GAB2 in metastatic melanoma

GAB2在转移性黑色素瘤中的作用

• 批准号: 8193116
• 负责人: Julide T. Celebi
• 金额: $ 32.41万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193116
• 关键词: 11q14.1; Actins; Adaptor Signaling Protein; Anchorage-Independent Growth; Animals; BRAF gene; Biological; Cell Line; Cells; Clinical; Competence; Complement; Correlative Study; Cyclin D1; Cytoskeleton; Development; Event; Extracellular Matrix Degradation; Family; Future; GAB2 gene; Gelatinase A; Gelatinase B; Genes; Genetic; Growth Factor; Growth Factor Inhibition; Guanosine Triphosphate Phosphohydrolases; Human; Interstitial Collagenase; Lead; MAP Kinase Gene; MEKs; MMP14 gene; Malignant Neoplasms; Mediating; Melanocytic nevus; Melanoma Cell; Metastatic Melanoma; Molecular; Mutation; Neoplasm Metastasis; Oncogenic; Other Genetics; Outcome; PDPK1 gene; PTEN gene; Pathway interactions; Patients; Phenotype; Play; Proteolysis; Proto-Oncogene Proteins c-akt; Role; Sampling; Series; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; System; Testing; Thick; Tumorigenicity; Work; adapter protein; base; cell motility; gain of function mutation; genome-wide; human GAB2 protein; in vivo; inhibitor/antagonist; insight; melanocyte; melanoma; migration; mutant; neoplastic cell; novel; outcome forecast; overexpression; protein expression; public health relevance; response; rho; src Homology Region 2 Domain; tissue culture; tumor; tumor progression

DESCRIPTION (provided by applicant): Metastatic melanoma is an aggressive tumor with a poor prognosis. Critical biologic features of melanoma metastasis are the acquisition of migratory competence, growth factor independence, and invasive potential. In an attempt to identify genes that contribute to melanoma metastasis, a genome-wide search using BAC array CGH and SNP arrays in a series of metastatic melanoma samples identified increased copy numbers of GAB2 located on 11q14.1. GAB2 is an adaptor molecule that potentiates activation of various signal transduction cascades such as RAS-ERK and PI3K-AKT pathways and has recently been implicated in human cancer; however, its role in melanoma is undefined. In our Preliminary Studies, we found GAB2 as either amplified (~11%) and/or overexpressed (~47%) in melanoma. Clinical correlative studies identified GAB2 as a novel genetic event amplified in a subset of acral and mucosal melanomas independent of genetic alterations in BRAF, NRAS, and KIT. GAB2 protein expression correlated with clinical melanoma progression and higher levels of expression were seen in metastatic melanomas compared to primary melanoma (p=0.0137) and melanocytic nevi (p=0.004). We found that overexpression of GAB2 potentiates, whereas silencing of GAB2 reduces, migration and invasion of melanoma cells. GAB2 mediated hyperactivation of PI3/PDK1/AKT signaling in the absence of growth factors, and inhibition of the PI3K-AKT pathway decreased GAB2-mediated tumor cell migration and invasion potential. Furthermore, GAB2 stimulated Cdc42-GTPase activity suggesting its potential as a regulator of Rho family GTPases. These studies demonstrate a previously undefined role for GAB2 in melanoma metastasis and highlight the significance of GAB2 adaptor molecule, critical for various signal transduction pathways, in melanoma. However, the mechanisms of GAB2-mediated tumor cell motility and invasion in cancer are uncharacterized. Moreover, the role of GAB2 in melanoma is unexplored. In the proposed studies, we plan probe mechanistic insights into GAB2-mediated signaling in melanoma, mechanisms of tumor cell motility and invasion, and cooperation of GAB2 with additional genetic events during tumor progression and metastasis. We expect to define the biological significance of GAB2 in melanoma that will provide the basis for development of targeted therapies. PUBLIC HEALTH RELEVANCE: GAB2 is an adapter protein with critical functions in signal transduction pathways and has recently been implicated to play a role in human cancer. This proposal involves studying the contribution of GAB2 in melanoma to provide a basis whether its targeting would be therapeutically beneficial.

描述（由申请人提供）：转移性黑色素瘤是一种侵袭性肿瘤，预后不良。黑色素瘤转移的关键生物学特征是迁移能力，生长因子独立性和侵入性潜力的获得。为了鉴定有助于黑色素瘤转移的基因，在一系列转移性黑色素瘤样品中，使用BAC阵列CGH和SNP阵列进行了全基因组搜索，确定了位于11 Q14.1的GAB2的拷贝数增加。 GAB2是一种适配器分子，可以增强各种信号转导级联的激活，例如RAS-ERK和PI3K-AKT途径，并且最近与人类癌症有关。但是，其在黑色素瘤中的作用是不确定的。在我们的初步研究中，我们发现GAB2在黑色素瘤中被扩增（约11％）和/或过表达（〜47％）。临床相关研究将GAB2鉴定为一种新的遗传事件，该事件在a骨和粘膜黑色素瘤的子集中放大，与BRAF，NRAS和KIT中的遗传改变无关。与原发性黑色素瘤（P = 0.0137）和黑色素细胞NEVI相比，在转移性黑色素瘤中观察到与临床黑色素瘤进展和较高表达相关的GAB2蛋白表达与较高的表达相关（P = 0.004）。我们发现GAB2增强剂的过表达，而GAB2的沉默减少，迁移和侵袭黑色素瘤细胞。在没有生长因子的情况下，GAB2介导的PI3/PDK1/AKT信号传导的过度激活，PI3K-AKT途径的抑制降低了GAB2介导的肿瘤细胞迁移和浸润潜力。此外，GAB2刺激了CDC42-GTPase活性，表明其作为Rho家族GTPase的调节剂的潜力。这些研究表明，GAB2在黑色素瘤转移中的先前不确定的作用，并强调了GAB2适配器分子的重要性，这对于黑色素瘤中的各种信号转导途径至关重要。但是，GAB2介导的肿瘤细胞运动和癌症侵袭的机制未经表征。此外，GAB2在黑色素瘤中的作用尚未探索。在拟议的研究中，我们计划了对黑色素瘤中GAB2介导的信号传导的探针机理见解，肿瘤细胞运动和侵袭的机制，以及在肿瘤进展和转移过程中GAB2与其他遗传事件的合作。我们期望定义GAB2在黑色素瘤中的生物学意义，这将为靶向疗法的发展提供基础。公共卫生相关性：GAB2是一种衔接蛋白，在信号转导途径中具有关键功能，最近被牵涉到在人类癌症中发挥作用。该建议涉及研究GAB2在黑色素瘤中的贡献，以提供基础，其靶向是否在治疗上有益。