Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cell Death Dis. 2013 Nov 21;4(11):e928. doi: 10.1038/cddis.2013.458.
Natural killer (NK) cells are important in host to eliminate circulating tumour cells (CTCs) in turn preventing the development of tumour cells into metastasis but the mechanisms are very poorly defined. Here we find that the expression level of miR-296-3p is much lower in the non-metastatic human prostate cancer (PCa) cell line P69 than that in the highly metastatic cell line M12, which is derived from P69. We demonstrate that miR-296-3p directly targets and inhibits the expression of intercellular adhesion molecule 1 (ICAM-1) in the malignant M12. The data from clinical tissue microarrays also show that miR-296-3p is frequently upregulated and ICAM-1 is reversely downregulated in PCa. Interestingly, ectopic expression of miR-296-3p in P69 increases the tolerance to NK cells whereas knockdown of miR-296-3p in M12 reduces the resistance to NK cells, which both phenotypes can be rescued by re-expression or silencing of ICAM-1 in P69 and M12, respectively. These results are also manifested in vivo by the decrease in the incidence of pulmonary tumour metastasis exhibited by knockdown of miR-296-3p in M12 when injected into athymic nude mice via tail vein, and consistently down-expression of ICAM-1 reverses this to increase extravasation of CTCs into lungs. Above results suggest that this newly identified miR-296-3p-ICAM-1 axis has a pivotal role in mediating PCa metastasis by possible enhancing survival of NK cell-resistant CTC. Our findings provide novel potential targets for PCa therapy and prognosis.
自然杀伤 (NK) 细胞在宿主中消除循环肿瘤细胞 (CTC) 以防止肿瘤细胞发展为转移方面非常重要，但这些机制尚未完全确定。在这里，我们发现非转移性人前列腺癌 (PCa) 细胞系 P69 中 miR-296-3p 的表达水平明显低于高转移性细胞系 M12，而 M12 是由 P69 衍生而来的。我们证明 miR-296-3p 可以直接靶向并抑制恶性 M12 中细胞间黏附分子 1 (ICAM-1) 的表达。来自临床组织微阵列的数据还显示，miR-296-3p 在 PCa 中经常上调，而 ICAM-1 则下调。有趣的是，P69 中转染 miR-296-3p 会增加对 NK 细胞的耐受性，而 M12 中 miR-296-3p 的敲低会降低对 NK 细胞的抵抗力，这两种表型都可以通过在 P69 和 M12 中分别重新表达或沉默 ICAM-1 来挽救。这些结果在体内也得到了体现，即通过尾静脉注射敲低 M12 中的 miR-296-3p，可降低肺转移瘤的发生率，而 ICAM-1 的持续下调则会增加 CTC 向肺部的外渗。上述结果表明，这个新发现的 miR-296-3p-ICAM-1 轴通过可能增强 NK 细胞耐药 CTC 的存活，在介导 PCa 转移方面发挥着关键作用。我们的研究结果为 PCa 的治疗和预后提供了新的潜在靶点。
