Scatter factor induced carcinoma cell migration

散射因子诱导癌细胞迁移

基本信息

  • 批准号:
    6795137
  • 负责人:
  • 金额:
    $ 11.01万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-09-01 至 2006-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Interactions between growth factors secreted by the stroma cells, extracellular matrix, and their receptors on carcinoma cells resulting in signal transduction are key to understanding the mechanisms underlying carcinoma cell migration and invasion. Such understanding requires identification of the genes induced by these interactions and the convergence of signaling pathways. Scatter factor, also known as Hepatocyte growth factor, (SF) and its tyrosine kinase protooncogene, Met, are upregulated in most metastatic cancers and is associated with a poor prognosis. SF causes migration of cancer cells, a process that requires de novo gene transcription. However, the early genes expressed by this new transcription are not known. Our long range goal is to determine carcinoma cell specific targets to inhibit metastasis. We have isolated a novel cDNA we call Mig-7 that is induced by SF in the human endometrial carcinoma cell lines, RL-95 [and HECIA, as well as the pancreatic carcinoma cell line FG] before migration occurs. Homology searches show that Mig-7 cDNA sequence possesses 99% homology with two human ESTs. However, no full length cDNA, gene or protein homologies were found. Expression of this gene is lacking in normal tissue as determined by reverse transcription and polymerase chain reaction. In contrast, it is detected in various metastatic human tumors such as ovary, colon, endometrial and squamous cell. Furthermore, the Mig-7 induction by SF is also regulated by ?v?5 integrin ligation. The focus of this proposal is to understand the role of Mig-7 in expression in carcinoma cell migration. Our hypothesis is that Mig-7 expression plays a role in migration of cancer cells. To test this hypothesis and accomplish the objective of this application we will pursue the following two specific aims: Aim 1 is to determine if the degree of cell migration is dependent upon the level of Mig-7 expression in carcinoma cells to test our hypothesis that Mig-7 expression leads to migration of carcinoma cells. [We base our hypothesis on our preliminary results showing that we can inhibit carcinoma cell migration by 83.50% +/- 2.77% (p<0.05) in vitro using antisense oligonucleotides specific to Mig-7 as compared to irrelevant oligonucleotide.] We will overexpress Mig-7 in carcinoma cell lines and measure migration and invasion capabilities as compared to controls using migration [and invasion] assays. Aim 2 is to determine the signaling mechanism underlying the cross talk between the Met and alphavbeta5 integrln signal transduction pathways because our studies indicate that both Met and alphavbeta5 integrin signaling pathways are required to induce Mig-7 expression. [Met activation has been shown to activate focal adhesion kinase (FAK). Further, tyrosine kinase receptor induction of FG carcinoma cell migration requires alphavbeta5 integrin binding. However, gene expression resulting from this cross-talk signaling has not been determined.] Mig-7 is a novel gene expressed in this signaling system. We expect that these studies will lead to a significant advance in the knowledge of how carcinoma cells migrate and could lead to a target for new anti-metastatic therapy.
描述(由申请人提供):基质细胞分泌的生长因子、细胞外基质及其在癌细胞上的受体之间的相互作用导致信号转导,这是理解癌细胞迁移和侵袭机制的关键。这种理解需要识别这些相互作用诱导的基因和信号通路的收敛。分散因子,也称为肝细胞生长因子(SF)及其酪氨酸激酶原癌基因Met,在大多数转移性癌症中上调,并与预后不良相关。SF导致癌细胞迁移,这是一个需要从头基因转录的过程。然而,这种新转录表达的早期基因尚不清楚。我们的长期目标是确定癌细胞特异性靶点以抑制转移。我们已经分离出一种新的cDNA,我们称之为Mig-7,它在人子宫内膜癌细胞系RL-95 [和HECIA,以及胰腺癌细胞系FG]中由SF诱导,然后发生迁移。同源性分析表明,Mig-7 cDNA序列与两个人类EST序列的同源性为99%。然而,没有发现全长cDNA,基因或蛋白质同源性。通过逆转录和聚合酶链反应测定,该基因在正常组织中缺乏表达。相反,在各种转移性人类肿瘤如卵巢、结肠、子宫内膜和鳞状细胞中检测到。此外,米格-7诱导SF也调节?v?5整合素连接。该建议的重点是了解Mig-7在癌细胞迁移中表达的作用。我们的假设是Mig-7的表达在癌细胞的迁移中起作用。为了检验这一假设并实现本申请的目的,我们将追求以下两个具体目标:目标1是确定细胞迁移的程度是否依赖于癌细胞中Mig-7表达的水平,以检验我们的Mig-7表达导致癌细胞迁移的假设。[We我们的假设基于我们的初步结果,表明我们可以在体外使用Mig-7特异性的反义寡核苷酸与无关寡核苷酸相比抑制癌细胞迁移83.50% +/-2.77%(p<0.05)。我们将在癌细胞系中过表达Mig-7,并使用迁移[和侵袭]测定与对照相比测量迁移和侵袭能力。目的2是确定Met和α v β 5整联蛋白信号转导途径之间的串扰的潜在信号传导机制,因为我们的研究表明Met和α v β 5整联蛋白信号传导途径都是诱导Mig-7表达所必需的。[Met活化已显示活化粘着斑激酶(FAK)。此外,FG癌细胞迁移的酪氨酸激酶受体诱导需要α v β 5整联蛋白结合。然而,由这种串扰信号传导引起的基因表达尚未确定。Mig-7是在该信号系统中表达的新基因。我们希望这些研究将导致癌细胞如何迁移的知识的重大进展,并可能导致新的抗转移治疗的目标。

项目成果

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J. Suzanne Lindsey其他文献

J. Suzanne Lindsey的其他文献

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{{ truncateString('J. Suzanne Lindsey', 18)}}的其他基金

Pem Homeobox Gene Function During Spermatogenesis
Pem 同源框基因在精子发生过程中的功能
  • 批准号:
    6950249
  • 财政年份:
    2004
  • 资助金额:
    $ 11.01万
  • 项目类别:
Scatter factor induced carcinoma cell migration
散射因子诱导癌细胞迁移
  • 批准号:
    6900210
  • 财政年份:
    2003
  • 资助金额:
    $ 11.01万
  • 项目类别:
Scatter factor induced carcinoma cell migration
散射因子诱导癌细胞迁移
  • 批准号:
    6681190
  • 财政年份:
    2003
  • 资助金额:
    $ 11.01万
  • 项目类别:

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