Cellular Interactions of TGF-B Pathway Members and Regulators of Foregut Cancers

TGF-B 通路成员和前肠癌调节因子的细胞相互作用

• 批准号: 8379849
• 负责人: Lopa Mishra
• 金额: $ 20.5万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8379849
• 关键词: Adaptor Signaling Protein; Adenocarcinoma; Beckwith-Wiedemann Syndrome; CDK4 gene; Cancer cell line; Carcinoma; Cell Cycle; Characteristics; Colonic Adenoma; Cyclin D1; Cyclin-Dependent Kinase Inhibitor 2A; Detection; Development; Dysplasia; Early Diagnosis; Exons; Gastrointestinal Neoplasms; Goals; Human; Inherited; Intestines; Liver; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Metaplasia; Molecular; Molecular Profiling; Mus; Mutant Strains Mice; Mutate; Mutation; Oncogenic; Pancreas; Pathway interactions; Primary carcinoma of the liver cells; Primitive foregut structure; Proteins; Role; Signal Transduction; Splice-Site Mutation; Staging; Syndrome; Testing; Therapeutic; Transforming Growth Factor beta; Tumor Suppressor Proteins; Visceromegaly; Vitamin D Analog; adenoma; base; c-myc Genes; cancer therapy; enzyme activity; inhibitor/antagonist; malignant stomach neoplasm; member; molecular marker; mouse model; novel therapeutics; therapeutic target; treatment response; tumor; tumorigenesis; ubiquitin-protein ligase

The Smad3/4 adaptor protein ELF is emerging as a potent regulator of tumorigenesis by its ability to effect TGF-beta tumor suppressor function. However, to date the role of the TGF-beta pathway at specific stages in gastrointestinal (Gl) tumor development such as metaplasia, dysplasia and carcinoma remains poorly delineated, particularly in conjunction with activation of oncogenic pathways. We previously found that deletion of ELF results in a dramatic and spontaneous formation of liver and gastrointestinal (Gl) cancers, with a splice site mutation in elf exon 15 in 11% of human Gl cancer cell lines tested so far. A surprising and serendipitous recent discovery by us is that elf' and elf^/SmadS^' mice develop visceromegaly and multiple Gl cancers (70% of mice), including metastatic pancreatic, hepatocellular, intestinal adenocarcinomas and others spontaneously, providing compelling evidence as a mouse model of Beckwith-Wiedemann syndrome (BWS), a hereditary human cancer syndrome. In addition, 90% of elf''' /Smad4*/~ mice develop gastric cancer, 20% develop colonic adenomas, and ELF expression is lost in human gastric cancer as well as Dukes B1 adenomas indicating a role for ELF in suppression of early human gastrointestinal cancer. Molecular profiling of the tumors in these mice and human Gl cancers demonstrate markedly high levels of cell cycle regulators that include CDK4, cyclin D1 and PRAJA an ELF/Smad3 specific E3 ligase. Interestingly, SmadS has recently been shown to be a CDK4 substrate, yet Smad3 mutant mice do not develop cancers. Thus, activated CDK4 and PRAJA associate with ELF with or without Smad3 and most likely exert their oncogenic activity through suppression ofELF/SmadS. Our AIMS are to: 1. Determine a functional interaction between ELF, SmadS, and CDK4, and the effect of loss elf, SmadS or Smad4 on CDK4 enzyme activity, towards testing CDK4 inhibitors from project 4, Vitamin D analogs from project 2, as well as developing new therapaeutics targeted allosterically at CDK4 -ELF-Smad3 interaction. 2. Investigate the molecular basis for the differential effects of PRAJA on ELF and SmadS towards generating new inhibitors targeted at PRAJA. 3. Test whether ELF is mutated in BWS, and potentially whether loss of ELF in combination with PRAJA, CDK4, Smad3, Smad4,TBRII, TERT and c-Myc (the latter two from project 3) represent new specific molecular markers for early tumor detection/ treatment response of hepatocellular, gastric and pancreatic cancers. Results from this study promise to yield important new therapeutics and will be a first step toward the goal of individualized cancer treatment based on the functional molecular characteristics of these lethal tumors.

SMAD3/4适配器蛋白ELF通过其作用的能力而成为肿瘤发生的有效调节剂 TGF-β肿瘤抑制器功能。但是，迄今为止，TGF-beta途径在特定阶段的作用 胃肠道（GL）肿瘤发育，例如化生，发育不全和癌的疾病 划定了，特别是与致癌途径的激活结合在一起。我们以前发现 删除ELF会导致肝脏和胃肠道（GL）癌的戏剧性和自发形成， 到目前为止，在11％的人类GL癌细胞系中，ELF外显子15中的剪接部位突变在迄今为止测试。 我们最近发现的一个令人惊讶且偶然的发现是Elf'和Elf^/smads^'鼠标发展 内脏瘤和多种GL癌（70％的小鼠），包括转移性胰腺，肝细胞， 肠道腺癌和其他人自发地提供了令人信服的证据作为小鼠模型 贝克维斯 - 威德曼综合征（BWS），一种遗传性人类癌综合征。此外，90％的小精灵'' /smad4*/〜小鼠患胃癌，20％发展为结肠腺瘤，而ELF表达在 人类胃癌以及公爵B1腺瘤，表明ELF在抑制早期 人胃肠道癌。这些小鼠和人类GL癌的肿瘤的分子分析 证明包括CDK4，Cyclin D1和Praja AN在内的细胞周期调节剂明显高水平 ELF/SMAD3特异性E3连接酶。有趣的是，最近已显示SMADS是CDK4底物 SMAD3突变小鼠不会发育癌症。因此，激活的CDK4和PRAJA与ELF与OR相关 没有smad3，很可能通过抑制/smads发挥其致癌活性。 我们的目标是： 1。确定精灵，SMAD和CDK4之间的功能相互作用，以及损失精灵，SMAD或 CDK4酶活性上的SMAD4，朝着项目4的CDK4抑制剂，维生素D类似物中的CDK4抑制剂。 项目2，以及以CDK4 -FELL -SMAD3相互作用的变构为目标的新疗法。 2。研究praja对小精灵和smads的差异作用的分子基础 产生针对Praja的新抑制剂。 3。测试ELF是否在BW中突变，并可能与Praja结合使用ELF， CDK4，SMAD3，SMAD4，TBRII，TERT和C-MYC（项目3中的后两个）代表新的特定 肝细胞，胃和胰腺的早期肿瘤检测/治疗反应的分子标记 癌症。 这项研究的结果承诺将产生重要的新疗法，并将成为朝着目标的第一步 基于这些致命肿瘤的功能分子特征的个性化癌症治疗。