Inhibition of nuclear factor-kappaB suppresses peritoneal dissemination of gastric cancer by blocking cancer cell adhesion
Inhibition of nuclear factor-kappaB suppresses peritoneal dissemination of gastric cancer by blocking cancer cell adhesion
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DOI：
10.1111/j.1349-7006.2011.01901.x
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发表时间：
2011-05-01
期刊：
影响因子：
5.7
通讯作者：
Todo, Satoru
中科院分区：
文献类型：
--
作者：
Mino, Kazuhiro;Ozaki, Michitaka;Todo, Satoru
目前，由于没有标准的有效治疗方法，胃癌腹膜播散性患者必须接受预后不良的治疗。为了抑制腹膜扩散，重要的是抑制细胞外基质(ECM)和细胞表面整合素之间的相互作用，而细胞表面整合素是癌细胞黏附的重要因素。尽管核因子-kappaB(NF-kappa B)参与了肿瘤发展的多个过程，但其对整合素表达的影响尚不清楚。我们使用了一种新型的核因子-kappa B抑制剂脱羟甲氧奎诺米星(DHMEQ)，在小鼠胃癌扩散模型中研究了核因子-kappa B是否通过整合素阻止了癌细胞的黏附，发现DHMEQ是一种有效的癌细胞扩散抑制因子。与对照组相比，去羟甲氧奎诺米星抑制人胃癌细胞株NUGC-4和44As3Luc的核因子-kappaB活性，并阻断癌细胞与细胞外基质的黏附。在体外研究中，脱羟甲氧奎诺米星还抑制整合素(α2、α3、β1)的表达。在体内模型中，我们将经DHMEQ处理过的44As3Luc细胞注射到小鼠的腹膜腔内，并在注射癌细胞后进行腹腔灌洗。通过活体成像对腹膜腔内可存活的癌细胞进行连续评价。在注射DHMEQ处理过的细胞并灌洗的小鼠中，腹膜中的活癌细胞与对照组相比显著减少，这些小鼠存活的时间更长。这些结果表明，DHMEQ可能通过抑制整合素的表达而抑制癌细胞与腹膜的黏附。核因子-kappaB抑制可能是抑制肿瘤术后转移的一种新的治疗选择。(《癌症科学》2011；102：1052-1058)。
Currently, patients with peritoneal dissemination of gastric cancer must accept a poor prognosis because there is no standard effective therapy. To inhibit peritoneal dissemination it is important to inhibit interactions between extracellular matrices (ECM) and cell surface integrins, which are important for cancer cell adhesion. Although nuclear factor-kappa B (NF-kappa B) is involved in various processes in cancer progression, its involvement in the expression of integrins has not been elucidated. We used a novel NF-kappa B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), to study whether NF-kappa B blocks cancer cell adhesion via integrins in a gastric cancer dissemination model in mice and found that DHMEQ is a potent suppressor of cancer cell dissemination. Dehydroxymethylepoxyquinomicin suppressed the NF-kappa B activity of human gastric cancer cells NUGC-4 and 44As3Luc and blocked the adhesion of cancer cells to ECM when compared with the control. Dehydroxymethylepoxyquinomicin also inhibited expression of integrin (alpha 2, alpha 3, beta 1) in in vitro studies. In the in vivo model, we injected 44As3Luc cells pretreated with DHMEQ into the peritoneal cavity of mice and performed peritoneal lavage after the injection of cancer cells. Viable cancer cells in the peritoneal cavities were evaluated sequentially by in vivo imaging. In mice injected with DHMEQ-pretreated cells and lavaged, live cancer cells in the peritoneum were significantly reduced compared with the control, and these mice survived longer. These results indicate that DHMEQ could inhibit cancer cell adhesion to the peritoneum possibly by suppressing integrin expression. Nuclear factor-kappa B inhibition may be a new therapeutic option for suppressing postoperative cancer dissemination. (Cancer Sci 2011; 102: 1052-1058).