Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
Oncol Rep. 2010 Jan;23(1):121-8.
MicroRNAs (miRNAs) have recently taken center stage in the field of human molecular oncology. Most of the chemotherapeutics are able to interfere with nucleic acid metabolism and gene expression. The purpose of this study was to determine how 5-fluorouracil (5-FU) and oxaliplatin (L-OHP) modify the expression profiles of miRNAs in HCT-8 and HCT-116 colon cancer cells and whether the pharmacodynamic mechanisms of the chemotherapeutics could rely in part on their influence on miRNA expression. The expression profiles of miRNAs were determined using a miRNA microarray containing 856 human miRNA probes. The expression of selected miRNAs was then validated by real-time RT-PCR. Fifty-six up- and 50 down-regulations of miRNA expression with statistical significance were identified in colon cancer cells following exposure to 5-FU or L-OHP compared to matched control cells. The down-regulations of miR-197, miR-191, miR-92a, miR-93, miR-222 and miR-1826, whose expression was significantly down-regulated in both cell lines after the treatment of one drug or in one cell line following exposure to either drug, were further validated. Analysis of the relevant literature indicated that, in line with the tumor suppressive activity of 5-FU and L-OHP, the six down-regulated miRNAs might function as oncogenes due to their overexpression in cancers, and some of them correlated with the poor prognosis and treatment-resistance of cancer. In conclusion, we identify the modification of miRNA expression profiles in colon cancer cells following exposure to 5-FU and L-OHP, and our results indicate that their pharmacodynamic mechanisms could rely in part on their influence on the down-regulated miRNA expression. Further studies are needed to determine whether these miRNAs and their target genes might potentially provide for novel molecular markers and act as novel targets for treatment by interference.
微小 RNA（miRNA）在人类分子肿瘤学领域中最近占据了中心地位。大多数化疗药物能够干扰核酸代谢和基因表达。本研究旨在确定 5-氟尿嘧啶（5-FU）和奥沙利铂（L-OHP）如何改变 HCT-8 和 HCT-116 结肠癌细胞中 miRNA 的表达谱，以及化疗药物的药效学机制是否部分依赖于它们对 miRNA 表达的影响。使用包含 856 个人类 miRNA 探针的 miRNA 微阵列确定 miRNA 的表达谱。然后通过实时 RT-PCR 验证选定 miRNA 的表达。与匹配的对照细胞相比，在结肠癌细胞中，5-FU 或 L-OHP 暴露后，有 56 个 miRNA 的表达上调和 50 个 miRNA 的表达下调具有统计学意义。在两种细胞系中的一种药物处理后或在一种细胞系中暴露于一种药物后，miR-197、miR-191、miR-92a、miR-93、miR-222 和 miR-1826 的表达明显下调，对其进一步验证。对相关文献的分析表明，与 5-FU 和 L-OHP 的肿瘤抑制活性一致，由于在癌症中过度表达，这 6 个下调的 miRNA 可能作为癌基因发挥作用，其中一些与癌症的不良预后和治疗耐药性相关。总之，我们确定了在暴露于 5-FU 和 L-OHP 后结肠癌细胞中 miRNA 表达谱的修饰，并且我们的结果表明它们的药效学机制可能部分依赖于它们对下调的 miRNA 表达的影响。需要进一步的研究来确定这些 miRNA 和它们的靶基因是否可能为新的分子标志物提供潜在的作用，并作为干扰治疗的新靶点。
