Stat3 and anti-VEGF therapy in cancer

Stat3 和抗 VEGF 疗法在癌症中的应用

• 批准号: 7185041
• 负责人: Hua E Yu
• 金额: $ 28.52万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-21 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7185041
• 关键词: Affect; Apoptosis; Apoptotic; Binding; Biological; Cancer Patient; Cell Death; Data; Development; Disease regression; Doctor of Philosophy; Down-Regulation; Endothelial Cells; Event; Frequencies; Gene Expression; Gene Targeting; Genes; Human; Hypoxia; Immune; Lead; Malignant Neoplasms; Mediating; Molecular; Mutation; Neoplasm Metastasis; Oncogenic; PTEN gene; Pathway interactions; Phosphotransferases; Protein Tyrosine Kinase; Protein p53; Proteins; Regulation; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction; Stream; Survival Rate; TP53 gene; Testing; Therapeutic; Therapeutic Agents; Time; Transcription Coactivator; Transcriptional Activation; Tumor Angiogenesis; Tumor Suppressor Proteins; Tumor-Suppressor Gene Inactivation; Ubiquitination; Up-Regulation; VEGFA gene; Vascular Endothelial Growth Factors; angiogenesis; base; cancer therapy; in vivo; inhibitor/antagonist; mutant; neoplastic cell; novel; programs; promoter; protein degradation; research study; src-Family Kinases; tumor; v-src Oncogenes

DESCRIPTION (provided by applicant): Vascular endothelial growth factor (VEGF) is critical for tumor angiogenesis and tumor immune suppression. Its elevated expression in tumors has been correlated with increased metastasis, resistance to conventional therapeutic agents and poor survival rates for cancer patients. However, effective anti-VEGF therapy remains a challenge in part because numerous transforming events, including activation of oncogenic kinases and inactivation of tumor suppressor genes, induce VEGF expression. Recently, we have identified Stat3 as a novel transcriptional regulator of the VEGF promoter. Significantly, Stat3 is constitutively-activated with 50-90% frequency in diverse cancers and many known VEGF-inducers signal through Stat3. Moreover, the tumor suppressors, PTEN and p53, are important negative regulators of VEGF gene expression. PTEN has recently been shown to inhibit Stat3 activity, suggesting that loss of PTEN activity would increase Stat3-mediated VEGF up-regulation. Furthermore, our preliminary studies have shown that Stat3 inhibits p53 expression, indicating a role of Stat3 in negating p53 effects on VEGF down-regulation. In addition, our preliminary results show that Stat3 signaling is required for induction of hypoxia-inducing factor 1 (HIF-1) alpha. Prior to discovery the Stat3/VEGF connection, HIF-1 was the only known VEGF transcriptional factor and its important role in mediating VEGF induction by oncogenic kinases and the p53/PTEN tumor suppressors has been established. These findings led us to hypothesize that Stat3 is not only a direct regulator of the VEGF promoter but also an effector and/or regulator of numerous other VEGF inducers. Our results demonstrate that binding of Stat3 to the VEGF promoter is obligatory for Src tyrosine kinase-induced VEGF up-regulation. Here we propose to determine whether Stat3 also transmits signals from other VEGF inducers up-stream of Stat3 directly to the VEGF promoter. We will also assess the molecular mechanism(s) by which Stat3 controls HIF-1 alpha expression. Finally, because Stat3 blockade inhibits VEGF expression and angiogenesis while at the same time down-regulates several key antiapoptotic genes and induces tumor cell apoptosis and tumor regression, we will have a unique opportunity to assess how endothelial cell death/vessel collapse affects tumor cell apoptosis/tumor regression and vice versa. Collectively, these studies may lead to development of more potent VEGF inhibitors for cancer therapy.

描述（由申请人提供）：血管内皮生长因子（VEGF）对肿瘤血管生成和肿瘤免疫抑制至关重要。它在肿瘤中的表达升高与癌症患者的转移增加、对常规治疗剂的抗性和低存活率相关。然而，有效的抗VEGF治疗仍然是一个挑战，部分原因是许多转化事件，包括致癌激酶的激活和肿瘤抑制基因的失活，诱导VEGF表达。最近，我们已经确定Stat 3作为一种新的VEGF启动子的转录调节因子。值得注意的是，Stat 3在各种癌症中以50-90%的频率被组成性激活，并且许多已知的VEGF诱导剂通过Stat 3发出信号。此外，肿瘤抑制因子PTEN和p53是VEGF基因表达的重要负调节因子。最近已显示PTEN抑制Stat 3活性，表明PTEN活性的丧失将增加Stat 3介导的VEGF上调。此外，我们的初步研究表明，Stat 3抑制p53表达，表明Stat 3在否定p53对VEGF下调的作用。此外，我们的初步研究结果表明，Stat 3信号是诱导缺氧诱导因子1（HIF-1）α所必需的。在发现Stat 3/VEGF连接之前，HIF-1是唯一已知的VEGF转录因子，并且已经确定了其在通过致癌激酶和p53/PTEN肿瘤抑制因子介导VEGF诱导中的重要作用。这些发现使我们假设Stat 3不仅是VEGF启动子的直接调节子，而且是许多其他VEGF诱导剂的效应子和/或调节子。我们的研究结果表明，Stat 3的VEGF启动子的结合是强制性的Src酪氨酸激酶诱导的VEGF上调。在这里，我们建议，以确定是否Stat 3也传输信号从其他VEGF诱导剂上游的Stat 3直接的VEGF启动子。我们还将评估Stat 3控制HIF-1 α表达的分子机制。最后，由于Stat 3阻断抑制VEGF表达和血管生成，同时下调几个关键的抗凋亡基因，并诱导肿瘤细胞凋亡和肿瘤消退，我们将有一个独特的机会来评估内皮细胞死亡/血管塌陷如何影响肿瘤细胞凋亡/肿瘤消退，反之亦然。总的来说，这些研究可能会导致开发更有效的VEGF抑制剂用于癌症治疗。

项目成果

Signal transducer and activator of transcription 3 is required for hypoxia-inducible factor-1alpha RNA expression in both tumor cells and tumor-associated myeloid cells.

• DOI: 10.1158/1541-7786.mcr-07-2177
• 发表时间: 2008-07
• 期刊: Molecular cancer research : MCR
• 作者: Niu G;Briggs J;Deng J;Ma Y;Lee H;Kortylewski M;Kujawski M;Kay H;Cress WD;Jove R;Yu H
• 通讯作者: Yu H