Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
Division of Molecular Genetics Research, Life Science Research Center, University of Toyama, Toyama 930-0194, Japan.
Int J Mol Med. 2014 Jul;34(1):334-40. doi: 10.3892/ijmm.2014.1758. Epub 2014 Apr 25.
Hyperthermia (HT) is an important modality in cancer treatment; however, the acquisition of thermal resistance in cancer cells due to the elevation of heat shock proteins (HSPs) makes HT less effective. Accumulating evidence suggests that microRNAs (miRNAs) play an important role in regulating cellular stress sensitivities, such as drug sensitivity and radio-sensitivity, in cancer cells. However, few studies have investigated the involvement of miRNAs in thermal sensitivity. The aim of this study was thus to investigate the contribution of miRNAs to the thermal sensitivity of human oral squamous cell carcinoma (OSCC) cells. When the HSC-2, HSC-3 and HSC-4 OSCC cell lines were treated with HT at 44˚C for 60 min, a significant increase in cell death was observed in HSC-2 and HSC-3 cells but not HSC-4 cells, suggesting that HSC-4 cells were thermally resistant under the present experimental conditions. Moreover, the expression levels of HSPs were most elevated in HSC-4 cells. When the basal expression levels of miRNAs were monitored using two different microarray systems in thermal-sensitive HSC-2 and HSC-3 cells and thermal-resistant HSC-4 cells, five miRNAs that were differentially expressed were identified. Among these miRNAs, the expression level of miR-27a in HSC-4 cells was markedly reducec compared to the expression levels in HSC-2 and HSC-3 cells. Interestingly, treatment of HSC-4 cells with a miR-27a mimic oligonucleotide significantly enhanced HT-induced cell death. Furthermore, the miR-27a mimic oligonucleotide suppressed the elevation of the expression of Hsp90 and Hsp110 in HSC-4 cells, suggesting that these HSPs may be involved in a mechanism of thermal resistance. From these findings, we concluded that in OSCC cells, miR-27a may contribute to thermal sensitivity by modulating the HSP expression.
热疗（HT）是癌症治疗的重要手段；然而，由于热休克蛋白（HSPs）的升高，癌细胞获得了耐热性，使得 HT 的效果降低。越来越多的证据表明，microRNAs（miRNAs）在调节癌细胞的细胞应激敏感性方面发挥着重要作用，例如药物敏感性和放射敏感性。然而，很少有研究调查 miRNAs 参与热敏感性。因此，本研究旨在研究 miRNAs 对人口腔鳞状细胞癌（OSCC）细胞热敏感性的贡献。当 HSC-2、HSC-3 和 HSC-4 OSCC 细胞系在 44°C 下用 HT 处理 60 分钟时，HSC-2 和 HSC-3 细胞中的细胞死亡明显增加，但 HSC-4 细胞中没有，这表明在目前的实验条件下，HSC-4 细胞具有耐热性。此外，HSC-4 细胞中 HSPs 的表达水平最高。当使用两种不同的微阵列系统监测热敏感的 HSC-2 和 HSC-3 细胞和热抵抗的 HSC-4 细胞中的 miRNA 的基础表达水平时，鉴定出 5 个差异表达的 miRNA。在这些 miRNA 中，miR-27a 在 HSC-4 细胞中的表达水平明显低于 HSC-2 和 HSC-3 细胞中的表达水平。有趣的是，用 miR-27a 模拟寡核苷酸处理 HSC-4 细胞显著增强了 HT 诱导的细胞死亡。此外，miR-27a 模拟寡核苷酸抑制了 HSC-4 细胞中 Hsp90 和 Hsp110 表达的升高，表明这些 HSPs 可能参与了耐热性的机制。从这些发现中，我们得出结论，在 OSCC 细胞中，miR-27a 可能通过调节 HSP 表达来促进热敏感性。
