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首页> 外文学位 >Dual-specificity Phosphatase-1 Regulates the Inflammatory Milieu in Head and Neck Squamous Cell Carcinoma.
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Dual-specificity Phosphatase-1 Regulates the Inflammatory Milieu in Head and Neck Squamous Cell Carcinoma.

机译：双重特异性磷酸酶1调节头颈部鳞状细胞癌中的炎症环境。

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摘要

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 that control these diverse cellular processes. Negative regulation of MAPK activity is provided by MAPK phosphatases that dephosphorylate MAPK proteins. The founding member of this class of phosphatases is dual-specificity phosphatase-1 (DUSP1) and has been shown to be crucial for negatively regulating innate immune responses. Initial studies revealed significant over-expression of DUSP1 in a range of human epithelial tumors including prostate, colon, and bladder, with loss of DUSP1 expression in tumors of higher histological grade and in metastases. Based on the above, this study hypothesized that DUSP1 is a negative regulator of tumor-promoting inflammation in head and neck cancer. To test this hypothesis, we first assessed the effect of Dusp1 deficiency in animal models of tumor progression. Dusp1 deficiency enhanced tumor progression in a carcinogen-induced model of oral cancer with higher levels of inflammatory infiltrate and gene expression. Deficiency in hematopoietic-derived cells by bone marrow transplant did not recapitulate the advanced disease phenotype seen in Dusp1 deficient animals. However, Dusp1 deficiency also enhanced the progression of subcutaneous syngeneic breast and prostate allograft tumors. Examination of Dusp1 deficient bone marrow macrophages revealed enhanced expression of inflammatory cytokine IL-1beta after stimulation with lipopolysaccharide. Elevated levels of IL-1beta were shown to be due to increased de novo transcription in addition to enhanced mRNA stability. Inflammasome activation was not affected by Dusp1 deficiency. Lastly, in human HNSCC tissues, both mRNA and protein DUSP1 was decreased in tumor compared to adjacent non-tumor samples, and IL-1beta protein was increased. These studies demonstrate DUSP1 expression is deregulated in HNSCC and suggests an important role for DUSP1 as a negative regulator of tumor-promoting inflammation through suppression of inflammatory cytokines, such as IL-1beta. Understanding the role of these inflammatory mediators and the upstream signaling pathways in the tumor microenvironment in head and neck cancer may yield novel therapeutic targets for prevention and treatment.
机译：在美国，头颈癌约占诊断出的恶性肿瘤的6％，每年估计有35,000例发病和7,000例死亡。头颈部鳞状细胞癌（HNSCC）占大多数头颈部癌，全球发病率超过500,000例。头颈癌患者通常处于疾病的晚期，尽管正在进行研究，但存活率仍低于其他较常见的恶性肿瘤。已经证明细胞因子和促炎因子在恶性转化的各个步骤中具有关键作用，包括肿瘤生长，存活，侵袭，血管生成和转移。丝裂原激活的蛋白激酶（MAPK），例如p38，JNK和ERK，将信息从细胞外信号传递到控制这些不同细胞过程的效应子。通过使MAPK蛋白脱磷酸的MAPK磷酸酶提供了MAPK活性的负调控。这类磷酸酶的创始成员是双特异性磷酸酶-1（DUSP1），并已被证明对负调节先天免疫反应至关重要。初步研究表明，DUSP1在一系列人类上皮肿瘤（包括前列腺癌，结肠癌和膀胱癌）中明显过表达，而在较高组织学级别和转移灶中的DUSP1表达却丢失了。基于上述，本研究假设DUSP1是头颈癌中促肿瘤炎症的负调节剂。为了验证这一假设，我们首先评估了Dusp1缺乏症在肿瘤进展动物模型中的作用。 Dusp1缺乏症在致癌物诱导的口腔癌模型中以较高的炎症浸润和基因表达水平增强了肿瘤的进展。骨髓移植造血干细胞的缺乏不能概括在Dusp1缺乏动物中看到的晚期疾病表型。但是，Dusp1缺乏症也促进了同种皮下乳腺癌和前列腺同种异体移植肿瘤的进展。缺乏Dusp1的骨髓巨噬细胞检查显示，用脂多糖刺激后，炎症细胞因子IL-1beta的表达增强。显示IL-1β水平升高是由于除了增强的mRNA稳定性之外还增加了从头转录。炎性体激活不受Dusp1缺乏症的影响。最后，在人类HNSCC组织中，与相邻的非肿瘤样品相比，肿瘤中的mRNA和蛋白DUSP1均降低，而IL-1β蛋白则升高。这些研究表明，DUSP1表达在HNSCC中被失调，并表明DUSP1通过抑制炎症细胞因子（例如IL-1beta）作为促进肿瘤的炎症反应的负调节剂发挥着重要作用。了解这些炎症介质和上游信号通路在头颈癌的肿瘤微环境中的作用可能会为预防和治疗提供新的治疗靶点。

著录项

  • 作者

    Zhang, Xiaoyi.;

  • 作者单位

    Medical University of South Carolina.;

  • 授予单位 Medical University of South Carolina.;
  • 学科 Oncology.;Immunology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 199 p.
  • 总页数 199
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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