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Author Notes:

E-mail: ccyun@emory.edu

Conceived and designed the experiments: MY CCY. Performed the experiments: MY PH. Analyzed the data: MY CCY.

Wrote the paper: MY PH CCY.

The authors have declared that no competing interests exist.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Subjects:

Research Funding:

This work was supported by the National Institutions of Health grant DK071597 to C.C. Yun. M. Yoshida is a recipient of Grants-in-Aid for Scientific Research (KAKENHI, no. 25860552).

We acknowledge the Mouse Transgenic and Gene Targeting Core for generating transgenic mice and the Winship and Emory Integrated Cellular Imaging Core, which is supported by the NIH/NCI P30CA138292.

http://dx.doi.org/10.13039/100000062National Institute of Diabetes and Digestive and Kidney Diseases DK071597 to C. Chris Yun.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • COLON-CANCER CELLS
  • PROTEIN-COUPLED RECEPTOR
  • COLORECTAL-CANCER
  • OVER-EXPRESSION
  • GROWTH-FACTOR
  • TUMORIGENESIS
  • PROLIFERATION
  • INDUCTION
  • GENE
  • MICE

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

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Journal Title:

PLoS ONE

Volume:

Volume 11, Number 4

Publisher:

, Pages e0154527-e0154527

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2016 Yoshida et al

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

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