Dysregulation of miR-31 and miR-21 induced by zinc deficiency promotes esophageal cancer
Dysregulation of miR-31 and miR-21 induced by zinc deficiency promotes esophageal cancer
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DOI：
10.1093/carcin/bgs204
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发表时间：
2012-09-01
期刊：
影响因子：
4.7
通讯作者：
Fong, Louise Y. Y.
中科院分区：
文献类型：
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作者：
Alder, Hansjuerg;Taccioli, Cristian;Fong, Louise Y. Y.
缺锌（ZD）会增加食管鳞状细胞癌（ESCC）的风险。在大鼠模型中，慢性 ZD 会诱导炎症基因特征，从而促进食管鳞癌的发展。 microRNA 调节基因表达并在癌症中异常表达。在这里，我们研究了慢性 ZD（23 周）是否也会诱导促肿瘤 microRNA 特征。使用 nanoString 技术，我们评估了 ZD 食道和其他六种组织（皮肤、肺、胰腺、肝脏、前列腺和外周血单核细胞 [PBMC]）中的 microRNA 谱。 ZD 会导致炎症基因过度表达，并改变所有分析组织中的 microRNA 表达，从而预测疾病的发展。重要的是，炎症 ZD 食管具有类似于人类 ESCC 或舌 SCC miRNA 的独特 microRNA 特征，其中 miR-31 和 miR-21 作为上调物种。循环 miR-31 也是 PBMC 中最高上调的物种。在 ZD 食管和舌中，致癌 miR-31 和 miR-21 过表达伴随着各自的肿瘤抑制靶点 PPP2R2A 和 PDCD4 的下调。重要的是，与锌充足或补充锌的无癌大鼠相比，ZD 大鼠食管 miR-31 和 miR-21 水平与 ESCC 的出现直接相关。大鼠和人舌 SCC 的原位杂交分析将 miR-31 定位于肿瘤细胞，将 miR-21 定位于基质细胞。在补充锌的大鼠的舌鳞状细胞癌消退过程中，miR-31 和 miR-21 的表达同时降低，从而确定了它们对锌治疗的反应。对假定的 microRNA 靶标的搜索揭示了对炎症途径中基因的偏向。我们发现 ZD 会导致与炎症相关的 miR-31 和 miR-21 失调，从而深入了解 ZD 促进 ESCC 的机制。
Zinc deficiency (ZD) increases the risk of esophageal squamous cell carcinoma (ESCC). In a rat model, chronic ZD induces an inflammatory gene signature that fuels ESCC development. microRNAs regulate gene expression and are aberrantly expressed in cancers. Here we investigated whether chronic ZD (23 weeks) also induces a protumorigenic microRNA signature. Using the nanoString technology, we evaluated microRNA profiles in ZD esophagus and six additional tissues (skin, lung, pancreas, liver, prostate and peripheral blood mononuclear cells [PBMC]). ZD caused overexpression of inflammation genes and altered microRNA expression across all tissues analyzed, predictive of disease development. Importantly, the inflammatory ZD esophagus had a distinct microRNA signature resembling human ESCC or tongue SCC miRNAomes with miR-31 and miR-21 as the top-up-regulated species. Circulating miR-31 was also the top-up-regulated species in PBMCs. In ZD esophagus and tongue, oncogenic miR-31 and miR-21 overexpression was accompanied by down-regulation of their respective tumor-suppressor targets PPP2R2A and PDCD4. Importantly, esophageal miR-31 and miR-21 levels were directly associated with the appearance of ESCC in ZD rats, as compared with their cancer-free Zn-sufficient or Zn-replenished counterparts. In situ hybridization analysis in rat and human tongue SCCs localized miR-31 to tumor cells and miR-21 to stromal cells. In regressing tongue SCCs from Zn-supplemented rats, miR-31 and miR-21 expression was concomitantly reduced, establishing their responsiveness to Zn therapy. A search for putative microRNA targets revealed a bias toward genes in inflammatory pathways. Our finding that ZD causes miR-31 and miR-21 dysregulation associated with inflammation provides insight into mechanisms whereby ZD promotes ESCC.