近日,，國(guó)際知名學(xué)術(shù)期刊《歐洲分子生物學(xué)學(xué)會(huì)會(huì)刊》（The EMBO Journal）在線刊登了上海生科院生化與細(xì)胞所劉默芳研究組,、王恩多研究組關(guān)于miR-155/miR-143介導(dǎo)炎癥促進(jìn)腫瘤細(xì)胞糖代謝的最新研究成果。該工作與中山醫(yī)院張宏偉教授,、瑞金醫(yī)院李彪教授,、美國(guó)路易斯維爾大學(xué)李勇教授、中科院上海生命科學(xué)信息中心李黨生研究員等合作完成,。
區(qū)別于正常細(xì)胞，腫瘤細(xì)胞即使在有氧條件下,，也主要通過糖酵解方式分解葡萄糖獲能,，而非通過三羧酸循環(huán)和氧化磷酸化途徑生產(chǎn)ATP，腫瘤細(xì)胞的這種有氧糖酵解現(xiàn)象被稱為Warburg效應(yīng),。Warburg效應(yīng)對(duì)腫瘤微環(huán)境形成和維持,、腫瘤細(xì)胞增殖、抗凋亡和轉(zhuǎn)移等至關(guān)重要,。慢性炎癥和感染是腫瘤發(fā)生的一個(gè)重要誘因,，已發(fā)現(xiàn)炎癥信號(hào)參與調(diào)控腫瘤發(fā)生發(fā)展的各個(gè)步驟，但目前對(duì)促癌性炎癥與Warburg效應(yīng)之間是否有關(guān)聯(lián)還知之甚少,。
劉默芳研究組蔣帥博士和助理實(shí)驗(yàn)師張凌飛等發(fā)現(xiàn),，促炎細(xì)胞因子（如IL-6、TNFa,、IL-1b和IFN-g等）可在乳腺癌細(xì)胞中促進(jìn)糖酵解,、調(diào)控Warburg效應(yīng),。有趣的是，繼發(fā)現(xiàn)miR-155作用為炎癥-腫瘤發(fā)生之間的橋梁分子后,，該工作發(fā)現(xiàn)miR-155也可以作為炎癥-腫瘤細(xì)胞能量代謝之間的關(guān)鍵中轉(zhuǎn)信號(hào)分子,。機(jī)制上，miR-155從兩個(gè)層面上調(diào)了Warburg效應(yīng)中的一個(gè)關(guān)鍵糖代謝酶基因--己糖激酶II（hexokinase 2,， hk2）的表達(dá)：一方面,，miR-155通過激活轉(zhuǎn)錄因子STAT3促進(jìn)hk2的轉(zhuǎn)錄；另外一方面,，miR-155通過靶向C/EBPb抑制miR-143的表達(dá),，在轉(zhuǎn)錄后水平解除了miR-143對(duì)靶基因hk2的抑制，保證了HK2蛋白的表達(dá),。更為重要的是,，這種miR-155介導(dǎo)的雙通路hk2上調(diào)機(jī)制也存在于其它癌細(xì)胞中，可能是聯(lián)系炎癥-腫瘤細(xì)胞能量代謝的普遍機(jī)制,。該工作揭示了炎癥信號(hào)通路參與調(diào)控腫瘤細(xì)胞能量代謝的新機(jī)理,，對(duì)了解炎癥相關(guān)腫瘤的發(fā)生機(jī)制具有重要意義。
該項(xiàng)研究工作得到了國(guó)家科技部,、國(guó)家基金委,、中國(guó)科學(xué)院及上海市科委的資助。（生物谷Bioon.com）
doi:10.1038/emboj.2012.45
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A novel miR-155/miR-143 cascade controls glycolysis by regulating hexokinase 2 in breast cancer cells
Shuai Jiang1,2,3,8, Ling-Fei Zhang1,2,3,8, Hong-Wei Zhang4, Song Hu1,2,3, Ming-Hua Lu1,2,3, Sheng Liang5, Biao Li5, Yong Li6, Dangsheng Li7, En-Duo Wang1,3 and Mo-Fang Liu1,2,3
Cancer cells preferentially metabolize glucose through aerobic glycolysis. This phenomenon, known as the Warburg effect, is an anomalous characteristic of glucose metabolism in cancer cells. Chronic inflammation is a key promoting factor of tumourigenesis. It remains, however, largely unexplored whether and how pro-tumourigenic inflammation regulates glucose metabolism in cancer cells. Here, we show that pro-inflammatory cytokines promote glycolysis in breast cancer cells, and that the inflammation-induced miR-155 functions as an important mediator in this process. We further show that miR-155 acts to upregulate hexokinase 2 (hk2), through two distinct mechanisms. First, miR-155 promotes hk2 transcription by activation of signal transducer and activator of transcription 3 (STAT3), a transcriptional activator for hk2. Second, via targeting C/EBPβ (a transcriptional activator for mir-143), miR-155 represses mir-143, a negative regulator of hk2, thus resulting in upregulation of hk2 expression at the post-transcriptional level. The miR-155-mediated hk2 upregulation also appears to operate in other types of cancer cells examined. We suggest that the miR-155/miR-143/HK2 axis may represent a common mechanism linking inflammation to the altered metabolism in cancer cells.
