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:
    7523291
  • 负责人:
  • 金额:
    $ 33.2万
  • 依托单位:
  • 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 2012-03-31
  • 项目状态:
    已结题

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(由申请方提供):Barrett食管是一种癌前病变,可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,AGR 2基因在巴雷特食管和食管腺癌中高度表达。AGR 2还在多种其它腺癌中表达,包括结肠癌、胰腺癌、乳腺癌和前列腺癌。使用RNA干扰抑制基因表达的巴雷特相关的腺癌细胞系,SEG-1,我们建立了AGR 2显示与其他基因在癌症中的重要的许多属性。SEG-1 AGR 2敲减细胞显示软琼脂中集落形成减少,并且作为裸鼠中的异种移植物生长减少。含有AGR 2的组织培养上清液在体外测定中增加细胞迁移。AGR 2还显示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NIH 3 T3细胞的能力,例如灶形成和在软琼脂中锚定独立生长的能力。对AGR 2在正常细胞中表达的研究表明,其表达的分布与整个胃肠道的肠隐窝中的细胞增殖区域一致。我们已经确定,肠细胞的分泌谱系特异性表达AGR 2。结果表明,AGR 2可能代表了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AGR 2的作用机制。我们将定义其作用所需的基本AGR 2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AGR 2影响的基因和蛋白质。AGR 2的作用可能是通过激活信号转导途径介导的,其身份也将被确定。专注于AGR 2的研究将为食管癌生物学提供有价值的见解,并作为治疗干预的有希望的靶点。许多其他表达AGR 2的腺癌也可能受益于对该基因生物学的理解。公共卫生相关性: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。Barrett食管的存在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AGR 2的基因特别活跃。我们的实验室最近发现,活性AGR 2基因促进食管癌细胞生长。我们还发现AGR 2基因在正常胃肠道中通常与干细胞相关的区域中表达。这些干细胞在胃肠道中产生所有不同的细胞类型,并负责老化细胞的正常替换。目前的假说认为,干细胞的失调可能导致癌症。其他研究表明,表达AGR 2的细胞属于肠的分泌谱系,这是发展成腺癌的细胞类型。数据支持AGR 2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AGR 2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AGR 2表达以及AGR 2本身诱导的信号通路。腺癌是在结肠、胰腺、乳腺和前列腺中也常见的腺癌。由于AGR 2基因在所有这些癌症中都是活跃的,因此专注于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。

项目成果

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ANSON W LOWE其他文献

ANSON W LOWE的其他文献

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{{ truncateString('ANSON W LOWE', 18)}}的其他基金

The Role of AGR2 in a Murine Model of Pancreatic Adenocarcinoma
AGR2 在小鼠胰腺癌模型中的作用
  • 批准号:
    8189795
  • 财政年份:
    2011
  • 资助金额:
    $ 33.2万
  • 项目类别:
The Role of AGR2 in a Murine Model of Pancreatic Adenocarcinoma
AGR2 在小鼠胰腺癌模型中的作用
  • 批准号:
    8290308
  • 财政年份:
    2011
  • 资助金额:
    $ 33.2万
  • 项目类别:
Making a Digestive Sciences Career Palatable
让消化科学职业变得愉快
  • 批准号:
    7080384
  • 财政年份:
    2003
  • 资助金额:
    $ 33.2万
  • 项目类别:
Making a Digestive Sciences Career Palatable
让消化科学职业变得愉快
  • 批准号:
    7217961
  • 财政年份:
    2003
  • 资助金额:
    $ 33.2万
  • 项目类别:
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
  • 批准号:
    7792335
  • 财政年份:
    2002
  • 资助金额:
    $ 33.2万
  • 项目类别:
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
  • 批准号:
    8059699
  • 财政年份:
    2002
  • 资助金额:
    $ 33.2万
  • 项目类别:
Epithelial-Refluxate Interactions in Barrett's Esophagus
巴雷特食管上皮反流相互作用
  • 批准号:
    7114259
  • 财政年份:
    2002
  • 资助金额:
    $ 33.2万
  • 项目类别:
Epithelial-Refluxate Interactions in Barrett's Esophagus
巴雷特食管上皮反流相互作用
  • 批准号:
    6947280
  • 财政年份:
    2002
  • 资助金额:
    $ 33.2万
  • 项目类别:
Epithelial-Refluxate Interactions in Barrett's Esophagus
巴雷特食管上皮反流相互作用
  • 批准号:
    6787772
  • 财政年份:
    2002
  • 资助金额:
    $ 33.2万
  • 项目类别:
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
  • 批准号:
    7633336
  • 财政年份:
    2002
  • 资助金额:
    $ 33.2万
  • 项目类别:

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