MiR-338-5p sensitizes glioblastoma cells to radiation through regulation of genes involved in DNA damage response
MiR-338-5p sensitizes glioblastoma cells to radiation through regulation of genes involved in DNA damage response
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DOI：
10.1007/s13277-015-4654-x
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发表时间：
2016-06-01
期刊：
影响因子：
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通讯作者：
Slaby, Ondrej
中科院分区：
文献类型：
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作者：
Besse, Andrej;Sana, Jiri;Slaby, Ondrej
多形性胶质母细胞瘤（GBM）是最具侵袭性的脑肿瘤。尽管有根治性手术和化疗支持的放射治疗，该疾病仍然无法治愈，从最初诊断时起的中位生存率极低，为12-15个月。治疗失败的主要原因被认为是存在对治疗有抗性的细胞。microRNAs（miRNAs）作为基因表达的调节因子参与了包括GBM在内的肿瘤的发病机制。miR-338是一种脑特异性miRNA，已被描述为靶向参与增殖和分化的途径。在我们的研究中，与非肿瘤脑组织相比，miR-338- 3 p和miR-338- 5 p在GBM组织中差异表达。用miRNA模拟物过表达miR-338- 3 p在GBM细胞系（A172、T98 G、U87 MG）中未显示出任何增殖率变化。另一方面，pre-miR-338- 5 p显著降低增殖并引起细胞周期停滞。由于放射是目前GBM的主要治疗方式，我们将pre-miR-338- 5 p的过表达与放射相结合，与仅放射的细胞相比，这导致细胞增殖显著降低，细胞周期停滞增加和细胞凋亡。为了更好地阐明作用机制，我们进行了基因表达谱分析，发现miR-338- 5 p的靶点是Ndfip 1、Rheb和ppp 2 R5 a。这些基因已被描述为参与DNA损伤反应、增殖和细胞周期调节。据我们所知，这是第一项描述miR-338- 5 p在GBM中的作用及其提高GBM对辐射敏感性的潜力的研究。
Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor. Despite radical surgery and radiotherapy supported by chemotherapy, the disease still remains incurable with an extremely low median survival rate of 12-15 months from the time of initial diagnosis. The main cause of treatment failure is considered to be the presence of cells that are resistant to the treatment. MicroRNAs (miRNAs) as regulators of gene expression are involved in the tumor pathogenesis, including GBM. MiR-338 is a brain-specific miRNA which has been described to target pathways involved in proliferation and differentiation. In our study, miR-338-3p and miR-338-5p were differentially expressed in GBM tissue in comparison to non-tumor brain tissue. Overexpression of miR-338-3p with miRNA mimic did not show any changes in proliferation rates in GBM cell lines (A172, T98G, U87MG). On the other hand, pre-miR-338-5p notably decreased proliferation and caused cell cycle arrest. Since radiation is currently the main treatment modality in GBM, we combined overexpression of pre-miR-338-5p with radiation, which led to significantly decreased cell proliferation, increased cell cycle arrest, and apoptosis in comparison to irradiation-only cells. To better elucidate the mechanism of action, we performed gene expression profiling analysis that revealed targets of miR-338-5p being Ndfip1, Rheb, and ppp2R5a. These genes have been described to be involved in DNA damage response, proliferation, and cell cycle regulation. To our knowledge, this is the first study to describe the role of miR-338-5p in GBM and its potential to improve the sensitivity of GBM to radiation.