Transgenic Expression of Human Lysophosphatidic Acid Receptor LPA(2) in Mouse Intestinal Epithelial Cells Induces Intestinal Dysplasia

Lysophosphatidic acid (LPA) acts on LPA(2) receptor to mediate multiple pathological effects that are associated with tumorigenesis. The absence of LPA(2) attenuates tumor progression in rodent models of colorectal cancer, but whether overexpression of LPA(2) alone can lead to malignant transformation in the intestinal tract has not been studied. In this study, we expressed human LPA(2) 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 LPA(2); 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 LPA(2) 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 LPA(2) compromised the terminal epithelial differentiation, consistent with epithelial dysplasia. Furthermore, we showed that epithelial dysplasia was observed in founder mouse intestine, correlating LPA(2) overexpression with epithelial dysplasia. The current study demonstrates that overexpression of LPA(2) alone can lead to intestinal dysplasia.