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.

修订后的抽象

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