About this item:

651 Views | 0 Downloads

Author Notes:

Address for reprint requests and other correspondence: C. Chris Yun, Division of Digestive Disease, Emory Univ., Whitehead Bldg. Suite 201, 615 Michael St., Atlanta, GA 30322 (e-mail: ccyun@emory.edu).

Subject:

Research Funding:

This work was supported by National Institutes of Health Grants R01DK-071597 and R01DK-071597-03S1 to C. C. Yun. and R01MH-51699 and R01HD-050685 to J. Chun. S. Lin was supported by a Crohn's and Colitis Foundation of America Research Fellowship Award.

Keywords:

  • lysophosphatidic acid
  • multiple intestinal neoplasia
  • familial adenomatous polyposis
  • adenomatous polyposis coli

The absence of LPA receptor 2 reduces the tumorigenesis by ApcMin mutation in the intestine

Tools:

Journal Title:

AJP - Gastrointestinal and Liver Physiology

Volume:

Volume 299, Number 5

Publisher:

, Pages G1128-G1138

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Lysophosphatidic acid (LPA) is a lipid mediator that mediates several effects that promote cancer progress. The LPA receptor type 2 (LPA2) expression is often elevated in several types of cancers, including colorectal cancer (CRC). In this study, we investigated the role of LPA2 in the development of intestinal adenomas by comparing ApcMin/+ mice with ApcMin/+/Lpar2−/− mice. There were 50% fewer intestinal adenomas in ApcMin/+/Lpar2−/− mice than ApcMin/+ mice. Smaller-size adenomas (<1 mm) were found at higher frequencies in ApcMin/+/Lpar2−/− mice compared with ApcMin/+ mice at the two age groups examined. The expression level of LPA2 correlated with increased size of intestinal adenomas. Reduced tumor multiplicity and size in ApcMin/+/Lpar2−/− mice correlated with decreased proliferation of intestinal epithelial cells. ApcMin/+/Lpar2−/− mice showed an increased level of apoptosis, suggesting that LPA2-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 ApcMin/+/Lpar2−/− mice compared with ApcMin/+ 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 LPA2. In summary, intestinal tumor initiated by Apc mutations is altered by LPA2-mediated signaling, which regulates tumor growth and survival by altering multiple targets.

Copyright information:

© 2010 the American Physiological Society

Export to EndNote