Role of JNK Pathway in Lung Tumorigenesis

JNK 通路在肺肿瘤发生中的作用

• 批准号: 7366994
• 负责人: LYNN E HEASLEY
• 金额: $ 25.51万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7366994
• 关键词: Accounting; Adenocarcinoma; Alleles; Anchorage-Independent Growth; Antibodies; Apoptosis; Archives; Behavior; Bioluminescence; Cancer cell line; Carcinogens; Cell Line; Clinical; Complement component C1s; Complex; Data; Diagnosis; Dominant-Negative Mutation; Epidermal Growth Factor Receptor; Epithelial Cells; Family; Family member; Gene Transfer; Growth; Growth Factor Oncogenes; Human; Image; Immunohistochemistry; In Situ; In Vitro; JUN gene; Knock-out; Knockout Mice; Lead; Literature; Luciferases; Lung; Lung Adenoma; Lung Neoplasms; MAPK10 gene; MAPK8 gene; MAPK9 gene; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Messenger RNA; Mitogen-Activated Protein Kinases; Modeling; Molecular; Monitor; Mus; Mutate; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Pathologic; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Primary Neoplasm; Protein Isoforms; Proteins; Protocols documentation; Rate; Relative (related person); Research Personnel; Retroviral Vector; Reverse Transcriptase Polymerase Chain Reaction; Role; Running; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; Small Interfering RNA; Specificity; Squamous Cell; Structure of parenchyma of lung; Testing; Therapeutic; Tissue Microarray; Transfection; Tumor Suppression; Tumor Suppressor Proteins; Tumor Tissue; Urethane; cancer cell; cell transformation; gain of function; in vivo; inhibitor/antagonist; loss of function; lung carcinogenesis; lung tumorigenesis; metaplastic cell transformation; mutant; novel; polypeptide; programs; research study; stress-activated protein kinase 1; therapeutic target; tumor; tumor growth; tumor progression; tumorigenic

K-Ras and mutated/over-expressed EGFR family members function as dominant oncogenes in non-small cell lung cancer (NSCLC). Yet, the signal pathways that mediate transformation by these oncogenes remainill- defined. Moreover, oncogenes stimulate both pro- and anti-tumorigenic signaling. In this regard, the JNK MAPKs, encoded by/n/c1, jnk2 and jnK3, are activated by growth factors and oncogenes and the literature documents both positive and negative roles for JNKs in cellular transformation. MKK4, a dual-specificity kinase activator of the JNKs, has emerged as a tumor metastasis suppressor in diverse human cancers. Consistent with this finding, our experiments with JNK1 and JNK2-deficient mice reveal increased carcinogen- induced lung tumorigenesis relative to wild-type littermates. Also, multiple human NSCLC cell lines show decreased JNK activity relative to non-transformed lung epithelial cells and transfected gain-of-function JNK1 inhibits anchorage-independent NSCLC growth. Thus, we propose that JNK1 and JNK2 function as components of a tumor suppressor pathway in lung cancer. By contrast, preliminary studies with JNK3- deficient mice reveal decreased carcinogen-induced lung tumorigenesis. In addition, JNKS mRNA and protein is expressed in NSCLC cell lines and primary tumors relative to non-transformed lung epithelial cells or uninvolved lung tissue. Thus, we hypothesize that JNKS is induced during lung cancer progression and represents a pro-tumorigenic JNK isoform. To test these hypotheses, we will complete the following specific aims. Aim 1: Determine the in vivo role for specific JNKs in murine lung tumorigenesis with mice lacking y'n/c1, jnk2 orjnkS. The role of specific JNKs as signal components of the host lung microenvironment regulating lung tumorigenesis will also be tested. Aim 2: Test the in vitro role of specific JNKs in tumor suppression or cellular transformation. Non-transformed lung epithelial cell lines expressing molecular inhibitors of the JNKs will be transduced with oncogenic K-Ras and criteria of transformation, differentiation and apoptosis will be measured. Also, NSCLC cells transduced with gain-of-function JNKs or dominant-negative JNKS will be monitored for criteria of cellular transformation. Aim 3: Define the mechanism(s) accounting for decreased JNK1 and JNK2 activity in NSCLC cell lines. The role of MKPs as oncogene-induced negative regulators of JNK1 and JNK2 activity will be highlighted. Aim 4: The activation state of JNKs and expression status of specific signaling molecules defined in Aims 1-3 will be measured in archived primary human lung tumors with IHC and quantitative RT-PCR and correlated with clinical behaviour. Completion of these specific aims will lead to a comprehensive understanding of the complex role of this family of MAP kinases in lung tumorigenesis and provide a format for exploration of the role of these kinases in other human cancers. Furthermore, a detailed understanding of the multi-faceted role of the JNK MAP kinases in lung cancer is absolutely required for rationale and precise therapeutic targeting of this pathway to combat lung cancer.

K-Ras 和突变/过度表达的 EGFR 家族成员在非小细胞中充当显性癌基因 肺癌（NSCLC）。然而，介导这些癌基因转化的信号通路仍然存在问题。 定义的。此外，癌基因刺激促肿瘤和抗肿瘤信号传导。对此，JNK MAPK 由/n/c1、jnk2 和 jnK3 编码，由生长因子和癌基因和文献激活 记录了 JNK 在细胞转化中的积极和消极作用。 MKK4，双重特异性 JNK 激酶激活剂已成为多种人类癌症的肿瘤转移抑制剂。 与这一发现一致的是，我们对 JNK1 和 JNK2 缺陷小鼠进行的实验揭示了致癌物质的增加—— 相对于野生型同窝小鼠，诱导肺部肿瘤发生。此外，多种人类 NSCLC 细胞系显示 相对于未转化的肺上皮细胞和转染功能获得性 JNK1 的 JNK 活性降低 抑制不依赖贴壁的 NSCLC 生长。因此，我们建议 JNK1 和 JNK2 的功能为 肺癌中肿瘤抑制途径的组成部分。相比之下，JNK3-的初步研究 缺陷小鼠显示致癌物诱导的肺部肿瘤发生减少。此外，JNKS mRNA 和 相对于未转化的肺上皮细胞，该蛋白在 NSCLC 细胞系和原发性肿瘤中表达 或未受累的肺组织。因此，我们假设 JNKS 在肺癌进展过程中被诱导，并且 代表促肿瘤 JNK 亚型。为了检验这些假设，我们将完成以下具体工作 目标。目标 1：确定特定 JNK 在缺乏 y'n/c1 的小鼠肺部肿瘤发生中的体内作用， jnk2 或jnkS。特定 JNK 作为宿主肺微环境调节信号成分的作用 还将测试肺部肿瘤的发生。目标 2：测试特定 JNK 在肿瘤抑制或肿瘤抑制中的体外作用 细胞转化。表达 JNK 分子抑制剂的非转化肺上皮细胞系 将用致癌 K-Ras 转导，并且转化、分化和凋亡的标准将是 测量。此外，用功能获得性 JNK 或显性失活 JNKS 转导的 NSCLC 细胞将 监测细胞转化的标准。目标 3：定义解释减少的机制 NSCLC 细胞系中的 JNK1 和 JNK2 活性。 MKP 作为癌基因诱导的负调节因子的作用 JNK1 和 JNK2 活动将突出显示。目标4：JNKs的激活状态和表达状态 目标 1-3 中定义的特定信号分子将在存档的原发性人肺肿瘤中进行测量 IHC 和定量 RT-PCR 并与临床行为相关。完成这些具体目标将 全面了解 MAP 激酶家族在肺中的复杂作用 肿瘤发生并为探索这些激酶在其他人类癌症中的作用提供了一种形式。 此外，对 JNK MAP 激酶在肺癌中的多方面作用的详细了解 绝对需要针对该途径对抗肺癌的基本原理和精确治疗靶向。