PP5-ROLE OF A TRANSMEMBRANE PROTEASE, DIPEPTIDYL PEPTIDASE IN NEUROBLASTOMAS

PP5-跨膜蛋白酶、二肽基肽酶在神经母细胞瘤中的作用

• 批准号: 7381258
• 负责人: UMADEVI V WESLEY
• 金额: $ 9.14万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381258
• 关键词: endopeptidases; growth factor; neoplasm /cancer; peptidases; phenotype; role

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Neuroblastoma (NB) is a pediatric tumor that originates from precursor cells of the sympathetic nervous system that have discontinued their normal differentiation program. The factors implicated in the differentiation program are therefore of importance in the study of the genesis of NB. About 70% of children with widespread metastatic or aggressive localized tumors have overall poor prognosis. Evidence, such as expression of genes normally expressed only during embryonic and fetal stages, suggests that the tumor is of embryonic origin. Molecular mechanisms involved in NB are not well understood. As a neuroendocrine tumor, NB expresses high levels of growth factors and peptide hormones that exert tumor promoting effects. The differentiation of precursor cells into neurons is influenced by both growth factor and the Notch signaling pathways. The role of Notch and growth factor interaction in NB remains to be determined. The cell surface protease, dipeptidyl peptidase IV (DPPIV) is a differentiating antigen that regulates activity of many neuropeptides and growth factors by proteolytic cleavage, and its expression is lost in many cancers. We have recently shown that DPPIV decreases the levels of basic fibroblast growth factor bFGF, a potent mitogen, an anti-apoptotic, and an angiogenic inducer. Our previous work provides compelling evidence that DPPIV functions as a tumor suppressor gene for prostate cancer, lung cancer, and melanoma (a cancer of neuroectodermal origin) by inducing differentiation and apoptosis. Interestingly, DPPIV is expressed in mammalian neurons and its expression is lost in poorly differentiated NBs. Despite these correlative observations, the role of DPPIV in NB is unknown. Our initial studies show that DPPIV is decreased in NB derived cell lines and re-expression of DPPIV leads to induction of the differentiated phenotype. These data imply an important role for DPPIV in regulating the development of NB. The goal of this proposal is to define the roles of DPPIV on malignant phenotype of NB and to identify the link, if any, to bFGF and Notch signaling that play an important role in neuronal development. Taken together, the results from these studies represent an important step towards our long term goal of establishing pathways critical for modulating differentiation program and suppression of cancerous phenotype of NB derived cells by serine proteases including DPPIV. Hypothesis: We hypothesize that DPPIV is a negative regulator of NB progression. We predict that loss of DPPIV results in increased bFGF levels and activation of Notch signaling that halts the differentiation program, and provides growth stimulatory signals for proliferation/survival and malignant transformation of NB cells.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。神经母细胞瘤（NB）是一种儿科肿瘤，起源于已停止其正常分化程序的交感神经系统的前体细胞。因此，与分化程序有关的因素在研究NB的起源的研究中至关重要。大约70％的患有广泛转移性或侵略性局部肿瘤的儿童的预后总体不良。诸如通常仅在胚胎和胎儿阶段中通常表达的基因表达的证据表明肿瘤是胚胎起源的。 NB涉及的分子机制尚不清楚。作为神经内分泌肿瘤，NB表达了高水平的生长因子和肽激素，这些激素会促进肿瘤促进作用。前体细胞向神经元的分化受生长因子和Notch信号通路的影响。 Notch和生长因子相互作用在NB中的作用仍有待确定。细胞表面蛋白酶，二肽基肽酶IV（DPPIV）是一种分化的抗原，可通过蛋白水解裂解调节许多神经肽和生长因子的活性，并且在许多癌症中其表达丧失。我们最近表明，DPPIV降低了碱性成纤维细胞生长因子BFGF的水平，有效的有丝分裂原，抗凋亡和血管生成诱导剂的水平。我们以前的工作提供了令人信服的证据，表明DPPIV充当前列腺癌，肺癌和黑色素瘤（神经皮质起源癌）的肿瘤抑制基因，通过诱导分化和凋亡。有趣的是，DPPIV在哺乳动物神经元中表达，其表达在分化差的NB中失去。尽管有这些相关性观察，但DPPIV在NB中的作用尚不清楚。我们的初步研究表明，NB衍生细胞系中的DPPIV降低和DPPIV的重新表达导致诱导分化表型。这些数据暗示了DPPIV在调节NB发展中的重要作用。该提案的目的是定义DPPIV在NB的恶性表型中的作用，并确定与BFGF和Notch信号在神经元发展中起重要作用的联系。综上所述，这些研究的结果是朝着我们的长期目标迈出的重要步骤，即建立对通过包括DPPIV在内的丝氨酸蛋白酶调节NB衍生细胞的癌症表型至关重要的途径。假设：我们假设DPPIV是NB进展的负调节剂。我们预测，DPPIV的丧失会导致BFGF水平升高和停止分化程序的Notch信号的激活，并为NB细胞的增殖/生存和恶性转化提供了生长刺激信号。