The absence of LPA receptor 2 reduces the tumorigenesis by <i>Apc</i>^<i>Min</i> mutation in the intestine

<jats:p> Lysophosphatidic acid (LPA) is a lipid mediator that mediates several effects that promote cancer progress. The LPA receptor type 2 (LPA<jats:sub>2</jats:sub>) expression is often elevated in several types of cancers, including colorectal cancer (CRC). In this study, we investigated the role of LPA<jats:sub>2</jats:sub> in the development of intestinal adenomas by comparing Apc<jats:sup> Min/+</jats:sup> mice with Apc<jats:sup> Min/+</jats:sup> /Lpar2<jats:sup> −/−</jats:sup> mice. There were 50% fewer intestinal adenomas in Apc<jats:sup> Min/+</jats:sup> /Lpar2<jats:sup> −/−</jats:sup> mice than Apc<jats:sup> Min/+</jats:sup> mice. Smaller-size adenomas (<1 mm) were found at higher frequencies in Apc<jats:sup> Min/+</jats:sup> /Lpar2<jats:sup> −/−</jats:sup> mice compared with Apc<jats:sup> Min/+</jats:sup> mice at the two age groups examined. The expression level of LPA<jats:sub>2</jats:sub> correlated with increased size of intestinal adenomas. Reduced tumor multiplicity and size in Apc<jats:sup> Min/+</jats:sup> /Lpar2<jats:sup> −/−</jats:sup> mice correlated with decreased proliferation of intestinal epithelial cells. Apc<jats:sup> Min/+</jats:sup> /Lpar2<jats:sup> −/−</jats:sup> mice showed an increased level of apoptosis, suggesting that LPA<jats:sub>2</jats:sub>-mediated signaling stimulates intestinal tumor development and progress by regulating both cell proliferation and survival. In addition, the expression levels of Krüpple-like factor 5 (KLF5), β-catenin, cyclin D1, c-Myc, and hypoxia-inducible factor-1α (HIF-1α) were significantly altered in Apc<jats:sup> Min/+</jats:sup> /Lpar2<jats:sup> −/−</jats:sup> mice compared with Apc<jats:sup> Min/+</jats:sup> mice. In vitro studies using HCT116 cells showed that LPA induced cyclin D1, c-Myc, and HIF-1α expression, which was attenuated by knockdown of LPA<jats:sub>2</jats:sub>. In summary, intestinal tumor initiated by Apc mutations is altered by LPA<jats:sub>2</jats:sub>-mediated signaling, which regulates tumor growth and survival by altering multiple targets. </jats:p>