THE ROLE OF MALT1 IN MELANOMA GROWTH AND METASTASIS

Malt1 在黑色素瘤生长和转移中的作用

基本信息

批准号：
9102022
负责人：
Jennifer Yunyan Zhang
金额：
$ 7.95万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9102022
关键词：
3-Dimensional Amino Acids Animals Apoptosis Arginine B-Cell Lymphomas BRAF gene Biological Markers Bioluminescence Biopsy CASP3 gene Cell Line Cells Cleaved cell Clinical Combined Modality Therapy Culture Media Detection Development Dose Drug Targeting Gene Silencing Genes Genetic Goals Growth Health Human Immunodeficient Mouse Immunotherapy In Vitro Incidence Integrins Isotopes JUN gene Kinetics Label Lead Life Light Luciferases Lymphoma MAPK8 gene MEKs Malignant Neoplasms Mass Spectrum Analysis Measurement Mediating Melanoma Cell Metastatic Melanoma Molecular Mucosa- associated lymphoid tissue lymphoma translocation protein-1 Mucous Membrane Mus Neoplasm Metastasis Oncogenes Outcome Pathogenesis Pharmacotherapy Phenothiazines Play Population Process Proteins Proteolysis Proteomics Radial Radial Growth Phase Role Signal Pathway Site Skin Cancer Solid Stable Isotope Labeling T-Lymphocyte TNF gene Testing Therapeutic Tissues Translating Validation Vertical Growth Phase base bench to bedside cell growth cellular transduction clinical application gene function in vivo inhibitor/antagonist insight large cell Diffuse non-Hodgkin&apos s lymphoma loss of function melanocyte melanoma migration mutant novel pre-clinical protein expression response restoration small hairpin RNA subcutaneous targeted treatment therapeutic target therapy outcome tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The paracaspase MALT1 (Mucosa Associated Lymphoma Translocation 1 gene) is frequently activated in lymphoma. It functions as an activator of the NF-κB and JNK signaling pathways through sequence-specific proteolysis of a handful of substrates including CYLD, A20, RelB and Bcl10. Inhibition of MALT1 with the medicinally active phenothiazine compounds has proven to be very effective for the cure of the most aggressive and otherwise untreatable B-cell lymphoma. To date, little is understood about the role of MALT1 in other solid cancers such as melanoma which, despite recent advances in immunotherapy or BRAF600E/MEK oncogene-targeted therapies, continues to be the most deadly form of skin cancer. The goal of this study is to explore the role of MALT1 and its downstream targets in melanoma growth and metastasis. Towards this end, our preliminary studies have demonstrated that CYLD, a potential target of MALT1, is significantly reduced in metastatic melanoma cells, and that forced expression of CYLD inhibits melanoma growth and metastasis through the suppression of the NF-κB and JNK signaling pathways. In contrast, MALT1 is significantly increased in metastatic and vertical growth phase melanoma cells as compared to normal and radial growth phase melanoma cells. ShRNA-mediated gene silencing of MALT1 in a metastatic human melanoma cell line A2058 slows cell growth both in vitro and in vivo, and inhibits metastasis in vivo. Based on these findings, we hypothesize that MALT1 has an important role in melanoma growth and metastasis and is a potential target for combination therapies. This hypothesis will be tested in two separate Aims. Aim I is to determine the role of MALT1 and its downstream targets in melanoma growth, survival and metastasis. Aim II is to determine the effects of genetic MALT1-inhibition on BRAF600E/MEK-targeted therapies. We believe that findings of this study will lead to a better mechanistic understanding of melanoma pathogenesis, and provide insights to therapeutic strategies that may be translated into clinical applications.

描述（由申请人提供）：副半胱天冬酶 MALT1（粘膜相关淋巴瘤易位 1 基因）在淋巴瘤中经常被激活，它通过对包括 CYLD 在内的少数底物进行序列特异性蛋白水解，充当 NF-κB 和 JNK 信号通路的激活剂。、A20、RelB 和 Bcl10 具有药用活性的吩噻嗪化合物的抑制作用已被证明非常有效。迄今为止，人们对 MALT1 在黑色素瘤等其他实体癌中的作用知之甚少，尽管免疫疗法或 BRAF600E/MEK 癌基因靶向疗法最近取得了进展。仍然是最致命的皮肤癌，本研究的目的是探索 MALT1 及其下游靶点在黑色素瘤生长和转移中的作用，为此，我们的初步研究已经证明。 MALT1 的潜在靶标 CYLD 在转移性黑色素瘤细胞中显着减少，并且 CYLD 的强制表达通过抑制 NF-κB 和 JNK 信号通路来抑制黑色素瘤的生长和转移，相反，MALT1 在转移性黑色素瘤细胞中显着增加。在转移性人黑色素瘤细胞系中，ShRNA介导的MALT1基因沉默与垂直生长期黑色素瘤细胞相比。 A2058 在体外和体内均能减缓细胞生长，并抑制体内转移。基于这些发现，我们认为 MALT1 在黑色素瘤生长和转移中具有重要作用，并且是联合治疗的潜在靶标。目标 I 是确定 MALT1 及其下游靶标在黑色素瘤生长、存活和转移中的作用。目标 II 是确定遗传 MALT1 抑制的影响。我们相信，这项研究的结果将有助于更好地了解黑色素瘤发病机制，并为可转化为临床应用的治疗策略提供见解。