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5．甲基化
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半数以上的胃癌均有COX-2的表达，但部分胃癌不表达COX-2的原因尚不清楚。Kikuchi和Song均发现无COX-2表达的胃癌细胞株及原发性胃癌（11/93例）在COX-2CpG岛有高度甲基化，COX-2基因的甲基化与其表达下降有密切关系。使用甲基化抑制剂或脱甲基治疗能恢复COX-2的表达，进一步研究表明甲基化的COX-2促进子上出现组蛋白的脱乙酰基。COX-2的甲基化可能是部分胃癌的发生与进展独立于COX-2之外的原因。
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6．细胞内信号传导机制的激活
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有丝分裂原活化蛋白激酶（MAPK）是包括细胞外信号调节激酶（ERK)、蛋白激酶P38和C-Jun-N末端激酶（JNK）在内的细胞信号分子家族，可调节细胞增殖、分化、凋亡及细胞因子产物。MAPK可被上游的激酶（MAPK磷酸酶）和细胞外许多刺激物激活，并把信号从细胞表面传递至细胞核内调节基因的表达。Husain采用凝胶电泳滞留测定法发现选择性COX-2抑制剂NS-398及非选择性COX抑制剂消炎痛均能抑制MKN-28胃癌细胞株的MAPK活性，抑制率分别为53％和70％，同时细胞增殖明显受抑。体外实验发现MAPK特异性抑制剂能够抑制由白介素-1β（interleukin-1β, IL-1β）诱导的胃腺癌细胞株AGS的COX-2表达，而且MAPK活性下调。在胃癌发生、发展和转移过程中众多的因素、基因并非孤立地作用于某一时间段、某一位点，它们可能在某时间段发挥主要作用，并且相互之间互为制约、互为促进，其复杂的调节关系构成了胃癌发生、发展和转移的一张不甚清晰的网络图，尚有待于大家进一步的探索。
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7．抑制免疫调节
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机体主要通过细胞免疫机制来发挥抗肿瘤免疫效应。COX-2通过抑制调节性淋巴因子，抑制T细胞和B细胞增殖，抑制自然杀伤细胞（NK细胞）、淋巴因子激活杀伤细胞（LAK细胞）及细胞毒性T淋巴细胞的活性，抑制干扰素7（IFN-7)、CD25、CD71、IL-2的产生，是外周血淋巴细胞和巨噬细胞的潜在诱导剂；PGE2可以抑制肿瘤坏死因子的产生以及诱导IL-10的生成，而后者是一种免疫抑制因子。这些作用可能使肿瘤的免疫识别形成屏蔽，从而抑制免疫反应，导致肿瘤生长。
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【思考题】
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1．与胃癌形成和生长相关的基因有哪些？
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2．试述与胃癌浸润和转移相关的基因。
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参考文献
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