MicroRNA-21 Inhibitor Sensitizes Human Glioblastoma U251 Stem Cells to Chemotherapeutic Drug Temozolomide
MicroRNA-21 Inhibitor Sensitizes Human Glioblastoma U251 Stem Cells to Chemotherapeutic Drug Temozolomide
复制标题
MicroRNA-21 抑制剂使人胶质母细胞瘤 U251 干细胞对化疗药物替莫唑胺敏感
DOI：
10.1007/s12031-012-9759-8
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发表时间：
2012-06-01
影响因子：
3.1
通讯作者：
Shi, Lei
中科院分区：
文献类型：
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作者：
Zhang, Shuguang;Wan, Yi;Shi, Lei
microRNA（miRNAs）是一种非编码RNA小分子，通过切割或抑制靶mRNA的翻译来调节蛋白质的表达。在哺乳动物中，它们的功能主要是通过靶mRNA的3 'UTR中的不完全互补序列来抑制靶mRNA转录。最近有报道称，几种miRNA参与了胶质瘤发展的调控，特别是一些上调的miRNA，如microRNA-21（miR-21），已发现其在培养的多形性胶质母细胞瘤细胞中作为癌基因发挥作用。替莫唑胺（TMZ）是一种烷化剂，是一种很有前途的治疗胶质母细胞瘤的化疗药物。尽管替莫唑胺化疗可能会抑制肿瘤生长数月，但不变的肿瘤复发表明维持这些肿瘤的癌症干细胞持续存在。既往研究表明TMZ可抑制人胶质母细胞瘤干细胞（GSC）增殖，但不诱导细胞凋亡，这可能为胶质母细胞瘤复发提供了机会。越来越多的证据表明，胶质母细胞瘤细胞中miR-21的下调导致生长抑制和凋亡增加，所有这些在理论上都可以增强癌症治疗的化疗效果。本研究旨在探讨miR-21下调是否能增强TMZ的化疗效果并诱导GSC凋亡。有趣的是，结果表明miR-21抑制剂或TMZ均不能诱导GSC凋亡。然而，miR-21抑制剂与TMZ联合使用可显著促进GSC凋亡。总之，miR-21抑制剂和TMZ的组合可能是GSC凋亡的有效治疗策略，以防止潜在的胶质母细胞瘤复发。
MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate protein expression by cleaving or repressing the translation of target mRNAs. In mammals, their function mainly represses the target mRNA transcripts via imperfect complementary sequences in the 3'UTR of target mRNAs. Several miRNAs have been recently reported to be involved in modulation of glioma development, especially some upregulated 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. Although chemotherapy with temozolomide may contain tumor growth for some months, invariable tumor recurrence suggests that cancer stem cells maintaining these tumors persist. Previous research showed that TMZ could inhibit the proliferation of human glioblastoma stem cells (GSC), but not induced apoptosis, which could supply the chance for glioblastoma recurrence. Accumulating evidence indicated that downregulation of miR-21 in glioblastoma cells caused repression of growth and increased apoptosis, all of which could theoretically enhance the chemotherapeutic effects of cancer therapy. In this study, we aimed to explore whether miR-21 downregulation could enhance the chemotherapeutic effects of TMZ and induce apoptosis on GSC. Interestingly, the results demonstrated that either miR-21 inhibitor or TMZ could not induce apoptosis on GSC. However, miR-21 inhibitor combined with TMZ significantly enhanced GSC apoptosis. Taken together, a combination of miR-21 inhibitor and TMZ could be an effective therapeutic strategy for GSC apoptosis to prevent potential glioblastoma recurrence.