Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer.
Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer.
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DOI：
10.1186/1476-4598-10-25
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发表时间：
2011-03-09
期刊：
影响因子：
37.3
通讯作者：
Pidgeon GP
中科院分区：
文献类型：
--
作者：
Cathcart MC;Gately K;Cummins R;Kay E;O'Byrne KJ;Pidgeon GP
血栓烷合酶（TXS）将前列腺素H2代谢成血栓烷，血栓烷对癌细胞具有生物活性。TXS过表达已在一系列癌症中被报道，并且与不良预后相关。TXS抑制在体外诱导细胞死亡，为治疗干预提供了理论基础。我们的目的是确定TXS在NSCLC中的表达谱，以及它是否是该疾病的预后和/或生存因素。通过Western分析和IHC检测人NSCLC和匹配对照中的TXS表达。用EIA法测定TXS代谢物（TXB 2）水平。对204例NSCLC TMA进行考克斯-2和下游TXS表达染色。TXS组织表达与临床参数相关，包括总生存期。在选择性TXS抑制和稳定的TXS过表达后，在NSCLC细胞中检查细胞增殖/存活和侵袭。相对于匹配的正常对照，TXS在人NSCLC样品中过表达。NSCLC患者血浆TXB_2、TXS水平明显升高（P <0.01），而蛋白组TXB_2水平明显升高（P <0.05）。TXS在腺癌组织中的表达明显高于女性（P <0.05），在腺癌组织中的表达明显高于男性（P <0.001）。未观察到与患者生存率的显著相关性。选择性TXS抑制显着降低肿瘤细胞的生长和增加凋亡，而TXS过度表达刺激细胞增殖和侵袭，并对细胞凋亡的保护。TXS在NSCLC中过度表达，特别是在腺癌亚型中。这种酶的抑制抑制增殖并诱导凋亡。单独靶向血栓素合酶或联合常规化疗是NSCLC的潜在治疗策略。
Thromboxane synthase (TXS) metabolises prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease. TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB2 levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC.
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