MUC1 regulation of TGF-beta function in pancreatic cancer cells

MUC1 对胰腺癌细胞中 TGF-β 功能的调节

基本信息

批准号：
8598463
负责人：
Pinku Mukherjee
金额：
$ 7.2万
依托单位：
UNIVERSITY OF NORTH CAROLINA CHARLOTTE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8598463
关键词：
Adenocarcinoma Cell Apoptosis Apoptotic Cell Line Cells Cessation of life Clinical Complex Cytoplasmic Tail Data Disease Drug resistance Future Glycoproteins Goals Grant Growth Growth Factor Human In Vitro Knowledge Laboratories Length MAP Kinase Gene Malignant neoplasm of pancreas Mesenchymal Molecular Mucin-1 Staining Method Mucins Mutate Nature Neoplasm Metastasis Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pharmaceutical Preparations Phenotype Phenylalanine Pilot Projects Property Proteins Radiation therapy Regulation Resistance Role Signal Pathway Signal Transduction Small Interfering RNA System Testing Text Therapeutic Transforming Growth Factor beta Tumor Promoters Tumor Suppressor Proteins Tyrosine Tyrosine Phosphorylation base carcinogenesis epithelial to mesenchymal transition extracellular in vivo innovation interest mutant novel outcome forecast pancreatic cancer cells public health relevance receptor research study response success tumor

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer is a devastating disease with dismal median survival of 3-6 months. The disease is characterized by highly aggressive tumors that are resistant to standard chemo and radiation therapies. MUC1 is a transmembrane mucin glycoprotein that is significantly increased and differentially glycosylated in over 60% of human pancreatic adenocarcinomas (PDA). Further, MUC1 is a marker of aggressive PDA, as its expression is correlated with high metastases, drug resistance, and poor prognosis. However, the underlying mechanisms of MUC1 associated aggressiveness remain unclear. We have new preliminary evidence that PDA cells that do not express MUC1 undergo apoptosis in response to TGF-? whereas PDA cells that express MUC1 undergo EMT and invasion in response to TGF-?. The TGF-?-induced invasion is completely lost when the cytoplasmic tail of MUC1 (MUC1 CT) is mutated. Therefore signal transduction through MUC1 CT is necessary for TGF-?-induced invasion to occur. TGF-? is a major player in carcinogenesis, and is well known for its paradoxical role as both a tumor suppressor and a tumor promoter in pancreatic cancer. Understanding the factors and signals that drive TGF-? function to switch from tumor-suppressor to tumor-promoter is of great interest. We hypothesize that signaling through MUC1-CT supports TGF-?-induced EMT and invasion and inhibits TGF-?-induced apoptosis. The specific aims are: 1) to determine the differential effects of TGF-? induced EMT in MUC1+, MUC1-, and MUC1+ cells in which the tyrosine residues in the MUC1 CT have been mutated to phenylalanine (MUC1 Y0); 2) to determine the differential effects of TGF-? induced apoptosis in MUC1+, MUC1-, and MUC1 Y0 cells. Both in vitro and in vivo experiments are proposed for the aims. If the hypothesis is true, this will be the first demonstration that MUC1 acts as a switch in PDA cells, changing the pro-apoptotic property of TGF-? to an anti-apoptotic and pro-survival property. The knowledge gained will have to be considered when developing future therapies that aim to target the tumor promoting signals of TGF-? while still retaining the pro-apoptotic signals of TGF-?. So far, MUC1 therapeutics has focused on the extracellular region of MUC1 which has not led to clinical success. If the hypothesis holds true, then developing drugs that specifically target MUC1 CT signaling should become a priority.

描述（由申请人提供）：胰腺癌是一种毁灭性疾病，中位生存期3-6个月。该疾病的特征是高度攻击性的肿瘤，对标准化学疗法和辐射疗法具有抗性。 MUC1是一种跨膜粘蛋白糖蛋白，在超过60％的人类胰腺腺癌（PDA）中显着增加和差异化糖基。此外，MUC1是侵略性PDA的标志，因为它的表达与高转移，耐药性和预后不良相关。但是，MUC1相关的侵略性的潜在机制尚不清楚。我们有新的初步证据表明，未表达MUC1的PDA细胞会对TGF-响应TGF-进行凋亡？而表达MUC1的PDA细胞会响应TGF-？当MUC1（MUC1 CT）的细胞质尾巴突变时，TGF - ？ - 诱导的浸润完全丢失。因此，通过MUC1 CT进行信号转导对于TGF - ？ - 引起的侵袭是必需的。 tgf-？是癌变的主要参与者，并以其作为肿瘤抑制剂和胰腺癌中肿瘤启动子的矛盾作用而闻名。了解驱动TGF-的因素和信号？从肿瘤抑制剂转换为肿瘤促进剂的功能引起了极大的关注。我们假设通过MUC1-CT信号传导支持TGF - ？ - 诱导的EMT和侵袭，并抑制TGF - ？ - 诱导的凋亡。具体目的是：1）确定TGF-的差异效应？在MUC1+，MUC1-和MUC1+细胞中诱导的EMT，其中MUC1 CT中的酪氨酸残基已突变为苯丙氨酸（MUC1 Y0）； 2）确定TGF-的差异效应？在MUC1+，MUC1-和MUC1 Y0细胞中诱导的凋亡。在体外和体内实验均针对目标提出。如果该假设是正确的，则将是MUC1充当开关的首次演示 PDA细胞，改变TGF-的促凋亡特性？到抗凋亡和促生物性特性。在开发旨在针对促进TGF-信号的未来疗法时，必须考虑获得的知识？同时仍保留TGF-的促凋亡信号。到目前为止，MUC1治疗药物一直集中在MUC1的细胞外区域，这并未导致临床成功。如果该假设成立，那么开发专门针对MUC1 CT信号传导的药物应成为优先级。