Lysophosphatidic Acid in Oncogenesis

溶血磷脂酸在肿瘤发生中的作用

• 批准号: 7876906
• 负责人: XIANJUN FANG
• 金额: $ 23万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7876906
• 关键词: 1-Phosphatidylinositol 3-Kinase; Age-Months; Anabolism; Animal Model; Attenuated; Biological Process; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Colon Carcinoma; Coupled; Cytoskeleton; DNA Sequence Rearrangement; Defect; Development; Distant; Edg-7 Receptor; Embryonic Development; Endothelial Cells; Environmental Carcinogens; Enzymes; Family; Fertility; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gene Targeting; Genes; Genetic Status; 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; Phospholipids; Pilomatrixoma; Plasmacytoma; Predisposition; Production; Purinoceptor; Receptor Signaling; Regulation; Renal carcinoma; Role; Serum; Signal Pathway; Signal Transduction; Sphingosine-1-Phosphate Receptor; Subgroup; Testing; Transgenic Organisms; Tumor Suppression; Tumor Suppressor Proteins; abstracting; carcinogenesis; cell growth; 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

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，是一种至少的配体 五个G蛋白偶联受体（LPA15）。 LPA13受体是内皮的成员 细胞分化基因（EDG）家族和夫妇与G蛋白的GI，GQ和G12/13亚基至 激活一系列细胞内信号传导级联反应，导致细胞骨架重排，细胞 扩散，生存和迁移。 EDG LPA受体的过表达和上调 通过lysopld/autotaxin（AIX）产生LPA的常见异常 人类癌。但是，由于缺乏，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信号参与肿瘤发育。 最近，嘌呤能受体家族的P2Y9/GPR23/LPA4和相关 GPR92/LPA5被鉴定为新型LPA受体。这两个受体在结构上是 远离EDG LPA1..3受体和夫妻远至GQ，GI 2/13和GS亚基。这 LPA4和LPA5受体的生物学功能，尤其是其在癌症中的作用 以前已经研究过。我们最近通过小鼠的靶向缺失破坏了IPA4基因。 尽管胚胎发育和生育不需要LPA4，但我们观察到 IPA4突变小鼠自发性肿瘤发育的发育急剧增加。肿瘤 包括恶性淋巴瘤，肺腺癌，高级肉瘤，平滑肌肉瘤， 浆细胞瘤和毛乳杆菌瘤。这些小鼠中发现的广泛的肿瘤不仅 提供了肿瘤发生中异常LPA信号传导的直接证据，但也提高了 LPA4起肿瘤抑制的可能性。我们的初步结果进一步表明 缺乏LPA4会使细胞对LPA诱导的细胞运动和特定细胞内的激活敏感 途径。因此，我们假设，与EDG LPA受体相反，LPA4 负调节特定的LPA信号通路和LPA的致癌活性。作为 结果，缺乏LPA4使小鼠倾向于肿瘤的发育。假设将是 通过以下三个特定目标进行测试： 目的1。确定LPA4在小鼠肿瘤抑制中的作用； 目标2。阐明LPA4在LPA信号转导中的功能； 目的3。评估LPA4的缺失是否增加了小鼠对化学的敏感性 致癌作用 我们将确定两种肿瘤的发病率，组织型和肿瘤的转移率 AIM 1中的IPA4敲除小鼠的独立线。我们将利用LPA4缺陷型 细胞和其他敲低或过表达的方法来研究生物学 LPA4在LPA信号转导和细胞反应调节中的功能（AIM 2）。 在AIM 3中，通过检查LPA4的肿瘤抑制功能将进一步探索 LPA4无效小鼠对化学致癌物的敏感性。这些提出的研究将一起 确定LPA4在肿瘤抑制中的作用，并可能导致新型抗癌的鉴定 目标。

项目成果

Large scale purification and characterization of recombinant human autotaxin/lysophospholipase D from mammalian cells.

从哺乳动物细胞中大规模纯化重组人自分泌运动因子/溶血磷脂酶 D 并对其进行表征。

• DOI: 10.5483/bmbrep.2010.43.8.541
• 发表时间: 2010
• 期刊: BMB reports
• 影响因子: 3.8
• 作者: Song,Yuanda;Dilger,Emily;Bell,Jessica;Barton,WilliamA;Fang,Xianjun
• 通讯作者: Fang,Xianjun

Sp-1 and c-Myc mediate lysophosphatidic acid-induced expression of vascular endothelial growth factor in ovarian cancer cells via a hypoxia-inducible factor-1-independent mechanism.

• DOI: 10.1158/1078-0432.ccr-08-1945
• 发表时间: 2009-01-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Song Y;Wu J;Oyesanya RA;Lee Z;Mukherjee A;Fang X
• 通讯作者: Fang X