Regulation of cysteinyl leukotriene receptor 2 expression--a potential anti-tumor mechanism.

Abstract

BACKGROUND:

The cysteinyl leukotrienes receptors (CysLTRs) are implicated in many different pathological conditions, such as inflammation and cancer. We have previously shown that colon cancer patients with high CysLT(1)R and low CysLT(2)R expression demonstrate poor prognosis. Therefore, we wanted to investigate ways for the transcriptional regulation of CysLT(2)R, which still remains to be poorly understood.

METHODOLOGY/PRINCIPAL FINDINGS:

We investigated the potential role of the anti-tumorigenic interferon α (IFN-α) and the mitogenic epidermal growth factor (EGF) on CysLT(2)R regulation using non-transformed intestinal epithelial cell lines and colon cancer cells to elucidate the effects on the CysLT(2)R expression and regulation. This was done using Western blot, qPCR, luciferase reporter assay and a colon cancer patient array. We found a binding site for the transcription factor IRF-7 in the putative promoter region of CysLT(2)R. This site was involved in the IFN-α induced activity of the CysLT(2)R luciferase reporter assay. In addition, IFN-α induced the activity of the differentiation marker alkaline phosphatase along with the expression of mucin-2, which protects the epithelial layer from damage. Interestingly, EGF suppressed both the expression and promoter activity of the CysLT(2)R. E-boxes present in the CysLT(2)R putative promoter region were involved in the suppressing effect. CysLT(2)R signaling was able to suppress cell migration that was induced by EGF signaling.

CONCLUSIONS/SIGNIFICANCE:

The patient array showed that aggressive tumors generally expressed less IFN-α receptor and more EGFR. Interestingly, there was a negative correlation between CysLT(2)R and EGFR expression. Our data strengthens the idea that there is a protective role against tumor progression for CysLT(2)R and that it highlights new possibilities to regulate the CysLT(2)R.

• Authors: Cecilia Magnusson, Astrid M Bengtsson, Minghui Liu, Jian Liu, Yvonne Ceder, Roy Ehrnström, Anita Sjölander
• Journal: PloS one (PLoS One) Vol. 6 Issue 12 Pg. e29060 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 22194989 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• IRF7 protein, human
• Interferon Regulatory Factor-7
• Interferon-alpha
• Receptors, Leukotriene
• Snail Family Transcription Factors
• Transcription Factors
• Epidermal Growth Factor
• cysteinyl leukotriene receptor 2
• Luciferases
• ErbB Receptors

Topics

• Base Sequence
• Binding Sites
• Caco-2 Cells
• Cell Differentiation (drug effects)
• Colorectal Neoplasms (genetics, pathology)
• E-Box Elements (genetics)
• Epidermal Growth Factor (pharmacology)
• ErbB Receptors (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, Reporter (genetics)
• Humans
• Interferon Regulatory Factor-7 (metabolism)
• Interferon-alpha (pharmacology)
• Luciferases (metabolism)
• Molecular Sequence Data
• Promoter Regions, Genetic (genetics)
• Receptors, Leukotriene (genetics, metabolism)
• Signal Transduction (drug effects)
• Snail Family Transcription Factors
• Transcription Factors (metabolism)