Aberrant expression of lysophosphatidic acid (LPA) receptors in human colorectal cancer

Abstract

Lysophosphatidic acid (LPA) is a simple bioactive phospholipid with diverse effects on various cells, that interacts with three G protein-coupled transmembrane receptors, LPA1, LPA2, and LPA3. The expression pattern and functions of these LPA receptors in various tumors have not been fully examined, except in ovarian cancer. To evaluate the LPA receptor expression profile in human colorectal cancer and in normal mucosa, we used real-time reverse transcription-polymerase chain reaction (RT-PCR) and measured the expression levels of LPA1, LPA2, and LPA3 messenger RNA (mRNA) in 26 colorectal cancers and 16 corresponding normal tissue samples. Normal epithelium expressed both LPA1 and LPA2 mRNA at similar levels. In comparison, colorectal cancers expressed LPA1 mRNA at a significantly lower level (0.3-fold; Po0.05), and LPA2 mRNA at a significantly higher level (three-fold; Po0.05), as compared with normal tissues. Thus, the ratio of LPA2/LPA1 increased markedly during malignant transformation (18-fold increase). LPA3 mRNA was expressed at only a low level in both normal and cancer tissues. We also assessed LPA2 expression immunohistochemically using a rat anti-LPA2 monoclonal antibody, and confirmed high expression of LPA2 in colorectal cancer at the protein level. As for LPA1, we examined Western blot analysis for 16 matched normal and cancer tissues. It revealed a significant decrease in the expression of LPA1 protein in cancer tissues compared to normal mucosa in nine of 16 cases, and in the remaining seven cases the expression levels was much the same. These results suggested that alteration of LPA receptor expression might be an important event in the development of colorectal cancer, and therefore, LPA and its receptors could be a chemopreventive target against colorectal cancer. Keywords: aberrant expression of LPA2; carcinogenesis; colorectal cancer; LPA receptor; lysophosphatidic acid; phospholipid Lysophosphatidic acid (LPA, 1-or 2-acyl-sn-glycero-3-phosphate), the simplest glycerophospholipid, mediates a broad range of cellular responses, including smooth muscle cell contraction, platelet aggregation, neurite retraction/cell rounding, regulation of cell proliferation, protection from apoptosis, modulation of chemotaxis, and transcellular migration.

Lysophosphatidic acid prevents apoptosis of Caco-2 colon cancer cells via activation of mitogen-activated protein kinase and phosphorylation of Bad

“…[17][18][19][20][21]. These studies, in conjunction with multiple effects mediated by LPA, suggest that over-expression of LPA 2 may enhance the development of cancer.…”

“…Many cancer cells are often hypersensitive to apoptosis induction, but can avoid apoptosis because they have lost or can bypass check points that control cell cycle progression [33,42]. Over-expression of LPA 2 has been associated with different types of cancers, including ovarian and colon cancers, suggesting that LPA may act to promote survival of cancerous cells even in the presence of chemotherapy [18][19][20][21]43]. Herein, we show that LPA provides survival signals to Caco-2 cells, protecting cells from etoposide-induced apoptosis via a NHERF2-dependent mechanism.…”

GPCRs and cancer

“…As a consequence, the transcriptional activation of multiple cancer-associated genes leads to cell survival and proliferation, migration, chemotaxis, vascular remodeling and angiogenesis [13] . Aberrant expressions and mutations of LPA receptors have been found in several types of tumors, suggesting their involvement in the growth advantage of cancer cells [3,14,15] . For instance, LPA1 was inversely correlated in breast cancer tissues with the Nm23 metastases regulator [16] and contributed to bone metastasis in breast cancer xenografts [17] .…”

Transactivation of Epidermal Growth Factor Receptor Is Involved in Leptin-Induced Activation of Janus-Activated Kinase 2 and Extracellular Signal–Regulated Kinase 1/2 in Human Gastric Cancer Cells

“…Immunoprecipitation and Western blot analysis were done as previously described (11,12). In brief, MKN28 and MKN74 cells were grown to 80% to 90% confluence in 10-cm dishes.…”