Stat3 Downstream Genes as Lung Adenocarcinoma Biomarkers

描述(申请人提供)：这项工作的长期目标是确定用于动物和人类肺腺癌诊断和预后的分泌性蛋白生物标记物。除了气体交换，肺还是通过炎症反应进行宿主防御的器官。炎症是一种保护性过程，有助于病原体清除和修复肺组织损伤。然而，旺盛的炎症可能会导致严重的后果，并导致癌症发生。白介素6(IL-6)家族细胞因子是肺部炎症过程中常见的促炎基因群。当IL-6家族成员与其细胞表面受体结合后，可通过Janus激活的蛋白激酶(JAK)激活信号转导和转录激活因子3(STAT3)。为了评估STAT3在肺内持续激活的后果，本实验室最近建立了强力霉素控制的CCSP-RTTA/(Teto)7-CMV-Stat3C双转基因小鼠模型，该模型在肺泡II型上皮细胞中高表达STAT3C(STAT3的组成活性形式)。在连续的步骤中，Stat3C的过度表达促进了肺部炎症和腺癌的发生，频率很高(80%)。这支持了一种观点，即STAT3信号引发的持续性炎症导致肺腺癌。在寻找人类肺癌样本时，STAT3上调与腺癌和鳞癌高度相关。因此，STAT3及其下游基因可作为动物和人类肺癌诊断的生物标志物。通过Affymetrix基因芯片芯片分析，在CCSP-RTTA/(Teto)7-CMV-Stat3C双价转基因小鼠中发现了多个STAT3下游基因。这一列表中一组变化最大的基因在人类腺癌中也显示了类似的变化，证实了STAT3下游基因适合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测试。这一建议的中心假设是，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。提出了两个目的来检验中心假说：1)STAT3下游基因在动物中作为肺癌生物标志物的特征。将使用三种与炎症相关的肺腺癌的动物模型。虽然它们在诱发肺腺癌的分子机制上有所不同，但STAT3基因上调和激活是三种动物模型中共同的机制；2)STAT3下游基因作为人类肺癌生物标志物的特征。将在肺腺癌、鳞状细胞癌和小细胞肺癌的肺组织和血液样本中筛选可能的分泌型生物标记物。在这些研究之后，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。 公共卫生相关性：肺癌是美国和许多其他国家面临的最大公共卫生挑战之一。这项工作将在人类和动物中识别肺癌诊断和预后的蛋白质生物标记物。

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. PUBLIC HEALTH RELEVANCE: Lung cancer is one of the biggest public health challenges facing the United States and many other countries. This work will identify protein biomarkers for lung cancer diagnosis and prognosis in humans and in animals.