role of MTF1 and its potential in treating ovarian cancer we propose two specific aims: 1) Test the hypothesis that MTF1 expression is transcriptionally activated by transcriptional factors and determine the regulatory network of MTF1 in ovarian cancer. 2) Test the hypothesis that inhibition of MTF1 suppresses tumor cell growth and tumor metastasis and also overcomes chemoresistance. This is an innovative and significant translational research project to investigate the MTF1 regulatory network using gain and loss of function approaches. In particular, testing a MTF1 small molecular inhibitor APTO-253, an FDA approved phase 1 drug in ovarian mouse model cancer will provide the experimental evidence for ovarian cancer treatment.