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（由适用提供）：癌症转移是大多数与癌症相关死亡的主要因素。了解有助于促进癌症转移的调节和分子机制对于开发新的预防测量和治疗至关重要。上皮间质转变（EMT）是一种基本生物学过程，上皮细胞转化为能够迁移和入侵其他组织的成纤维细胞间质细胞。越来越多的证据表明，癌细胞劫持EMT以成为转移性。当前对EMT和癌症转移调节的研究都集中在转录因子和信号事件上，但是替代的mRNA剪接正在成为控制EMT和转移过渡的主要调节网络。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替代剪接的剪接调节组件，以便深入了解癌症转移的调节。 EMT期间最不同的剪接基因之一是APLP2，APLP2是淀粉样蛋白前体蛋白家族的成员，该家族在许多组织中表达，并参与细胞迁移，粘附，增殖和伤口愈合。但是，APLP2的特定功能，尤其是其剪接同工型，尚不清楚。编码Kunitz蛋白酶抑制剂（KPI）结构域的APLP2的外显子在EMT期间被剪接，得出长的同工型（APLP2-L）和短同工型（APLP2-S）。该项目的中心假设是APLP2的替代剪接对于EMT和乳腺癌转移至关重要。 This hypothesis will be addressed through two specific aims that explore the mechanistic contribution of alternative splicing of APLP2 to APLP2 proteolytic Aim 1 seeks to determine if APLP2 alternative splicing is essential for EMT and cancer metastasis and whether APLP2 alternative splicing occurs accidentally controls switching of APLP2 proteolytic processing from an α-secretase to a ß-secretase pathway. AIM 2将确定APLP2前MRNA中的反式剪接因子和顺式作用元件，从而促进APLP2的替代剪接。这些目标共同描述了替代剪接在EMT和癌症转移中的关键作用，并通过靶向APLP2剪接途径，为治疗转移性乳腺癌的治疗提供令人兴奋的新治疗方法。