Cellular Interations of TGS-B Pathyway Members and Regulators of Foregut Cancers

前肠癌 TGS-B 通路成员和调节因子的细胞相互作用

• 批准号: 8744865
• 负责人: Lopa Mishra
• 金额: $ 20.95万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8744865
• 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; Generations; Goals; Human; Inherited; Intestines; Liver; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of liver; 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; 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; new therapeutic target; 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-B tumor suppressor function. However, to date the role of the TGF-B 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[+/-]/Smad3[+/-] 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 of ELF/Smad3. Our AIMS are to: 1. Determine a functional interaction between ELF, Smad3, and CDK4, and the effect of loss elf, Smad3 or Smad4 on CDK4 enzyme activity, towards testing CDK4 inhibitors from project 4, Vitamin D analogs from project 2, as well as developing new therapeutics targeted allosterically at CDK4 -ELF-Smad3 interaction. 2. Investigate the molecular basis for the differential effects of PRAJA on ELF and Smad3 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通过影响TGF-B肿瘤抑制器功能的能力而成为肿瘤发生的有效调节剂。但是，迄今为止，TGF-B途径在胃肠道（GL）肿瘤发育（例如化生，异常增生和癌）中的作用仍然很差，尤其是与致癌途径的激活结合在一起。我们先前发现，精灵的缺失会导致肝脏和胃肠道癌的戏剧性和自发形成，迄今为止，ELF外显子15中的剪接位点突变在迄今已测试的11％的人GL癌细胞系中。我们最近发现的一个令人惊讶和偶然的发现是，Elf [+/-]和Elf [+/-]/smad3 [+/--]小鼠会形成内脏瘤，多种GL癌症（占70％的小鼠）（70％）（70％）（包括转移性胰腺，肝细胞，肠道，肠道，肠道腺癌，并提供了一种既定的型号，均可构成型号，以构建一定的模型综合征（BWS），一种遗传性人类癌综合征。此外，有90％的ELF'' /smad4* /〜小鼠患胃癌，20％发展为结肠腺瘤，而ELF表达在人类胃癌中以及Dukes B1腺瘤中丧失，表明ELF在抑制早期人类胃肠道癌中的作用。这些小鼠和人类GL癌的肿瘤的分子分析表明，包括CDK4，Cyclin D1和Praja和Elf/Smad3特异性E3连接酶在内的细胞周期调节剂明显高。有趣的是，最近已证明SMAD是CDK4底物，但是SMAD3突变小鼠不会出现癌症。因此，活化的CDK4和PRAJA与ELF相关，有或没有SMAD3，并且很可能通过抑制Elf/Smad3发挥其致癌活性。我们的目的是：1。确定ELF，SMAD3和CDK4之间的功能相互作用，以及损失ELF，SMAD3或SMAD4对CDK4酶活性的影响，以测试项目4项目4的CDK4抑制剂，项目2的维生素D进行了类似物，以及在CDK4 -SMAD3上的新治疗方法，以及开发新的治疗方法。 2。研究Praja对ELF和SMAD3对产生针对Praja的新抑制剂的差异作用的分子基础。 3。测试ELF是否在BWS中突变，以及可能与Praja，CDK4，Smad3，Smad4，Smad4，Tbrii，Tert和C-Myc（项目3中的后两个）相结合的ELF损失是否代表了早期肿瘤检测/治疗肝细胞治疗的新特异性分子标记。这项研究的结果有望产生重要的新疗法，并将是基于这些致命肿瘤的功能分子特征的个性化癌症治疗目标的第一步。