LPA Receptor Signaling in Colonic Epithelia

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DESCRIPTION (provided by applicant): 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.