Determinants of AGR2 effects in Barrett's esophagus and esophageal adenocarcinoma

Barrett 食管和食管腺癌中 AGR2 作用的决定因素

基本信息

批准号：
8059699
负责人：
ANSON W LOWE
金额：
$ 33.04万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-30 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8059699
关键词：
AGR2 gene Adenocarcinoma Adenocarcinoma Cell Affect Agar Anchorage-Independent Growth Applications Grants Area Barrett Esophagus Barrett&apos s Adenocarcinoma Binding Biological Biological Assay Biology Breast Cancer Biology Cancer Cell Growth Cell Aging Cell Line Cell Proliferation Cells Cellular biology Clinical Colon Colon Carcinoma Critiques Cytokeratin DNA Microarray Chip Data Development Disease Endoscopic Biopsy Esophageal Adenocarcinoma Esophageal Tissue Exhibits Faculty Fine needle aspiration biopsy Funding Gastroenterologist Gastroesophageal reflux disease Gastrointestinal Neoplasms Gastrointestinal tract structure Gene Expression Gene Expression Profiling Gene Proteins Genes Genomics Goals Growth Health Heartburn Human Genome In Vitro Intestines Laboratories Lead Left Lesion Link Liver Malignant Neoplasms Malignant neoplasm of esophagus Malignant neoplasm of pancreas Malignant neoplasm of prostate Mediating Mediator of activation protein Molecular Profiling Names Normal Cell Nude Mice Nursing Faculty Oncogenes Pancreas Pancreatic Adenocarcinoma Pathogenesis Patient Recruitments Patients Premalignant Principal Investigator Private Practice Process Promoter Regions Property Prostate Publications Publishing RNA RNA Interference Recruitment Activity Regulation Reporter Research Resected Ribonucleases Risk Role Sampling Secondary to Secretory Cell Signal Pathway Signal Transduction Signal Transduction Pathway Source Stem cells Stomach Tertiary Protein Structure Therapeutic Intervention Tissue Sample Tissues Universities Work Xenograft procedure cancer stem cell career cell age cell motility cell type experience gastrointestinal human AGR2 protein human tissue improved in vitro Assay in vivo insight interest intestinal crypt malignant breast neoplasm member novel therapeutics promoter protein profiling response tissue culture tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Barrett's esophagus is a premalignant lesion that increases the risk for esophageal adenocarcinoma. During the last funding period, gene expression analysis revealed that compared to normal esophageal tissue, the AGR2 gene is highly expressed in Barrett's esophagus and esophageal adenocarcinoma. AGR2 is also expressed in a variety of other adenocarcinomas including colon, pancreatic, breast, and prostate cancers. Using RNA interference to repress gene expression in a Barrett's associated adenocarcinoma cell line, SEG-1, we established that AGR2 displays many properties associated with other genes important in cancer. SEG-1 AGR2 knockdown cells show a reduction in colony formation in soft agar and decreased growth as xenografts in nude mice. Tissue culture supernatant containing AGR2 increases cell migration in an in vitro assay. AGR2 also displayed features associated with previously described oncogenes in its ability to transform NIH3T3 cells in in vitro assays such as foci formation and the capacity for anchorage independent growth in soft agar. Studies of AGR2 expression in normal cells revealed that it is expressed in a distribution consistent with areas of cell proliferation in the intestinal crypts throughout the gastrointestinal tract. We have established that intestinal cells of secretory lineage specifically express AGR2. The results suggest that AGR2 may represent a link between gastrointestinal lineage-specific stem cells and cancer. During the next funding period, we propose to elucidate AGR2's mechanism of action. We will define the essential AGR2 protein domains required for its actions, the genomic domains and determinants for its expression, and the genes and proteins whose expression is affected by AGR2. It is likely that AGR2's effects are mediated via activation of signal transduction pathways, the identity of which will also be determined. Studies focused on AGR2 will provide valuable insights into esophageal cancer biology and serves as a promising target for therapeutic intervention. It is also likely that many other adenocarcinomas that express AGR2 will benefit from an understanding of this gene's biology. PUBLIC HEALTH RELEVANCE: Barrett's esophagus is an abnormal lesion commonly found in patients with gastroesophageal reflux, which commonly presents as heartburn. The presence of Barrett's esophagus increases one's risk for esophageal adenocarcinoma by up to 40-fold. Our laboratory recently performed a screen of the entire human genome looking for genes that are active in Barrett's esophagus and adenocarcinoma. We found a gene named AGR2 to be particularly active. Our laboratory has recently found that an active AGR2 gene promotes esophageal cancer cell growth. We also discovered that the AGR2 gene is expressed in the normal gastrointestinal tract in areas often associated with stem cells. These stem cells give rise to all the different cell types in the gastrointestinal tract and are responsible for the normal replacement of aged cells. Current hypotheses propose that deranged regulation of stem cells may give rise to cancer. Additional studies have revealed that cells expressing AGR2 belong to the secretory lineage of the intestine, which is the cell type that develops into adenocarcinomas. The data supports a significant role for AGR2 in the development of esophageal adenocarcinomas. We propose to determine during the next funding period how AGR2 promotes the development of Barrett's esophagus and esophageal adenocarcinoma. We will determine what cellular signals induce AGR2 expression as well as those signaling pathways that are induced by AGR2 itself. Adenocarcinomas are glandular cancers that are also common in the colon, pancreas, breast and prostate. Because the AGR2 gene is active in all these cancers, studies focused on this gene will increase our understanding of the mechanisms underlying many cancers and provide an opportunity for developing new therapeutic strategies.

描述（由申请人提供）：巴雷特食管是一种癌前病变，会增加食管腺癌的风险。在上一个资助期间，基因表达分析显示，与正常食管组织相比，AGR2基因在巴雷特食管和食管腺癌中高表达。 AGR2 还在多种其他腺癌中表达，包括结肠癌、胰腺癌、乳腺癌和前列腺癌。使用 RNA 干扰来抑制 Barrett 相关腺癌细胞系 SEG-1 中的基因表达，我们确定 AGR2 显示出与癌症中重要的其他基因相关的许多特性。 SEG-1 AGR2 敲低细胞在软琼脂中显示集落形成减少，并且在裸鼠中作为异种移植物的生长减少。在体外测定中，含有 AGR2 的组织培养上清液可增加细胞迁移。 AGR2 还表现出与先前描述的癌基因相关的特征，即其在体外测定中转化 NIH3T3 细胞的能力，例如病灶形成和在软琼脂中贴壁独立生长的能力。对正常细胞中 AGR2 表达的研究表明，它的表达分布与整个胃肠道肠隐窝中的细胞增殖区域一致。我们已经确定分泌谱系的肠细胞特异性表达 AGR2。结果表明，AGR2 可能代表胃肠道谱系特异性干细胞与癌症之间的联系。在下一个资助期内，我们建议阐明 AGR2 的作用机制。我们将定义其作用所需的基本 AGR2 蛋白结构域、其表达的基因组结构域和决定因素，以及其表达受 AGR2 影响的基因和蛋白。 AGR2 的作用很可能是通过信号转导途径的激活来介导的，其身份也将被确定。专注于 AGR2 的研究将为食管癌生物学提供有价值的见解，并作为治疗干预的一个有希望的目标。许多其他表达 AGR2 的腺癌也可能会受益于对该基因生物学的了解。公众健康相关性：巴雷特食管是一种常见于胃食管反流患者的异常病变，通常表现为胃灼热。巴雷特食管的存在会使食管腺癌的风险增加高达 40 倍。我们的实验室最近对整个人类基因组进行了筛选，寻找在巴雷特食管和腺癌中活跃的基因。我们发现一个名为 AGR2 的基因特别活跃。我们实验室最近发现一个活跃的AGR2基因可以促进食管癌细胞的生长。我们还发现 AGR2 基因在正常胃肠道中通常与干细胞相关的区域中表达。这些干细胞产生胃肠道中所有不同的细胞类型，并负责老化细胞的正常替换。目前的假设表明，干细胞的失调调节可能会导致癌症。其他研究表明，表达 AGR2 的细胞属于肠道分泌谱系，即发展为腺癌的细胞类型。该数据支持 AGR2 在食管腺癌的发展中发挥重要作用。我们建议在下一个资助期内确定 AGR2 如何促进巴雷特食管和食管腺癌的发展。我们将确定哪些细胞信号诱导 AGR2 表达以及 AGR2 本身诱导的信号通路。腺癌是腺癌，也常见于结肠、胰腺、乳腺癌和前列腺。由于 AGR2 基因在所有这些癌症中都很活跃，因此针对该基因的研究将增加我们对许多癌症潜在机制的理解，并为开发新的治疗策略提供机会。