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.
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.
|Lin, Songbai; Han, Yiran; Jenkin, Kayte et al. (2018) Lysophosphatidic Acid Receptor 1 Is Important for Intestinal Epithelial Barrier Function and Susceptibility to Colitis. Am J Pathol 188:353-366|
|Bai, Renren; Shi, Qi; Liang, Zhongxing et al. (2017) Development of CXCR4 modulators by virtual HTS of a novel amide-sulfamide compound library. Eur J Med Chem 126:464-475|
|Yoshida, Michihiro; Zhao, Luqing; Grigoryan, Gevorg et al. (2016) Deletion of Na+/H+ exchanger regulatory factor 2 represses colon cancer progress by suppression of Stat3 and CD24. Am J Physiol Gastrointest Liver Physiol 310:G586-98|
|Yoshida, Michihiro; He, Peijian; Yun, C Chris (2016) Transgenic Expression of Human Lysophosphatidic Acid Receptor LPA2 in Mouse Intestinal Epithelial Cells Induces Intestinal Dysplasia. PLoS One 11:e0154527|
|Yun, C Chris; Kumar, Ajay (2015) Diverse roles of LPA signaling in the intestinal epithelium. Exp Cell Res 333:201-7|
|Yeruva, Sunil; Chodisetti, Giriprakash; Luo, Min et al. (2015) Evidence for a causal link between adaptor protein PDZK1 downregulation and Na?/H? exchanger NHE3 dysfunction in human and murine colitis. Pflugers Arch 467:1795-807|
|Guo, Leilei; He, Peijian; No, Yi Ran et al. (2015) Krüppel-like factor 5 incorporates into the ?-catenin/TCF complex in response to LPA in colon cancer cells. Cell Signal 27:961-8|
|No, Yi Ran; Lee, Sei-Jung; Kumar, Ajay et al. (2015) HIF1?-Induced by Lysophosphatidic Acid Is Stabilized via Interaction with MIF and CSN5. PLoS One 10:e0137513|
|Lee, Hye Jeong; Kwon, Min Hyung; Lee, Soojung et al. (2014) Systematic family-wide analysis of sodium bicarbonate cotransporter NBCn1/SLC4A7 interactions with PDZ scaffold proteins. Physiol Rep 2:|
|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|
Showing the most recent 10 out of 22 publications