MicroRNA-21 Inhibitor Sensitizes Human Glioblastoma U251 Stem Cells to Chemotherapeutic Drug Temozolomide

Abstract

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.

Retracted - miR-423-5p knockdown enhances the sensitivity of glioma stem cells to apigenin through the mitochondrial pathway

“…Shi et al 9 also showed that miR-125b functions in the development of GSC resistance to TMZ and that inhibiting miR-125b enhances GSC sensitivity to TMZ with respect to cell invasion. In addition, Zhang et al 10 found that neither miR-21 inhibitor nor TMZ induced GSC apoptosis but that miR-21 inhibitor combined with TMZ significantly enhanced apoptosis in GSCs.…”

miR-125b promotes cell proliferation by directly targeting Lin28 in glioblastoma stem cells with low expression levels of miR-125b

“…Mature functional miRNAs of B22 nucleotides are generated from long primary miRNA (pri-miRNA) transcripts and control gene expression at the post-transcriptional level by degrading or repressing target mRNAs [13]. Several miRNA mutations or deletions have proapoptotic or antiapoptotic effects in multiple human cancer stem cells, including GSCs [14]. Recent reports have shown that the overexpression or underexpression of miR-125b can have different effects on the invasion between human primary glioblastoma cells and corresponding stem cells [5], suggesting that miR-125b plays a more significant role during the differentiation process of glioblastoma stem cells.…”

The role of micro-RNA in the regulation of signal pathways in gliomas

“…Блокирование данной микро-РНК с помощью anti-miR-21 способствует образованию фосфорилированного гистона g-H2AX (индикатор двухцепочечных разрывов ДНК) и подавлению экспрессии phospho-Akt, активизации автофагии и апоптоза (в том числе путём ингибирования экспрессии Cdc25A) после облучения в клеточных линиях глиом [103,104]. MiR-21 также играет значительную роль в химиорезистентности клеток глиобластомы: применение ингибитора miR-21 совместно с темозоломидом усиливало апоптоз ОСК глиомы [105].…”