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，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危险因素。尽管戒烟的吸烟者患肺癌的相对风险大幅下降，但曾经吸烟者仍然面临患肺癌的风险。最近的几项研究表明，超过50%的新诊断肺癌发生在前吸烟者身上。据估计，美国的吸烟者和曾经吸烟者的人数大致相等。由于戒烟是一项重大的公共卫生倡议，既往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，改进的疾病管理对现在和以前的吸烟者都是有益的。此外，肺癌患者的预后非常差。肺癌治疗中对化疗的耐药性仍然是一个主要问题，更好地了解耐药性的机制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(MAP)激酶，当MAP3K8基因第3端改变时，发现其具有致癌性和结构性激活。然而，该基因的突变在人类中似乎是罕见的事件，但MAP3K8表达的改变与多种肿瘤类型有关。MAP3K8具有激活多个级联通路的独特特性，包括增殖和凋亡信号转导通路，如MEK-1和SEK-1通路。在利用肺癌DNA进行的NIH3T3转染实验中，我们的实验室发现了MAP3K8的一个类似于先前报道的3个突变。我们首先假设MAP3K8可能是突变的目标，因为我们是第一个报告原发人类肿瘤中存在激活突变的小组。然而，突变在该基因的肿瘤发生中并不常见，这一点已经变得很清楚。随后，我们发现该基因在肺肿瘤细胞系中的表达水平不同。这导致我们研究了其他下游途径，可以解释MAP3K8的致瘤潜力。这些实验包括转录因子阵列分析和蛋白激酶阵列实验。我们证实了文献中的其他报道，证明了核因子-kappaB和AP-1的上调，并鉴定了文献中没有报道的其他重要的转录因子。这些和其他实验，以及发表的报告，使我们修改了我们的假设，即MAP3K8的表达增加在肺癌中发生，并有助于疾病的进展。我们最近发现，肺癌细胞系中MAP3K8蛋白的表达增加会导致下游信号通路的改变，最终导致细胞生存中重要基因的转录发生变化。为了测试MAP3K8在常用化疗药物紫杉醇存在下过表达对存活率的影响，我们用MAP3K8稳定地转染了正常的气管上皮细胞系。这些数据表明，MAP3K8在肺癌细胞系中的表达发生了变化，由于其在炎症反应和细胞生存中的作用，MAP3K8的过度表达可能参与了肿瘤的进展。未来的实验将证明MAP3K8在紫杉醇耐药中的重要性。我们还利用基因敲除小鼠模型和皮肤两步致癌模型来测试MAP3K8在肿瘤发生中的作用。

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.