Mari Emanuela, Zicari Alessandra, Fico Flavia, Massimi Isabella, Martina Lolli, Mardente Stefania
Department of Experimental Medicine, Sapienza University of Rome, I-00161 Rome, Italy.
Oncol Lett. 2016 Sep;12(3):2133-2138. doi: 10.3892/ol.2016.4876. Epub 2016 Jul 18.
microRNA (miR/miRNA) are small non-coding RNAs that control gene expression at the post-transcriptional level by targeting mRNAs. Aberrant expression of miRNAs is often observed in different types of cancer. Specific miRNAs function as tumor suppressors or oncogenes and interfere with various aspects of carcinogenesis, including differentiation, proliferation and invasion. Upregulation of miRNAs 221 and 222 has been shown to induce a malignant phenotype in numerous human cancers via inhibition of phosphatase and tensin homolog (PTEN) expression. Neuroblastoma is the most common extracranial solid malignancy in children, which is characterized by cellular heterogeneity that corresponds to different clinical outcomes. The different cellular phenotypes are associated with different gene mutations and miRs that control genetic and epigenetic factors. For this reason miRs are considered a potential therapeutic target in neuroblastoma. The aim of the present study was to investigate the mechanisms by which extracellular high mobility group box 1 (HMGB1) promotes cell growth in neuroblastoma. SK-N-BE(2) and SH-SY5Y neuroblastoma derived cell lines were transfected with the antisense oligonucleotides, anti-miR-221 and -222, followed by treatment with HMGB1 to investigate the expression of the oncosuppressor PTEN. In this study, it was demonstrated that HMGB1, which is released by damaged cells and tumor cells, upregulates miR-221/222 oncogenic clusters in the two human neuroblastoma derived cell lines. The results revealed that the oncogenic cluster miRs 221/222 were more highly expressed by the most undifferentiated cell line [SK-N-BE(2)] compared with the the less tumorigenic cell line (SH-SY5Y) and that exogenous HMGB1 increases this expression. In addition, HMGB1 modulates PTEN expression via miR-221/222, as demonstrated by transiently blocking miR-221/222 with anti-sense oligonucleotides. These results may lead to the development of novel therapeutic strategies for neuroblastoma.
微小RNA（miR/miRNA）是一类小的非编码RNA，通过靶向mRNA在转录后水平控制基因表达。在不同类型的癌症中经常观察到miRNA的异常表达。特定的miRNA发挥肿瘤抑制因子或癌基因的作用，并干扰致癌作用的各个方面，包括分化、增殖和侵袭。已表明miRNA 221和222的上调通过抑制磷酸酶和张力蛋白同源物（PTEN）的表达在多种人类癌症中诱导恶性表型。神经母细胞瘤是儿童最常见的颅外实体恶性肿瘤，其特征是细胞异质性，这与不同的临床结果相对应。不同的细胞表型与不同的基因突变和控制遗传及表观遗传因素的miR相关。因此，miR被认为是神经母细胞瘤潜在的治疗靶点。本研究的目的是探讨细胞外高迁移率族蛋白B1（HMGB1）促进神经母细胞瘤细胞生长的机制。用反义寡核苷酸抗-miR-221和-222转染SK-N-BE(2)和SH-SY5Y神经母细胞瘤衍生细胞系，然后用HMGB1处理以研究肿瘤抑制因子PTEN的表达。在本研究中，已证明由受损细胞和肿瘤细胞释放的HMGB1上调两个人类神经母细胞瘤衍生细胞系中的miR-221/222致癌簇。结果显示，与致瘤性较低的细胞系（SH-SY5Y）相比，最未分化的细胞系[SK-N-BE(2)]中致癌簇miR 221/222表达更高，并且外源性HMGB1增加了这种表达。此外，如用反义寡核苷酸瞬时阻断miR-221/222所证明的，HMGB1通过miR-221/222调节PTEN表达。这些结果可能会导致开发针对神经母细胞瘤的新型治疗策略。
