MAP Kinase signal transduction disruption in cancer

肺癌是男性和女性癌症相关死亡率的主要原因， 仍然是一个重大的健康问题。超过159，000人将死于肺癌， 超过乳腺癌、前列腺癌和结肠癌的总和。大多数肺癌 这些病例可归因于吸烟，在某些情况下还可归因于其他环境风险因素。 尽管吸烟者患肺癌的相对风险在吸烟者中显著下降， 戒烟后，以前的吸烟者仍然有患这种疾病的危险。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数量大致相等。以来 戒烟是一项重大的公共卫生举措， 占肺癌病例的比例更高。因此，两个高危人群 肺癌的治疗和疾病管理的改善对目前的 前吸烟者。此外，肺癌患者的预后非常差。 对肺癌治疗中使用的化疗药物的耐药性仍然是一个主要问题， 对耐药性机制的理解可能会导致更有效的治疗。的 MAP 3 K8基因是一种有丝分裂原活化蛋白激酶激酶，在多种细胞中表达。 发现当3端改变时是致癌的和组成性激活的。 然而，该基因的突变似乎是一个罕见的事件在人类，但改变MAP 3 K8 表达与多种肿瘤类型相关。MAP 3 K8具有独特的特性， 激活多个级联反应，包括增殖和凋亡信号 在一些实施方案中，它们分别通过转导途径如MEK-1和SEK-1途径来表达。在nih 3 t3 利用肺肿瘤DNA的转染实验，我们的实验室鉴定了MAP 3 K8的3个改变， 与以前的报告类似。我们首先假设MAP 3 K8可能是一个靶点， 因为我们是第一个报告原发性人类中激活突变的小组， 肿瘤然而，已经清楚的是，突变不是肿瘤发生中的常见事件， 这个基因。随后，我们发现该基因在肺肿瘤细胞中有不同水平的表达， 线这使我们研究了其他下游途径，可以解释肿瘤的发生。 MAP 3 K8的潜力。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， NF-κ B和AP-1的上调以及鉴定其他重要的转录因子 文献中未报道。这些和其他实验，以及已发表的报告导致 我们修改了我们的假设，即MAP 3 K8的表达增加发生在肺癌， 有助于疾病进展。我们最近的研究表明， 肺肿瘤细胞系中的MAP 3 K8导致下游信号通路的变化， 最终影响细胞存活的重要基因的转录。为了测试MAP 3 K8的效果， 在常用的化疗剂，紫杉醇， 我们用MAP 3 K8稳定转染了正常气管上皮细胞系。这些数据表明 MAP 3 K8在肺癌细胞系中的表达发生改变，由于其在肺癌细胞中的作用， MAP 3 K8的过度表达可能与肿瘤的发生、发展、炎症反应和细胞存活有关 进展未来的实验将证明MAP 3 K8在抗肿瘤中的重要性。 紫杉醇。我们还准备使用免疫组织化学方法检测MAP 3 K8对肿瘤发生的影响。 基因敲除小鼠模型和皮肤两步致癌模型。

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. It is estimated that 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, the prognosis for lung cancer patients is very poor. 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 end. However, mutation of the gene appears to be a rare event in humans, 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. 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 that could 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.