Alternative Splicing of Amyloid Precursor-Like Protein 2 during the Epithelial-Mesenchymal Transition and Cancer Metastasis

淀粉样前体样蛋白 2 在上皮-间质转化和癌症转移过程中的选择性剪接

• 批准号: 9246507
• 负责人: Samuel Emerson Harvey
• 金额: $ 3.84万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-07 至 2019-04-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9246507
• 关键词: APLP2 gene; Address; Adhesions; Alternative Splicing; Alzheimer' s Disease; Amyloid; Amyloid Beta A4 Precursor Protein; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animals; Automobile Driving; Biological Process; Breast cancer metastasis; C-terminal; Cause of Death; Cell Adhesion; Cell Nucleus; Cell Proliferation; Cells; Cessation of life; Cleaved cell; Data; Elements; Epithelial; Epithelial Cells; Event; Exons; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Homologous Protein; Integral Membrane Protein; Introns; Invaded; Link; Location; Malignant Neoplasms; Mediating; Mesenchymal; Messenger RNA; Metastatic breast cancer; Modeling; Molecular; Neoplasm Metastasis; Neuraxis; Organ; Pathway interactions; Phenotype; Play; Preventive measure; Preventive treatment; Process; Production; Protease Inhibitor; Protein Family; Protein Isoforms; Protein Precursors; Proteins; Proteolysis; Proteolytic Processing; RNA Splicing; RNA-Binding Proteins; Recruitment Activity; Regulation; Research; Role; Signal Transduction; Site; Spliced Genes; Testing; Tissues; Trans-Activators; Transcriptional Regulation; Wound Healing; alpha secretase; beta secretase; cancer cell; cell motility; cell transformation; cis acting element; exon skipping; experience; experimental study; gamma secretase; insight; knock-down; loss of function; mRNA Precursor; member; novel therapeutic intervention; organ growth; prevent; programs; public health relevance; reconstitution; role model; small hairpin RNA; transcription factor; transcriptome sequencing; tumor

 DESCRIPTION (provided by applicant): Cancer metastasis is the major contributing factor to the majority of cancer-related deaths. Understanding the regulation and molecular mechanisms contributing to the promotion of cancer metastasis is paramount to developing new preventative measures and treatments. The epithelial-mesenchymal transition (EMT) is a fundamental biological process where epithelial cells transform into fibroblastic mesenchymal cells capable of migrating and invading other tissues. Increasing evidence suggests that cancer cells hijack EMT in order to become metastatic. Much of the current research into the regulation of EMT and cancer metastasis focuses on transcription factors and signaling events, however alternative mRNA splicing is emerging as a major regulatory network that governs EMT and metastatic transitions. This proposal seeks to characterize the key splicing events that mechanistically drive EMT as well as the splicing regulatory components that control alternative splicing of these events in order to gain insight into the regulation of cancer metastasis. One of the most differentially spliced genes during EMT is APLP2, a member of the amyloid precursor protein family, which is expressed in many tissues and is involved in cell migration, adhesion, proliferation, and wound healing. However, the specific function of APLP2, especially its splice isoforms, is unknown. Exon 7 of APLP2 encoding a Kunitz Protease Inhibitor (KPI) domain is alternatively spliced during EMT yielding a long isoform (APLP2-L) and short isoform (APLP2-S). The central hypothesis of this project is that alternative splicing of APLP2 is essential for EMT and breast cancer metastasis. This hypothesis will be addressed through two specific aims that explore the mechanistic contribution of alternative splicing of APLP2 to APLP2 proteolytic processing, EMT, and cancer metastasis as well as the regulation of APLP2 alternative splicing. Aim 1 seeks to determine if APLP2 alternative splicing is essential for EMT and cancer metastasis and whether APLP2 alternative splicing causally controls switching of APLP2 proteolytic processing from an α-secretase to a ß-secretase pathway. Aim 2 will determine the trans-acting splicing factors and cis-acting elements in APLP2 pre-mRNA that facilitate alternative splicing of APLP2. Together these aims will describe the critical role of alternative splicing in EMT and cancer metastasis as well as offering an exciting new therapeutic approach for the treatment of metastatic breast cancer by targeting the APLP2 splicing pathway.

 描述（由申请人提供）：癌症转移是大多数癌症相关死亡的主要促成因素。了解促进癌症转移的调节和分子机制对于开发新的预防措施和治疗至关重要。上皮-间充质转化（EMT）是上皮细胞向间充质细胞转化的一个基本生物学过程，它能够迁移和侵入其他组织。越来越多的证据表明，癌细胞劫持EMT，以成为转移。目前对EMT和癌症转移调控的大部分研究集中在转录因子和信号事件上，然而mRNA剪接正在成为控制EMT和转移性转变的主要调控网络。该提案旨在表征机械驱动EMT的关键剪接事件以及控制这些事件的选择性剪接的剪接调节组分，以深入了解癌症转移的调节。EMT期间最差异剪接的基因之一是APLP 2，它是淀粉样前体蛋白家族的成员，在许多组织中表达，并参与细胞迁移、粘附、增殖和伤口愈合。然而，APLP 2的具体功能，特别是其剪接异构体，是未知的。编码Kunitz蛋白酶抑制剂（KPI）结构域的APLP 2的外显子7在EMT期间选择性剪接，产生长同种型（APLP 2-L）和短同种型（APLP 2-S）。该项目的中心假设是APLP 2的选择性剪接对于EMT和乳腺癌转移是必不可少的。这一假设将通过两个具体的目标，探索APLP 2的选择性剪接的APLP 2蛋白水解加工，EMT和癌症转移的机制贡献，以及APLP 2选择性剪接的调节来解决。目的1试图确定APLP 2选择性剪接是否是EMT和癌症转移所必需的，以及APLP 2选择性剪接是否因果地控制APLP 2蛋白水解加工从α-分泌酶途径转换为β-分泌酶途径。目的2确定APLP 2前体mRNA中促进APLP 2选择性剪接的反式作用剪接因子和顺式作用元件。这些目标将共同描述选择性剪接在EMT和癌症转移中的关键作用，并通过靶向APLP 2剪接途径为治疗转移性乳腺癌提供一种令人兴奋的新治疗方法。