title: Transgenic Expression of Human Lysophosphatidic Acid Receptor LPA2 in Mouse Intestinal Epithelial Cells Induces Intestinal Dysplasia.
abstract: Lysophosphatidic acid (LPA) acts on LPA2 receptor to mediate multiple pathological effects that are associated with tumorigenesis. The absence of LPA2 attenuates tumor progression in rodent models of colorectal cancer, but whether overexpression of LPA2 alone can lead to malignant transformation in the intestinal tract has not been studied. In this study, we expressed human LPA2 in intestinal epithelial cells (IECs) under control of the villin promoter. Less than 4% of F1-generation mice had germline transmission of transgenic (TG) human LPA2; as such only 3 F1 mice out of 72 genotyped had TG expression. These TG mice appeared anemic with hematochezia and died shortly after birth. TG mice were smaller in size compared with the wild type mouse of the same age and sex. Morphological analysis showed that TG LPA2 colon had hyper-proliferation of IECs resulting in increased colonic crypt depth. Surprisingly, TG small intestine had villus blunting and decreased IEC proliferation and dysplasia. In both intestine and colon, TG expression of LPA2 compromised the terminal epithelial differentiation, consistent with epithelial dysplasia. Furthermore, we showed that epithelial dysplasia was observed in founder mouse intestine, correlating LPA2 overexpression with epithelial dysplasia. The current study demonstrates that overexpression of LPA2 alone can lead to intestinal dysplasia.
authors.affiliation: Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia United State of America.|Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia United State of America.
authors.forename: Peijian
authors.initials: P
authors.lastname: He
authors.affiliation: Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia United State of America.|Winship Cancer Institute, Emory University, Atlanta, Georgia, United State of America.
authors.forename: C Chris
authors.initials: CC
authors.lastname: Yun
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology*; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism*
chemical_list: D008246:Lysophospholipids; D008840:Microfilament Proteins; D049368:Receptors, Lysophosphatidic Acid; C026615:villin; C032881:lysophosphatidic acid