Aberration in the growth factor signaling pathways leads to abnormal growth and differentiation that contribute to malignant transformation. Lysophosphatidic acid (LPA), one of the simplest phospholipids, mediates growth factor-like effects that are capable of regulating the fate of intestinal epithelial cells and the innate immunity. LPA mediates diverse biological effects by activating a family of G protein-coupled receptors: LPA1R~LPA5R. The pathological link between LPA and colon cancer has been suggested by the finding that the expression level of LPA2 receptor (LPA2R) is elevated in human colon cancer tissues and cell lines. LPA regulates proliferation, survival, and invasion of colon cancer cells in vitro, but direct in vivo evidence came from our studies that the absence of LPA2R results in decreased tumor burden in rodent models of colon cancer. Our studies have shown that LPA2R-mediated signaling targets several oncogenes and pro-inflammatory proteins, including c-Myc, cyclin D, hypoxia-inducible factor (HIF)-1?, HIF-2?, cyclooxygenase-2, and macrophage migration inhibitory factor (MIF). However, how LPA regulates the expression of these oncogenic targets and to what extend these genes and gene products contribute to the pathogenesis mediated by LPA has not been elucidated.
We aim to determine the mechanisms of the regulation of HIF-1?, HIF-2?, and MIF by LPA2R- mediated signaling and to test the hypothesis that LPA2R stimulates tumor growth, glycolysis, and secretion of pro-inflammatory cytokines through the activation of HIF and MIF (Specific Aim 1). LPA2R-signaling facilitates cell proliferation in part by activation of ?-catenin and we will determine the underlyng mechanism of LPA- induced activation of ?-catenin. We will determine the interaction between Kruppel-like factor 5 (KLF5) and ?- catenin and determine the importance of KLF5 in ?-catenin nuclear translocation in vivo. We will determine the importance of selected Wnt pathway genes in ?-catenin regulation by LPA (Specific Aim 2). Evidence shows the absence of LPA2R attenuates the pathogenesis of colon cancer. However, whether overexpression of LPA2R alone is sufficient for the development of cancer in the intestine is not known. We will generate LPA2R transgenic mice to determine the effects of LPA2R overexpression on tumor development in the intestine. In addition, we will determine whether the absence of NHERF2, which interacts with LPA2R to enhance its cellular signaling, is necessary for LPA-induced colon cancer progression in vivo using mice deficient in NHERF2 (Specific Aim 3). The significance of this proposal is that a better understanding of the LPA2R- mediated signaling pathways and mechanisms, together with the possibility of targeting LPA/LPA receptors, will provide better therapeutic modality for treatment of intestinal disorder, such as cancer and inflammation- associated diseases.

Public Health Relevance

Aberration in the growth factor signaling pathways results in abnormal growth and differentiation of cells that contribute to malignant transformation. Lysophosphatidic acid (LPA) acting on a family of receptors mediates growth factor-like that plays a major role in the pathogenesis of various diseases. The pathological link between LPA and cancer has been suggested by the aberrant LPA and LPA receptor expression in a broad range of cancer, but the understanding of the role of LPA on intestinal cancer progression has only begun to emerge recently. Hence, further understanding of the effects mediated by LPA and LPA2 receptor will ultimately shed lights on novel treatment strategies to patients with intestinal disorders including colon cancer. The goal of this proposal is to understand the mechanisms of colon cancer progression mediated by LPA2 receptor.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071597-07
Application #
8453353
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (03))
Program Officer
Hamilton, Frank A
Project Start
2005-07-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
7
Fiscal Year
2013
Total Cost
$325,326
Indirect Cost
$115,438
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Yun, C Chris; Kumar, Ajay (2015) Diverse roles of LPA signaling in the intestinal epithelium. Exp Cell Res 333:201-7
Lee, Sei-Jung; Leoni, Giovanna; Neumann, Philipp-Alexander et al. (2013) Distinct phospholipase C-? isozymes mediate lysophosphatidic acid receptor 1 effects on intestinal epithelial homeostasis and wound closure. Mol Cell Biol 33:2016-28
Lee, Sei-Jung; No, Yi Ran; Dang, Duyen T et al. (2013) Regulation of hypoxia-inducible factor 1* (HIF-1*) by lysophosphatidic acid is dependent on interplay between p53 and Kruppel-like factor 5. J Biol Chem 288:25244-53
Hu, Zhigang; Hu, Jie; Zhang, Zhonghua et al. (2013) Regulation of expression and function of scavenger receptor class B, type I (SR-BI) by Na+/H+ exchanger regulatory factors (NHERFs). J Biol Chem 288:11416-35
Lee, Sei-Jung; Ritter, Stefanie L; Zhang, Huanchun et al. (2011) MAGI-3 competes with NHERF-2 to negatively regulate LPA2 receptor signaling in colon cancer cells. Gastroenterology 140:924-34
Lin, Songbai; Yeruva, Sunil; He, Peijian et al. (2010) Lysophosphatidic acid stimulates the intestinal brush border Na(+)/H(+) exchanger 3 and fluid absorption via LPA(5) and NHERF2. Gastroenterology 138:649-58
Lin, Songbai; Lee, Sei-Jung; Shim, Hyunsuk et al. (2010) The absence of LPA receptor 2 reduces the tumorigenesis by ApcMin mutation in the intestine. Am J Physiol Gastrointest Liver Physiol 299:G1128-38
Lee, Sei-Jung; Yun, C Chris (2010) Colorectal cancer cells - Proliferation, survival and invasion by lysophosphatidic acid. Int J Biochem Cell Biol 42:1907-10
Lin, Songbai; Wang, Dongsheng; Iyer, Smita et al. (2009) The absence of LPA2 attenuates tumor formation in an experimental model of colitis-associated cancer. Gastroenterology 136:1711-20

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