Role of JNK Pathway in Lung Tumorigenesis

K-RAS和突变/过表达的EGFR家族成员在非小细胞中起主导癌基因的作用 肺癌(NSCLC)。然而，介导这些癌基因转化的信号通路仍然不完善。 已定义。此外，癌基因既能刺激促进肿瘤发生的信号，也能刺激抗肿瘤信号。在这方面，JNK MAPK由/n/c1、JNK2和JNK3编码，由生长因子、癌基因和文献报道激活 证明了JNK在细胞转化中的积极和消极作用。MKK4，一种双重特异性 JNKs的激活物，已在多种人类癌症中作为肿瘤转移抑制因子出现。 与这一发现一致的是，我们对JNK1和JNK2基因缺陷小鼠的实验显示，致癌物质- 诱导性肺肿瘤发生与野生型乳鼠相关。此外，多个人类非小细胞肺癌细胞系显示 相对于未转化的肺上皮细胞和转染型JNK1的JNK活性降低 抑制非锚定非小细胞肺癌生长。因此，我们认为JNK1和JNK2的功能是 肺癌中肿瘤抑制途径的组成部分。相比之下，对JNK3的初步研究- 基因缺陷的小鼠表现出致癌物诱导的肺肿瘤形成减少。此外，JNKS mRNA和 蛋白在非小细胞肺癌细胞系和原发肿瘤中的表达与未转化的肺上皮细胞相关 或未受累的肺组织。因此，我们假设JNKS是在肺癌进展和 代表促肿瘤的JNK亚型。为了验证这些假设，我们将完成以下具体操作 目标。目的1：探讨特异性JNKs在Y‘n/c1缺失小鼠肺肿瘤发生中的作用。 JNK2或JNKS。特异性JNKs作为宿主肺微环境调节的信号成分 肺肿瘤的发生也将被测试。目的2：检测特异性JNKs在体外抑制肿瘤生长中的作用 细胞转化。表达JNKs分子抑制物的未转化肺上皮细胞系 将用致癌K-RAS转导，转化、分化和凋亡的标准将 量过了。此外，转导了功能增益JNKs或显性阴性JNKs的NSCLC细胞将 监测细胞转化的标准。目标3：明确减少的机制(S) 非小细胞肺癌细胞株中JNK1和JNK2的活性。MKPs作为癌基因诱导的负性调节因子的作用 JNK1和JNK2活动将突出显示。目的4：JNKs的激活状态和表达状态 AIMS 1-3中定义的特定信号分子将在存档的原发人类肺肿瘤中进行测量 IHC和定量RT-PCR与临床行为相关。完成这些具体目标将 全面了解这一MAPK家族在肺中的复杂作用 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映射激酶在肺癌中的多方面作用的详细了解是 对于抗击肺癌的这一途径的基本原理和精确的治疗靶点来说，这是绝对必要的。

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.