Wang Wenju, Li Ruhong, Meng Mingyao, Wei Chuanyu, Xie Yanhua, Zhang Yayong, Jiang Lihong, Dong Ruiyi, Wang Chunhui, Zhong Yiming, Yang Fang, Tang Weiwei, Jin Xingfang, Liu Baohua, Hou Zongliu
1] Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, People's Republic of China [2] Yunnan Cell Biology and Clinical Translation Research Center, Kunming 650051, Yunnan, People's Republic of China.
Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, People's Republic of China.
Sci Rep. 2015 Mar 31;5:9571. doi: 10.1038/srep09571.
Studies have proven that IL-2 and IL-15 showed contrasting roles during CIK cells preparation. By employing microarray, we analyzed miRNA expression profiles of PBMC, CIKIL-2 and CIKIL-15. Advanced bioinformatic analyses were performed to explore the key miRNAs which may regulate cell proliferation and anti-tumor activity of CIK. We identified 261 differentially expressed miRNAs (DEMs) between PBMC and CIKIL-2, and 249 DEMs between PBMC and CIKIL-15. MiR-143-3p/miR-145-5p was miRNA cluster which may positively regulate cell proliferation. In contrast, miR-340-5p/miR-340-3p cluster may negatively regulate cell proliferation via induction apoptosis, which may cause decreased cell proliferation capacity of CIKIL-2. MiRNA-target interaction analysis indicated that 10 co-downregulated miRNAs may synergistically turn on the expression of a pool of tumor cytotoxic genes in CIK cells. The DEMs between CIKIL-2 and CIKIL-15 may contribute to enhanced tumor cytotoxic capacity of CIKIL-2. Importantly, we found that repressed miR-193a-5p may regulate the expressions of inhibitory receptor KLRD1. The results of the validation assay have shown that KLRD1 were upregulated in CIK cells. Our findings have provided new insights into mechanisms of CIK cells production and tumor cytotoxic function, and shed light on their safety for clinical trial.
研究已证明，白细胞介素-2（IL-2）和白细胞介素-15（IL-15）在细胞因子诱导的杀伤细胞（CIK）制备过程中发挥着相反的作用。通过使用微阵列技术，我们分析了外周血单个核细胞（PBMC）、CIKIL-2和CIKIL-15的微小RNA（miRNA）表达谱。进行了先进的生物信息学分析，以探索可能调节CIK细胞增殖和抗肿瘤活性的关键miRNA。我们鉴定出PBMC与CIKIL-2之间有261个差异表达的miRNA（DEM），PBMC与CIKIL-15之间有249个DEM。MiR-143-3p/miR-145-5p是一个可能正向调节细胞增殖的miRNA簇。相反，miR-340-5p/miR-340-3p簇可能通过诱导凋亡负向调节细胞增殖，这可能导致CIKIL-2细胞增殖能力下降。miRNA-靶标相互作用分析表明，10个共同下调的miRNA可能协同开启CIK细胞中一组肿瘤细胞毒性基因的表达。CIKIL-2和CIKIL-15之间的DEM可能有助于增强CIKIL-2的肿瘤细胞毒性能力。重要的是，我们发现受抑制的miR-193a-5p可能调节抑制性受体杀伤细胞凝集素样受体D1（KLRD1）的表达。验证试验结果表明，KLRD1在CIK细胞中上调。我们的研究结果为CIK细胞产生机制和肿瘤细胞毒性功能提供了新的见解，并为其临床试验安全性提供了线索。
