The role of mitogen-activated protein kinase phosphatase-1 in tumor progression

描述(申请人提供)：头颈癌约占美国被诊断的恶性肿瘤的6%，估计每年有35,000例发病率和超过7,000例死亡。头颈部鳞状细胞癌(HNSCC)是头颈部癌症的主要组成部分，全球发病率超过50万例。头颈癌患者通常处于疾病的晚期，尽管正在进行研究，但存活率仍然低于其他更常见的恶性肿瘤。细胞因子和促炎因子已被证明在肿瘤生长、存活、侵袭、血管生成和转移等恶性转化的各个步骤中起着关键作用。丝裂原活化蛋白激酶(MAPK)，如p38、JNK和ERK，将细胞外信号传递给控制这些不同细胞过程的效应器。MAPK活性的负调节是由使MAPK蛋白去磷酸化的MAPK磷酸酶(MKPs)提供的。这类磷酸酶的创始成员是丝裂原激活的蛋白激酶磷酸酶-1(MKP-1)。初步研究发现，MKP-1在一系列人类上皮性肿瘤中显著过度表达，仅在疾病的早期出现，而在组织学分级较高的肿瘤和转移瘤中，MKP-1的表达水平逐渐下降。我们假设HNSCC肿瘤微环境中低水平的MKP-1会产生高水平的促癌炎症。我们将讨论MKP-1通过MAPK活性对炎性细胞因子表达的调节如何在下列特定目标中影响HNSCC的发展和进展：1)确定MKP-1缺乏对致癌物诱导的口腔癌小鼠肿瘤发生和发展的影响；2)阐明MKP-1调控细胞因子IL-1b和CXCL1表达的机制；3)确定MKP-1在人HNSCC组织中的表达是否受到解除调控。了解炎症介质在头颈部癌症进展中的作用可能为预防和治疗产生新的治疗靶点。这项拟议的研究项目为天然免疫调节因子MKP-1在肿瘤微环境中的作用提供了必要的机制洞察。 公共卫生相关性：在美国，每年有3万多名患者被诊断为头颈癌。然而，几十年来，患者存活率并没有显著的改善。驱动肿瘤发展和进展的信号通路的解除调控还不是很清楚，特别是当它与肿瘤-间质间隔相互作用有关时。这些研究将确定先天免疫调节器对肿瘤变化做出反应以调节肿瘤微环境的潜在机制。

DESCRIPTION (provided by applicant): Head and neck cancer accounts for approximately 6% of diagnosed malignancies in the United States, with an estimated 35,000 incidences and over 7,000 deaths every year. Head and neck squamous cell carcinoma (HNSCC) comprises the majority of head and neck cancers, with a worldwide incidence of more than 500,000 cases. Head and neck cancer patients often present in advanced stages of disease, and despite ongoing research, survival rates remain lower than other more common malignancies. Cytokines and pro-inflammatory factors have been shown to have a critical role in the various steps of malignant transformation, including tumor growth, survival, invasion, angiogenesis, and metastasis. Mitogen-activated protein kinases (MAPK), such as p38, JNK, and ERK, relay information from extracellular signals to the effectors which control these diverse cellular processes. Negative regulation of MAPK activity is provided by MAPK phosphatases (MKPs) that dephosphorylate MAPK proteins. The founding member of this class of phosphatases is mitogen-activated protein kinase phosphatase-1 (MKP-1). Initial studies revealed significant over-expression of MKP-1 in a range of human epithelial tumors, seen only in the early phases of disease with levels of MKP-1 expression falling progressively in tumors of higher histological grade and in metastases. We hypothesize low levels of MKP-1 in the HNSCC tumor microenvironment generate high levels of tumor-promoting inflammation. We will address how MKP-1's regulation of inflammatory cytokine expression via MAPK activity may affect HNSCC development and progression in the following specific aims: 1) determine the impact of MKP-1 deficiency on tumor development and progression in a carcinogen-induced oral cancer murine model; 2) elucidate the mechanism by which MKP-1 regulates expression of the cytokines IL-1b and CXCL1; 3) determine whether MKP-1 expression is deregulated in human HNSCC tissues. Understanding the role of inflammatory mediators in head and neck cancer progression may yield novel therapeutic targets for prevention and treatment. This proposed research project provides necessary mechanistic insight into the function of innate immune regulator MKP-1 in the tumor microenvironment. PUBLIC HEALTH RELEVANCE: In the United States, head and neck cancer is diagnosed in over 30,000 patients annually. However, significant improvement in patient survival rates has not been made for several decades. The deregulation of signaling pathways driving tumor development and progression is not well understood, particularly as it pertains to tumor-stromal compartment interaction. These studies will identify underlying mechanisms by which an innate immune regulator responds to neoplastic changes to modulate the tumor microenvironment.