title: Involvement of store-operated calcium signaling in EGF-mediated COX-2 gene activation in cancer cells.
abstract: 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 Ca(2+) channel inhibitor. Transfection of siRNA against ORAI1 or STIM1, the key regulators of store-operated Ca(2+) channels, showed significant inhibitory effects on EGF-mediated COX-2 expression. In conclusion, store-operated Ca(2+) 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.
authors.affiliation: Division of Gastrointestinal and General Surgery, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Jaw-Yuan
authors.initials: JY
authors.lastname: Wang
authors.forename: Ben-Kuen
authors.initials: BK
authors.lastname: Chen
authors.forename: Yu-Shiuan
authors.initials: YS
authors.lastname: Wang
authors.forename: Yao-Ting
authors.initials: YT
authors.lastname: Tsai
authors.forename: Wei-Chiao
authors.initials: WC
authors.lastname: Chen
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Hou
authors.forename: Yang-Chang
authors.initials: YC
authors.lastname: Wu
authors.forename: Wei-Chiao
authors.initials: WC
authors.lastname: Chang
mesh_terms: D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology / Q000502:physiology*; D066246:ErbB Receptors / Q000819:agonists / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D000071740:ORAI1 Protein; D034622:RNA Interference; D020218:Response Elements; D000071737:Stromal Interaction Molecule 1
chemical_list: C538758:2-aminoethyl diphenylborinate; D001896:Boron Compounds; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D004815:Epidermal Growth Factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D002118:Calcium