Oncogene：舒林酸（Sulindac）抑制NF-κB介导的肿瘤细胞侵袭

非甾体类消炎药（NSAIDs）已被广泛研究报道有强大的癌症化学预防功效，但其作用机制知之甚少。目前最全面完善的有关NSAIDs的癌预防作用包括抑制肿瘤细胞增殖以及诱导肿瘤细胞的凋亡，但NSAIDs对肿瘤细胞侵袭的影响一直没有得到很好的研究。

近日一则发表在Oncogene杂志上的研究表明，类固醇消炎药舒林酸可以有效的抑制人乳腺癌细胞MDA-MB-231和结肠癌细胞HCT116在体外的侵袭能力，并且其抑制肿瘤细胞侵袭能力的浓度低于其抑制肿瘤细胞生长所需的浓度。

在研究其中分子基础，科学家重点考究了microRNA的参与机制。发现共有132个miRNA发生了改变当肿瘤细胞用舒林酸处理后，其中包括miR-10b、miR-17、miR-21和miR-9，这些miRNA此前已被证实在肿瘤侵袭和转移中发挥作用。

在确认这些miRNA可以刺激肿瘤细胞的侵袭后，研究人员证实舒林酸可以通过下调其表达抑制这些miRNA所诱导的肿瘤侵袭。采用荧光素酶和染色质免疫沉淀分析发现NF-κB与所有四个miRNA的启动子区域相结合在转录水平抑制其表达。

总之舒林酸可以通过减少IKKbeta和IkappaB的磷酸化抑制NF-κB的易位到细胞核，抑制NF-κB介导的miRNA转录抑制肿瘤细胞的侵袭。

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.