MAP Kinase signal transduction disruption in cancer

肺癌是男性和女性癌症相关死亡的主要原因，并且仍然是一个主要的健康问题。明年将有超过15.9万人死于肺癌，超过乳腺癌、前列腺癌和结肠癌的总和。大多数肺癌病例可归因于吸烟，在某些情况下还可归因于其他环境风险因素。虽然戒烟者患肺癌的相对风险大幅下降，但前吸烟者仍有患肺癌的风险。最近的几项研究表明，超过50%的新诊断的肺癌发生在以前的吸烟者中。据估计，在美国，吸烟者和前吸烟者的人数大致相等。由于戒烟是一项重大的公共卫生举措，因此前吸烟者在肺癌病例中所占的比例将越来越高。因此，存在两个肺癌高危人群，改善疾病管理对当前和以前的吸烟者都有益。此外，对肺癌治疗中使用的化疗的耐药性仍然是一个主要问题，更好地了解耐药性机制可能会导致更有效的治疗。MAP 3 K8基因是一种在多种细胞中表达的促分裂原活化蛋白（MAP）激酶，发现当在3'末端改变时是致癌的和组成性激活的。然而，该基因的突变是罕见的，但MAP 3 K8表达的改变与多种肿瘤类型有关。MAP 3 K8具有激活多个级联的独特特性，包括增殖和凋亡信号转导途径，例如分别为MEK-1和SEK-1途径。在利用肺肿瘤DNA的NIH 3 T3转染测定中，我们的实验室鉴定了与先前使用啮齿动物模型的报道类似的MAP 3 K8的3'改变。我们首先假设MAP 3 K8可能是突变的靶点，因为我们是第一个报告原发性人类肿瘤中激活突变的小组。然而，已经清楚的是，突变在该基因的肿瘤发生中不是常见事件。随后，我们发现该基因在肺肿瘤细胞系中的表达水平不同。这促使我们研究其他下游途径来解释MAP 3 K8的致瘤潜力。这些包括转录因子阵列分析和蛋白激酶阵列实验。我们能够证实文献中的其他报告，证明NF-κ B和AP-1的上调，以及确定其他重要的转录因子在文献中没有报道。这些和其他实验以及已发表的报告使我们假设MAP 3 K8的表达增加发生在肺癌中并有助于疾病进展。我们最近发现，肺肿瘤细胞系中MAP 3 K8蛋白表达的增加导致下游信号通路的变化，并最终导致细胞存活中重要基因的转录。为了测试在常用的化疗剂紫杉醇存在下MAP 3 K8过表达对存活的影响，我们用MAP 3 K8稳定转染正常气管上皮细胞系。这些数据表明MAP 3 K8表达在肺癌细胞系中改变，并且由于其在炎症反应和细胞存活中的作用，MAP 3 K8过表达可能参与肿瘤进展。我们现在已经证明了MAP 3 K8表达水平在紫杉醇耐药性中的重要性。

Lung cancer is the leading cause of cancer related mortality in both men and women and remains a major health issue. More than 159,000 individuals will die from lung cancer in the coming year, more than breast, prostate and colon cancer combined. The majority of lung cancer cases is attributable to tobacco smoking and in some cases other environmental risk factors. Although the relative risk of developing lung cancer declines dramatically in smokers who quit, former smokers remain at risk for the disease. Several recent studies show that greater than 50% of newly diagnosed lung cancers occur in former smokers. Estimates suggest there are approximately equal numbers of smokers and former smokers in the United States. Since smoking cessation is a major public health initiative, former smokers will increasingly account for a higher percentage of lung cancer cases. Therefore, two high-risk population groups exist for lung cancer and improved disease management can be beneficial to both current and former smokers. Additionally, resistance to chemotherapy used in lung cancer treatment remains a major problem and a better understanding of the mechanisms for resistance could lead to therapies that are more effective. The MAP3K8 gene is a mitogen activated protein (MAP) kinase kinase kinase expressed in a variety of cells and found to be oncogenic and constitutively activated when altered at the 3' terminus. However, mutation of the gene is rare, but altered MAP3K8 expression is associated with multiple tumor types. MAP3K8 possesses the unique characteristic of activating multiple cascades, including both proliferative and apoptotic signal transduction pathways such as the MEK-1 and SEK-1 pathways, respectively. In NIH3T3 transfection assays utilizing lung tumor DNA, our lab identified a 3' alteration of MAP3K8 similar to the previous reports using rodent models. We first hypothesized that MAP3K8 might be a target for mutation since we were the first group to report an activating mutation in a primary human tumor. However, it has become clear that mutations are not a common event in tumorigenesis for this gene. Subsequently we showed varied levels of expression of the gene in lung tumor cell lines. This led us to investigate other downstream pathways to explain the tumorigenic potential of MAP3K8. These included transcription factor array analysis and protein kinase array experiments. We were able to confirm other reports in the literature demonstrating upregulation of NF-kappaB and AP-1 as well as identify other important transcription factors not reported in the literature. These and other experiments, as well as published reports lead us to hypothesize that increased expression of MAP3K8 occurs in lung cancer and contributes to disease progression. We have recently shown that increased protein expression of MAP3K8 in lung tumor cell lines leads to changes in downstream signaling pathways and ultimately transcription of important genes in cell survival. To test the effects of MAP3K8 over expression on survival in the presence of a commonly used chemotherapeutic, paclitaxel, we stably transfected a normal tracheal epithelial cell line with MAP3K8. These data suggest MAP3K8 expression is altered in lung cancer cells lines and because of its role in the inflammatory response and cell survival, MAP3K8 over expression may be involved in tumor progression. We have now demonstrated the importance of MAP3K8 expression levels in resistance to paclitaxel.