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肺癌中作为显性癌基因发挥作用 肺癌（NSCLC）。然而，介导这些癌基因转化的信号通路仍然存在， 定义了此外，癌基因刺激促肿瘤和抗肿瘤信号传导。在这方面，JNK 由/n/c1、jnk 2和jnK 3编码的MAPK被生长因子和癌基因激活， 文献记载了JNK在细胞转化中的积极和消极作用。MKK 4，双特异性 JNK的激酶激活剂已经在多种人类癌症中作为肿瘤转移抑制剂出现。 与这一发现一致，我们对JNK 1和JNK 2缺陷小鼠的实验显示， 诱导肺肿瘤发生。此外，多种人NSCLC细胞系显示， 相对于未转化的肺上皮细胞和转染的功能获得性JNK 1，JNK活性降低 抑制非锚定依赖性NSCLC生长。因此，我们认为JNK 1和JNK 2的功能是 肺癌中的肿瘤抑制途径的组成部分。相比之下，JNK 3- 缺陷型小鼠显示致癌物诱导的肺肿瘤发生减少。此外，JNKS mRNA和 蛋白质在NSCLC细胞系和原发性肿瘤中相对于非转化肺上皮细胞表达 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， 代表促肿瘤发生JNK同种型。为了验证这些假设，我们将完成以下具体的 目标。目的1：确定特异性JNK在缺乏γ ′ n/c1的小鼠肺肿瘤发生中的体内作用， jnk 2或jnkS。特异性JNKs作为宿主肺微环境调节信号成分的作用 还将测试肺肿瘤发生。目的2：测试特异性JNK在肿瘤抑制或肿瘤生长中的体外作用。 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，转化、分化和凋亡的标准将是 测定了此外，用功能获得性JNK或显性阴性JNK转导的NSCLC细胞将被抑制。 监测细胞转化的标准。目标3：确定减少的机制 NSCLC细胞系中的JNK 1和JNK 2活性。MKPs作为癌基因诱导的负调节因子的作用 JNK 1和JNK 2活性将被突出显示。目的4：研究JNKs的激活状态和JNKs的表达状态， 在目的1-3中定义的特异性信号分子将在存档的原发性人肺肿瘤中测量， 免疫组化和定量RT-PCR，并与临床行为。实现这些具体目标将 从而全面了解该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，详细了解JNK MAP激酶在肺癌中的多方面作用， 这是绝对必要的理论基础和精确的治疗靶向这一途径，以打击肺癌。

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.