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首页> 外文学位 >Analysis of TWEAK Receptor (Fn14) Expression and Function in Non-small Cell Lung Cancer Cells.
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Analysis of TWEAK Receptor (Fn14) Expression and Function in Non-small Cell Lung Cancer Cells.

机译：非小细胞肺癌细胞中TWEAK受体（Fn14）表达和功能的分析。

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摘要

The cytokine tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a TNF superfamily member that is expressed by multiple cell types and is involved in many functions including proliferation, migration, survival, differentiation, de-differentiation, or cell death. It is the only ligand for the TNF receptor (TNFR) superfamily member Fibroblast Growth Factor-Inducible 14 (Fn14). The TWEAK:Fn14 signaling axis mediates multiple cellular processes including inflammation, angiogenesis, cell growth and death, and progenitor differentiation to aid in wound repair.;Fn14 is overexpressed in over a dozen solid tumor types and constitutive signaling of the receptor is thought to be involved in tumor growth and metastasis. We previously showed that Fn14 levels are elevated in non-small cell lung cancer (NSCLC) tumors and NSCLC cell lines expressing constitutively activated Epidermal Growth Factor Receptor (EGFR) mutants. Also, we found that treatment of EGFR-mutant cells with erlotinib, (an EGFR tyrosine kinase inhibitor that is FDA-approved for use in the treatment of advanced NSCLC) decreases Fn14 levels and that Fn14 levels regulate NSCLC cell migration in vitro.;In the present study, we extended these findings by showing that Fn14 levels also regulate NSCLC cell invasion. We also provide evidence that EGFR-mutant NSCLC cells that express high levels of Fn14 exhibit constitutive activation of the cytoplasmic tyrosine kinase Src. We found that inhibition of Src activity in NSCLC cells by dasatinib decreases Fn14 gene expression at both the mRNA and protein levels. Src depletion in NSCLC cells by siRNA also downregulates Fn14 protein expression. Finally, we show that Fn14 expression is significantly higher in an NIH 3T3 cell line engineered to express the constitutively active v-Src oncoprotein in comparison to parental NIH 3T3 cells, and that the NIH 3T3/v-Src cells require Fn14 expression for full invasive capacity. Taken together, these data demonstrate a functional role for Fn14 in NSCLC cell invasion and identify the Src tyrosine kinase as a new regulator of Fn14 gene expression.
机译：类似于细胞因子的肿瘤坏死因子（TNF）的凋亡微弱诱导剂（TWEAK）是TNF超家族成员，由多种细胞类型表达，并涉及许多功能，包括增殖，迁移，存活，分化，去分化或细胞死亡。它是TNF受体（TNFR）超家族成员成纤维细胞生长因子诱导型14（Fn14）的唯一配体。 TWEAK：Fn14信号轴介导多种细胞过程，包括炎症，血管生成，细胞生长和死亡以及祖细胞分化，以帮助伤口修复。; Fn14在十几种实体瘤类型中过表达，该受体的组成型信号传导被认为是参与肿瘤的生长和转移。我们以前显示Fn14水平在非小细胞肺癌（NSCLC）肿瘤和表达组成型激活的表皮生长因子受体（EGFR）突变体的NSCLC细胞系中升高。此外，我们发现用厄洛替尼（一种经FDA批准用于治疗晚期NSCLC的EGFR酪氨酸激酶抑制剂）治疗EGFR突变细胞会降低Fn14水平，并且Fn14水平在体外调节NSCLC细胞迁移。在本研究中，我们通过显示Fn14水平还调节NSCLC细胞侵袭来扩展这些发现。我们还提供证据表明，表达高水平Fn14的EGFR突变NSCLC细胞表现出细胞质酪氨酸激酶Src的组成型激活。我们发现达沙替尼抑制NSCLC细胞中Src活性会降低mRNA和蛋白质水平的Fn14基因表达。 siRNA在NSCLC细胞中的Src消耗也下调了Fn14蛋白的表达。最后，我们显示，与亲本NIH 3T3细胞相比，在经过工程改造以表达组成型活性v-Src癌蛋白的NIH 3T3细胞系中Fn14表达明显更高，并且NIH 3T3 / v-Src细胞需要Fn14表达才能实现全侵袭性容量。综上所述，这些数据证明了Fn14在NSCLC细胞侵袭中的功能性作用，并将Src酪氨酸激酶鉴定为Fn14基因表达的新调节剂。

著录项

  • 作者

    Cheng, Emily.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Molecular biology.;Oncology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 132 p.
  • 总页数 132
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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