Baguma-Nibasheka Mark, Barclay Christie, Li Audrey W, Geldenhuys Laurette, Porter Geoffrey A, Blay Jonathan, Casson Alan G, Murphy Paul R
Department of Physiology and Biophysics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
Mol Carcinog. 2007 Dec;46(12):971-80. doi: 10.1002/mc.20339.
Inhibition of cyclooxygenase (COX)-2 is reported to suppress growth and induce apoptosis in human esophageal adenocarcinoma (EADC) cells, although the precise biologic mechanism is unclear. In this study we tested the hypothesis that the antitumor activity of COX-2 inhibitors may involve modulation of basic fibroblast growth factor (FGF-2), which is overexpressed in EADC. We evaluated the effects of NS-398, a selective COX-2 inhibitor, on FGF-2 expression and proliferation of EADC cell lines that express COX-2 and those that do not. We also correlated COX-2 and FGF-2 expression with clinico-pathologic findings and outcome in a well-characterized series of surgically resected EADC tissues. Seg-1 cells robustly expressed COX-2 and FGF-2, whereas Bic-1 cells expressed neither transcript. FGF-2 was reduced to undetectable levels in Seg-1 cells following NS-398 treatment, but increased within 4 h of drug removal. NS-398 significantly inhibited the growth of Seg-1 cells, and this effect was ameliorated by addition of exogenous FGF-2. In contrast, NS-398 had no effect on Bic-1 cell proliferation and FGF-2 alone had no effect on proliferation of either cell line. NS-398, or a neutralizing anti-FGF-2 antibody, induced apoptosis in Seg-1 cells, and these effects were inhibited by addition of exogenous FGF-2. COX-2 protein was strongly expressed in 46% (10/22) of EADCs, and was associated with a trend towards reduced disease-free survival. These findings indicate that the antitumor effects of COX-2 inhibition in EADC cells may be mediated via suppression of FGF-2, and that COX-2 may be a clinically relevant molecular marker in the management of human EADC.
据报道，抑制环氧化酶（COX）-2可抑制人食管腺癌（EADC）细胞的生长并诱导其凋亡，尽管确切的生物学机制尚不清楚。在本研究中，我们检验了这样一个假设，即COX-2抑制剂的抗肿瘤活性可能涉及对碱性成纤维细胞生长因子（FGF-2）的调节，FGF-2在EADC中过度表达。我们评估了选择性COX-2抑制剂NS-398对表达COX-2和不表达COX-2的EADC细胞系中FGF-2表达和增殖的影响。我们还将COX-2和FGF-2的表达与一系列特征明确的手术切除EADC组织的临床病理结果及预后进行了关联分析。Seg-1细胞强烈表达COX-2和FGF-2，而Bic-1细胞两种转录本均不表达。NS-398处理后，Seg-1细胞中的FGF-2降至无法检测的水平，但在去除药物后4小时内又升高。NS-398显著抑制Seg-1细胞的生长，添加外源性FGF-2可改善这种作用。相反，NS-398对Bic-1细胞增殖没有影响，单独的FGF-2对两种细胞系的增殖均无影响。NS-39,或一种中和性抗FGF-2抗体可诱导Seg-1细胞凋亡，添加外源性FGF-2可抑制这些作用。46%（10/22）的EADC中COX-2蛋白强烈表达，且与无病生存期缩短的趋势相关。这些发现表明，COX-2抑制在EADC细胞中的抗肿瘤作用可能通过抑制FGF-2介导，且COX-2可能是人类EADC治疗中一个与临床相关的分子标志物。
