Lysophosphatidic Acid in Oncogenesis

溶血磷脂酸在肿瘤发生中的作用

基本信息

批准号：
7735592
负责人：
XIANJUN FANG
金额：
$ 23万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7735592
关键词：
Age-Months Animal Model Biological Biological Process Cell Differentiation process Cell Proliferation Cell physiology Cells Colon Carcinoma Cytoskeleton DNA Sequence Rearrangement Defect Development Distant Edg-7 Receptor Embryonic Development Endothelial Cells Enzymes Family Fertility G-Protein-Coupled Receptors GTP-Binding Proteins Gene Targeting Genes Human Incidence Knock-out Knockout Mice Lead Ligands Link Liver Lung Lung Adenocarcinoma Lymphoma Lysophosphatidic Acid Receptors Lysophospholipids Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of thyroid Mediating Minor Modeling Mus Mutant Strains Mice Neoplasm Metastasis Neoplastic Cell Transformation Oncogenic Pathway interactions Phenotype Phospholipids Pilomatrixoma Plasmacytoma Play Predisposition Production Purinoceptor Regulation Renal carcinoma Role Serum Signal Pathway Signal Transduction Sphingosine-1-Phosphate Receptor Subgroup Testing Tumor Suppression Tumor Suppressor Proteins abstracting cancer therapy cell motility chemical carcinogen chemical carcinogenesis effusion in vivo insight leiomyosarcoma lysophosphatidic acid malignant breast neoplasm member migration novel osteosarcoma overexpression receptor receptor coupling receptor upregulation response sarcoma synergism tumor tumorigenesis

项目摘要

Revised Abstract Lysophosphatidic acid (LPA), a naturally occurring lysophospholipid, is a ligand of at least five G protein-coupled receptors (LPA15). The LPA13 receptors are members of the endothelial cell differentiation gene (Edg) family and couple to Gi, Gq, and G12/13 subunits of G proteins to activate an array of intracellular signaling cascades, leading to cytoskeleton rearrangement, cell proliferation, survival, and migration. Overexpression of the Edg LPA receptors and upregulation of LPA production via LysoPLD/autotaxin (AIX) are common abnormalities found in various human cancers. However, studies of oncogenic roles of LPA have been hampered by lack of in vivo evidence or an animal model to show involvement of LPA signals in tumor development. Recently, p2y9/GPR23/LPA4 of the purinergic receptor family and a related GPR92/LPA5 are identified as novel LPA receptors. These two receptors are structurally distant from the Edg LPA1..3 receptors and couple to Gq, GI 2/13 and Gs subunits. The biological functions of LPA4 and LPA5 receptors, particularly their roles in cancer have not been previously studied. We recently disrupted the Ipa4 gene by targeted deletion in mice. Although the LPA4 is not required for embryonic development and fertility, we observed a dramatic increase in development of spontaneous tumors in Ipa4 mutant mice. The tumors include malignant lymphoma, lung adenocarcinoma, high-grade sarcoma, leiomyosarcoma, plasmacytoma and pilomatrixoma. The wide spectrum of tumors found in these mice not only provides direct evidence for aberrant LPA signaling in tumorigenesis but also raises the possibility that LPA4 acts as a tumor suppressor. Our preliminary results further suggest that lack of LPA4 sensitizes cells to LPA-induced cell motility and activation of specific intracellular pathways. We therefore hypothesize that, in contrast to the Edg LPA receptors, LPA4 negatively regulates specific LPA signaling pathways and oncogenic activity of LPA. As a result, the lack of LPA4 predisposes mice to tumor development. The hypothesis will be tested through the following three Specific Aims: Aim 1. To determine the role of LPA4 in tumor suppression in mice; Aim 2. To elucidate the functions of LPA4 in LPA signal transduction; Aim 3. To evaluate whether deletion of LPA4 increases susceptibility of mice to chemical carcinogenesis We will determine tumor incidence, histotypes and metastasis rate of tumors in two independent lines of Ipa4 knockout mice in Aim 1. We will take advantage of the LPA4-deficient cells and other knockdown or overexpression approaches to investigate the biological functions of LPA4 in the regulation of LPA signal transduction and cellular responses (Aim 2). In Aim 3, the tumor suppressive function of LPA4 will be further explored by examining the susceptibility of LPA4 null mice to chemical carcinogens. These proposed studies together will establish the role of LPA4 in tumor suppression and may lead to identification of novel anticancer targets.

修订摘要溶血磷脂酸 (LPA) 是一种天然存在的溶血磷脂，是至少五个 G 蛋白偶联受体 (LPA15)。 LPA13 受体是内皮细胞的成员细胞分化基因 (Edg) 家族并与 G 蛋白的 Gi、Gq 和 G12/13 亚基偶联，激活一系列细胞内信号级联，导致细胞骨架重排，细胞增殖、生存和迁移。 Edg LPA 受体的过度表达和上调通过 LysoPLD/autotaxin (AIX) 产生的 LPA 是多种疾病中常见的异常现象。人类癌症。然而，由于缺乏相关证据，LPA 致癌作用的研究受到了阻碍。体内证据或动物模型显示 LPA 信号参与肿瘤发展。最近，嘌呤能受体家族的p2y9/GPR23/LPA4和相关的 GPR92/LPA5 被鉴定为新型 LPA 受体。这两种受体在结构上远离 Edg LPA1..3 受体并与 Gq、GI 2/13 和 Gs 亚基偶联。这 LPA4 和 LPA5 受体的生物学功能，特别是它们在癌症中的作用尚未明确之前已经研究过。我们最近通过在小鼠中进行定向删除来破坏 Ipa4 基因。虽然 LPA4 不是胚胎发育和生育所必需的，但我们观察到 Ipa4 突变小鼠中自发性肿瘤的发展显着增加。肿瘤包括恶性淋巴瘤、肺腺癌、高级肉瘤、平滑肌肉瘤、浆细胞瘤和毛基质瘤。在这些小鼠中发现的广泛肿瘤不仅为肿瘤发生中异常的 LPA 信号传导提供了直接证据，但也提出了 LPA4 可能充当肿瘤抑制因子。我们的初步结果进一步表明 LPA4 的缺乏会使细胞对 LPA 诱导的细胞运动和特定细胞内的激活变得敏感途径。因此，我们假设，与 Edg LPA 受体相比，LPA4 负调节特定的 LPA 信号通路和 LPA 的致癌活性。作为因此，缺乏 LPA4 会使小鼠容易患肿瘤。假设将是通过以下三个具体目标进行测试：目的1. 确定LPA4在小鼠肿瘤抑制中的作用；目的2.阐明LPA4在LPA信号转导中的功能；目标 3. 评估 LPA4 缺失是否会增加小鼠对化学物质的敏感性致癌作用我们将确定两种肿瘤的发病率、组织型和转移率目标 1 中 Ipa4 敲除小鼠的独立品系。我们将利用 LPA4 缺陷的优势细胞和其他敲低或过度表达方法来研究生物学 LPA4 在 LPA 信号转导和细胞反应调节中的功能（目标 2）。在目标 3 中，将通过检查 LPA4 的肿瘤抑制功能来进一步探讨 LPA4 缺失小鼠对化学致癌物的易感性。这些拟议的研究将共同确定 LPA4 在肿瘤抑制中的作用并可能导致新型抗癌药物的鉴定目标。