Department of Neurosurgery, The First People's Hospital of Kunshan affiliated with Jiangsu University, Suzhou, PR China.
Brain Res. 2010 Sep 17;1352:255-64. doi: 10.1016/j.brainres.2010.07.009. Epub 2010 Jul 13.
MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate protein expression by cleaving or repressing the translation of target mRNAs. In mammal animals, their function mainly represses the target mRNAs transcripts via imperfectly complementary to the 3'UTR of target mRNAs. Several miRNAs have been recently reported to be involved in modulation of glioma development, especially some up-regulated miRNAs, such as microRNA-21 (miR-21), which has been found to function as an oncogene in cultured glioblastoma multiforme cells. Temozolomide (TMZ), an alkylating agent, is a promising chemotherapeutic agent for treating glioblastoma. However, resistance develops quickly and with high frequency. To explore the mechanism of resistance, we found that miR-21 could protect human glioblastoma U87MG cells from TMZ induced apoptosis. Our studies showed that TMZ markedly enhanced apoptosis in U87MG cells compared with untreated cells (P<0.05). However, over-express miR-21 in U87MG cells could significantly reduce TMZ-induced apoptosis (P<0.05). Pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins are known to regulate the apoptosis of glioma cells. Bcl-2, resistance to induction of apoptosis, constitutes one major obstacle to chemotherapy in many cancer cells. Bax is shown to correlate with an increased survival of glioblastoma multiforme patients. Further research demonstrated that the mechanism was associated with a shift in Bax/Bcl-2 ratio and change in caspase-3 activity. Compared to control cells, cells treated with TMZ showed a significant increase in the Bax/Bcl-2 ratio and caspase-3 activity (P<0.01). However, such effect was partly prevented by treatment of cells with miR-21 overexpression before, which appeared to downregulate the Bax expression, upregulate the Bcl-2 expression and decrease caspase-3 activity. Taken together, these results suggested that over-express miR-21 could inhibit TMZ-induced apoptosis in U87MG cells, at least in part, by decreasing Bax/Bcl-2 ratio and caspase-3 activity, which highlighted the possibility of miR-21 overexpression in the clinical resistance to chemotherapeutic therapy of TMZ.
微小 RNA（miRNAs）是一类小的非编码 RNA 分子，通过与靶 mRNAs 的 3'UTR 不完全互补来抑制靶 mRNAs 的翻译，从而调节蛋白质的表达。在哺乳动物中，它们的功能主要通过抑制靶 mRNAs 的转录来实现。最近有报道称，一些 miRNAs 参与了胶质瘤的发展调节，特别是一些上调的 miRNAs，如 microRNA-21（miR-21），在培养的多形性成胶质细胞瘤细胞中被发现作为癌基因发挥作用。替莫唑胺（TMZ）是一种烷化剂，是治疗多形性成胶质细胞瘤的一种很有前途的化疗药物。然而，耐药性很快且频繁发生。为了探讨耐药机制，我们发现 miR-21 可以保护人胶质瘤 U87MG 细胞免受 TMZ 诱导的凋亡。我们的研究表明，与未经处理的细胞相比，TMZ 显著增强了 U87MG 细胞的凋亡（P<0.05）。然而，在 U87MG 细胞中过表达 miR-21 可以显著降低 TMZ 诱导的凋亡（P<0.05）。促凋亡 Bax 和抗凋亡 Bcl-2 蛋白被认为调节胶质瘤细胞的凋亡。Bcl-2 对凋亡诱导的耐药性是许多癌细胞化疗的主要障碍之一。Bax 与多形性成胶质细胞瘤患者的存活率增加有关。进一步的研究表明，这种机制与 Bax/Bcl-2 比值的变化和 caspase-3 活性的改变有关。与对照细胞相比，用 TMZ 处理的细胞 Bax/Bcl-2 比值和 caspase-3 活性显著增加（P<0.01）。然而，通过在转染前用 miR-21 过表达处理细胞，这种作用部分得到了预防，这似乎下调了 Bax 的表达，上调了 Bcl-2 的表达，并降低了 caspase-3 的活性。总之，这些结果表明，miR-21 的过表达至少部分通过降低 Bax/Bcl-2 比值和 caspase-3 活性来抑制 U87MG 细胞中 TMZ 诱导的凋亡，这突出了 miR-21 过表达在 TMZ 化疗耐药性的临床治疗中的可能性。
