The absence of LPA receptor 2 reduces the tumorigenesis by ApcMin mutation in the intestine.
Lysophosphatidic acid (LPA) is a lipid mediator that mediates several effects that promote cancer progress. The LPA receptor type 2 (LPA(2)) expression is often elevated in several types of cancers, including colorectal cancer (CRC). In this study, we investigated the role of LPA(2) in the development of intestinal adenomas by comparing Apc(Min/+) mice with Apc(Min/+)/Lpar2(-/-) mice. There were 50% fewer intestinal adenomas in Apc(Min/+)/Lpar2(-/-) mice than Apc(Min/+) mice. Smaller-size adenomas (<1 mm) were found at higher frequencies in Apc(Min/+)/Lpar2(-/-) mice compared with Apc(Min/+) mice at the two age groups examined. The expression level of LPA(2) correlated with increased size of intestinal adenomas. Reduced tumor multiplicity and size in Apc(Min/+)/Lpar2(-/-) mice correlated with decreased proliferation of intestinal epithelial cells. Apc(Min/+)/Lpar2(-/-) mice showed an increased level of apoptosis, suggesting that LPA(2)-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(Min/+)/Lpar2(-/-) mice compared with Apc(Min/+) 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(2). In summary, intestinal tumor initiated by Apc mutations is altered by LPA(2)-mediated signaling, which regulates tumor growth and survival by altering multiple targets.
Lin
Songbai
S
Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
Lee
Sei-Jung
SJ
Shim
Hyunsuk
H
Chun
Jerold
J
Yun
C Chris
CC
D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D017491:Genes, APC / Q000502:physiology*; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007422:Intestines / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D049368:Receptors, Lysophosphatidic Acid