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。未来一年将有超过15.9万人死于肺癌，超过乳腺癌、前列腺癌和结肠癌死亡人数的总和。大多数肺癌病例可归因于吸烟，在某些情况下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大降低，但曾经吸烟的人仍然有患肺癌的风险。最近的几项研究表明，超过50%的新诊断的肺癌发生在前吸烟者中。据估计，在美国，吸烟者和已戒烟者的人数大致相当。由于戒烟是一项重大的公共卫生倡议，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，改善疾病管理对现在和以前的吸烟者都是有益的。此外，对肺癌化疗的耐药性仍然是一个主要问题，对耐药性机制的更好理解可能会导致更有效的治疗。MAP3K8基因是一种在多种细胞中表达的有丝分裂原激活蛋白激酶，当3 '端发生改变时，它被发现是致癌的和组成性激活的。然而，该基因的突变是罕见的，但改变的MAP3K8表达与多种肿瘤类型有关。MAP3K8具有激活多种级联的独特特性，包括增殖和凋亡信号转导途径，如MEK-1和SEK-1途径。在利用肺肿瘤DNA的NIH3T3转染试验中，我们的实验室发现了MAP3K8的3 prime改变，与之前使用啮齿动物模型的报道相似。我们首先假设MAP3K8可能是突变的靶点，因为我们是第一个在原发性人类肿瘤中报告激活突变的小组。然而，很明显，突变并不是该基因发生肿瘤的常见事件。随后，我们在肺肿瘤细胞系中发现了不同水平的基因表达。这促使我们研究其他下游途径来解释MAP3K8的致瘤潜能。其中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其他报道的NF-kappaB和AP-1的上调，并确定文献中未报道的其他重要转录因子。这些和其他实验以及已发表的报告使我们修改了我们的假设，即MAP3K8的表达增加发生在肺癌中并有助于疾病进展。我们最近的研究表明，肺肿瘤细胞系中MAP3K8蛋白表达的增加导致下游信号通路的改变，最终导致细胞存活中重要基因的转录。为了测试MAP3K8过表达对常用化疗紫杉醇存在下存活的影响，我们用MAP3K8稳定转染了正常气管上皮细胞系。这些数据表明，MAP3K8在肺癌细胞系中的表达发生了改变，并且由于其在炎症反应和细胞存活中的作用，MAP3K8的过表达可能参与了肿瘤的进展。未来的实验将证明MAP3K8在紫杉醇抗性中的重要性。我们还将使用敲除小鼠模型和皮肤两步癌变模型来测试MAP3K8对肿瘤发生的影响。

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 more effective therapies. 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 prime 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 prime 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 modify our hypothesis that increased expression of MAP3K8 occur in lung cancer and contribute 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. Future experiments will demonstrate the importance of MAP3K8 in resistance to paclitaxel. We are also positioned to test the effect of MAP3K8 on tumorigenesis using the knockout mouse model and the skin two step carcinogenesis model.