Journal
CELLULAR SIGNALLING
Volume 24, Issue 1, Pages 162-169Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2011.08.017
Keywords
ORAI1/CRACM1; STIM1; Store-operated calcium channel; EGF; Cyclooxygenase-2
Categories
Funding
- Excellence for Cancer Research Center [DOH100-TD-C-111-002]
- Department of Health, Executive Yuan, Taiwan (NSC)
- National Science Council, Taiwan [100-2320-B-037-002, 99-2911-I-037-003]
- Kaohsiung Medical University Hospital [KMUH98-8I04]
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Growing evidence shows that chronic inflammation drives the progression of colorectal cancer (CRC). Cyclooxygenase-2 (COX-2) is one of the most important inflammatory genes involved in solid tumor metastasis. Epidermal growth factor receptor (EGFR) also plays a key role in cancer cell development. We compared the expression levels of EGFR and COX-2 between tumor and normal tissues from 20 CRC patients and studied the molecular mechanism of EGFR-mediated COX-2 gene expression in cancer cells. Our results indicated that COX-2 expression was markedly increased after EGF stimulation. COX-2 promoter analysis indicated the involvement of cyclic AMP-responsive element (CRE) and nuclear factor of activated T cells/nuclear factor interleukin-6 (NFAT/NF-IL6)-binding sites in EGF-mediated signaling pathways. Furthermore, EGF-mediated COX-2 activation was prevented by 2-aminoethoxydiphenyl borate (2-APB), a store-operated Ca2+ channel inhibitor. Transfection of siRNA against ORAI1 or STIM1, the key regulators of store-operated Ca2+ channels, showed significant inhibitory effects on EGF-mediated COX-2 expression. In conclusion, store-operated Ca2+ entry is involved in the activation of transcription factors (CREB/NFAT) that are responsible for delivering EGF-mediated signals to evoke inflammatory cascades and is eventually related to CRC tumorigenesis. (C) 2011 Elsevier Inc. All rights reserved.
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