非甾體類消炎藥（NSAIDs）已被廣泛研究報(bào)道有強(qiáng)大的癌癥化學(xué)預(yù)防功效,，但其作用機(jī)制知之甚少,。目前最全面完善的有關(guān)NSAIDs的癌預(yù)防作用包括抑制腫瘤細(xì)胞增殖以及誘導(dǎo)腫瘤細(xì)胞的凋亡，但NSAIDs對(duì)腫瘤細(xì)胞侵襲的影響一直沒有得到很好的研究,。
近日一則發(fā)表在Oncogene雜志上的研究表明,，類固醇消炎藥舒林酸可以有效的抑制人乳腺癌細(xì)胞MDA-MB-231和結(jié)腸癌細(xì)胞HCT116在體外的侵襲能力，并且其抑制腫瘤細(xì)胞侵襲能力的濃度低于其抑制腫瘤細(xì)胞生長所需的濃度,。
在研究其中分子基礎(chǔ),，科學(xué)家重點(diǎn)考究了microRNA的參與機(jī)制。發(fā)現(xiàn)共有132個(gè)miRNA發(fā)生了改變當(dāng)腫瘤細(xì)胞用舒林酸處理后,，其中包括miR-10b,、miR-17、miR-21和miR-9,，這些miRNA此前已被證實(shí)在腫瘤侵襲和轉(zhuǎn)移中發(fā)揮作用,。
在確認(rèn)這些miRNA可以刺激腫瘤細(xì)胞的侵襲后，研究人員證實(shí)舒林酸可以通過下調(diào)其表達(dá)抑制這些miRNA所誘導(dǎo)的腫瘤侵襲,。采用熒光素酶和染色質(zhì)免疫沉淀分析發(fā)現(xiàn)NF-κB與所有四個(gè)miRNA的啟動(dòng)子區(qū)域相結(jié)合在轉(zhuǎn)錄水平抑制其表達(dá),。
總之舒林酸可以通過減少IKKbeta和IkappaB的磷酸化抑制NF-κB的易位到細(xì)胞核，抑制NF-κB介導(dǎo)的miRNA轉(zhuǎn)錄抑制腫瘤細(xì)胞的侵襲,。（生物谷：Bioon.com）
doi:10.1038/onc.2011.655
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Sulindac inhibits tumor cell invasion by suppressing NF-κB-mediated transcription of microRNAs.
Li X, Gao L, Cui Q, Gary BD, Dyess DL, Taylor W, Shevde LA, Samant RS, Dean-Colomb W, Piazza GA, Xi Y.
Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely reported to display strong efficacy for cancer chemoprevention, although their mechanism of action is poorly understood. The most well-documented effects of NSAIDs include inhibition of tumor cell proliferation and induction of apoptosis, but their effect on tumor cell invasion has not been well studied. Here, we show that the NSAID, sulindac sulfide (SS) can potently inhibit the invasion of human MDA-MB-231 breast and HCT116 colon tumor cells in vitro at concentrations less than those required to inhibit tumor cell growth. To study the molecular basis for this activity, we investigated the involvement of microRNA (miRNA). A total of 132 miRNAs were found to be altered in response to SS treatment, including miR-10b, miR-17, miR-21 and miR-9, which have been previously implicated in tumor invasion and metastasis. We confirmed that these miRNA can stimulate tumor cell invasion and show that SS can attenuate their invasive effects by downregulating their expression. Employing luciferase and chromatin immunoprecipitation assays, NF-κB was found to bind the promoters of all four miRNAs to suppress their expression at the transcriptional level. We show that SS can inhibit the translocation of NF-κB to the nucleus by decreasing the phosphorylation of IKKβ and IκB. Analysis of the promoter sequences of the miRNAs suppressed by SS revealed that 81 of 115 sequences contained NF-κB-binding sites. These results show that SS can inhibit tumor cell invasion by suppressing NF-κB-mediated transcription of miRNAs.
