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Lysophosphatidic Acid in Oncogenesis

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:
$23.0万
依托单位国家:
美国
项目类别:
财政年份:
2004
资助国家:
美国
项目状态:
已结题
起止时间:
2004-08-01 至 2012-06-30

项目摘要

项目成果

XIANJUN FANG的其他基金

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中文摘要
翻译
修订后的抽象
英文摘要
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.
期刊论文(6)
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会议论文
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
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
影响因子: --
作者: [Song Y, Wu J, Oyesanya RA, Lee Z, Mukherjee A, Fang X]
通讯作者: Fang X
Metabolic reprograming of fatty acid beta-oxidation to improve cancer immunotherapy
  • 批准号:
    10599149
  • 项目类别:
  • 资助金额:
    $40.49万
  • 财政年份:
    2019
  • 负责人:
    XIANJUN FANG
  • 依托单位:
Metabolic reprograming of fatty acid beta-oxidation to improve cancer immunotherapy
  • 批准号:
    10361537
  • 项目类别:
  • 资助金额:
    $40.63万
  • 财政年份:
    2019
  • 负责人:
    XIANJUN FANG
  • 依托单位:
Regulation of lipogenesis by lysophosphatidic acid in ovarian cancer
  • 批准号:
    8333999
  • 项目类别:
  • 资助金额:
    $19.51万
  • 财政年份:
    2011
  • 负责人:
    XIANJUN FANG
  • 依托单位:
Regulation of lipogenesis by lysophosphatidic acid in ovarian cancer
  • 批准号:
    8177055
  • 项目类别:
  • 资助金额:
    $16.26万
  • 财政年份:
    2011
  • 负责人:
    XIANJUN FANG
  • 依托单位: