Stat3 Downstream Genes as Lung Adenocarcinoma Biomarkers

Stat3 下游基因作为肺腺癌生物标志物

• 批准号: 8605808
• 负责人: Cong Yan
• 金额: $ 33.32万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605808
• 关键词: Adenocarcinoma; Alveolar; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Biological Markers; Blood; Blood Tests; Blood specimen; Bronchoalveolar Lavage; Cancer Patient; Cancer Prognosis; Cell Surface Receptors; Cells; Country; Cytomegalovirus; Diagnosis; Doxycycline; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Family; Family member; Frequencies; Gases; Gene Chips; Genes; Goals; Host Defense; Human; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-6; Laboratories; Lead; Liquid substance; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Messenger RNA; Microarray Analysis; Modeling; Molecular; Mus; Organ; Outcome; Phosphorylation; Phosphotransferases; Plasma Proteins; Play; Pneumonia; Process; Proteins; Public Health; Role; STAT3 gene; Sampling; Signal Transduction; Squamous cell carcinoma; Stat3 protein; Structure of parenchyma of lung; Testing; Time; United States; Up-Regulation; Western Blotting; Work; c-fms Proto-Oncogenes; cancer diagnosis; carcinogenesis; chemokine; cytokine; lung small cell carcinoma; mouse model; outcome forecast; pathogen; public health relevance; secretory protein; tissue repair

DESCRIPTION (provided by applicant): The long-term goal of this work is to identify secretory protein biomarkers for lung adenocarcinoma diagnosis and prognosis in animals and in humans. In addition to gas exchange, the lung is an organ for host defense through inflammatory responses. Inflammation is a protective process that facilitates pathogen clearance and repairs tissue injury in the lung. However, exuberant inflammation can cause severe consequences and lead to carcinogenesis. One commonly induced pro-inflammatory gene group during pulmonary inflammation is the interleukin 6 (IL-6) family cytokines. Upon binding to their cell-surface receptors, IL-6 family members trigger activation (phosphorylation) of signal transducer and activator of transcription 3 (Stat3) by Janus-activated kinases (JAKs). To assess the consequences of STAT3 persistent activation in the lung, a doxycycline-controlled CCSP-rtTA/(tetO)7-CMV-Stat3C bitransgenic mouse model was generated recently in our laboratory that over-expresses STAT3C (the constitutively active form of STAT3) in alveolar type II (AT II) epithelial cells. In sequential steps, Stat3C over-expression promoted inflammation and adenocarcinoma in the lung with a high frequency (80%). This supports a concept that persistent inflammation triggered by the Stat3 signaling induces lung adenocarcinoma. In searching for human lung cancer samples, Stat3 up-regulation was highly associated with adenocarcinoma and squamous cell carcinoma. Therefore, Stat3 and its downstream genes can be used as biomarkers for lung cancer diagnosis in animals and humans. By Affymetrix GeneChip microarray analysis, multiple Stat3 downstream genes were identified in CCSP-rtTA/(tetO)7-CMV-Stat3C bitransgenic mice. A set of mostly-changed-genes from this list showed similar changes in human adenocarcinoma, confirming that Stat3 downstream genes are suitable for lung cancer diagnosis and prognosis. Since many Stat3 downstream genes are plasma proteins, we plan to use them for blood testing in both animal lung adenocarcinoma models and in human lung cancer patients. The central hypothesis for this proposal is that secreted protein products of Stat3 downstream genes can be used for diagnosis and prognosis of lung adenocarcinomas in animal models and in humans. Two aims are proposed to test the central hypothesis: 1) Characterization of Stat3 downstream genes as lung cancer biomarkers in animals. Three animal models that developed lung adenocarcinoma in association with inflammation will be used. Although they represent different molecular mechanisms for inducing lung adenocarcinoma, Stat3 gene up-regulation and activation are the common mechanism in all three animal models; 2) Characterization of Stat3 downstream genes as lung cancer biomarkers in humans. Putative secreted biomarkers will be screened in lung tissues and blood samples that are from human adenocarcinoma, squamous cell carcinoma and small cell lung cancer. After these studies, we would like to formulate a panel of protein biomarkers for diagnosis and prognosis in the blood of animal models and in human lung cancer patients.

描述（由申请人提供）：这项工作的长期目标是鉴定用于动物和人类肺腺癌诊断和预后的分泌蛋白生物标志物。除了气体交换之外，肺还是通过炎症反应进行宿主防御的器官。炎症是一种保护过程，有助于清除病原体并修复肺部组织损伤。然而，旺盛的炎症会导致严重的后果并导致癌变。肺部炎症过程中常见的一种促炎基因组是白细胞介素 6 (IL-6) 家族细胞因子。在与其细胞表面受体结合后，IL-6 家族成员通过 Janus 激活激酶 (JAK) 触发信号转导器和转录激活剂 3 (Stat3) 的激活（磷酸化）。为了评估肺中 STAT3 持续激活的后果，我们实验室最近生成了强力霉素控制的 CCSP-rtTA/(tetO)7-CMV-Stat3C 双转基因小鼠模型，该模型在肺泡 II 型 (AT II) 上皮细胞中过度表达 STAT3C（STAT3 的组成型活性形式）。在连续的步骤中，Stat3C 过度表达以高频率 (80%) 促进肺部炎症和腺癌。这支持了 Stat3 信号传导引发的持续炎症会诱发肺腺癌的概念。在寻找人类肺癌样本时，Stat3 上调与腺癌和鳞状细胞癌高度相关。因此，Stat3及其下游基因可以作为动物和人类肺癌诊断的生物标志物。通过 Affymetrix GeneChip 微阵列分析，在 CCSP-rtTA/(tetO)7-CMV-Stat3C 双转基因小鼠中鉴定出多个 Stat3 下游基因。该列表中的一组变化最多的基因在人类腺癌中显示出类似的变化，证实了 Stat3 下游基因适用于肺癌的诊断和预后。由于许多 Stat3 下游基因是血浆蛋白，我们计划将它们用于动物肺腺癌模型和人类肺癌患者的血液检测。该提议的中心假设是 Stat3 下游基因的分泌蛋白产物可用于动物模型和人类肺腺癌的诊断和预后。提出了两个目标来检验中心假设：1）表征 Stat3 下游基因作为动物肺癌生物标志物的特征。将使用三种与炎症相关的肺腺癌动物模型。尽管它们代表了诱导肺腺癌的不同分子机制，但 Stat3 基因上调和激活是所有三种动物模型中的共同机制； 2) Stat3下游基因作为人类肺癌生物标志物的表征。将在来自人类腺癌、鳞状细胞癌和小细胞肺癌的肺组织和血液样本中筛选假定的分泌生物标志物。经过这些研究，我们希望制定一组蛋白质生物标志物，用于动物模型和人类肺癌患者血液中的诊断和预后。