miR-195, miR-455-3p and miR-10a∗ are implicated in acquired temozolomide resistance in glioblastoma multiforme cells

Abstract

Running title: miRNAs and temozolomide resistance in glioblastoma Key words: glioblastoma, resistance, microRNA,, miR-10a*, temozolomide. ABSTRACTTo identify microRNAs (miRNAs) specifically involved in the acquisition of temozolomide (TMZ) resistance in glioblastoma multiforme (GBM), we first established a resistant variant, U251R cells from TMZ-sensitive GBM cell line, U251MG. We then performed a comprehensive analysis of miRNA expressions in U251R and parental cells using miRNA microarrays. miR-195, miR-455-3p and miR-10a* were the three most up-regulated miRNAs in the resistant cells. To investigate the functional role of these miRNAs in TMZ resistance, U251R cells were transfected with miRNA inhibitors consisting of DNA/LNA hybrid oligonucleotides. Suppression of miR-455-3p or miR-10a* had no effect on cell growth, but showed modest cell killing effect in the presence of TMZ. On the other hand, knockdown of miR-195 alone displayed moderate cell killing effect, and combination with TMZ strongly enhanced the effect. In addition, using in silico analysis combined with cDNA microarray experiment, we present possible mRNA targets of these miRNAs. In conclusion, our findings suggest that those miRNAs may play a role in acquired TMZ resistance and could be a novel target for recurrent GBM treatment.

STAT3 Inhibition Overcomes Temozolomide Resistance in Glioblastoma by Downregulating MGMT Expression

“…It has been reported that STAT3-regulated miR-17 played a critical role in MAP-ERK kinase (MEK) inhibitor resistance (42), as well as that STAT3 directly increased the levels of miR-21 and miR-181b-1 (43). Currently only correlation of some specific miRNA such as miR-21 or miR-195 and temozolomide resistance were reported (44,45). We should address whether miRNAs are involved in the regulation of MGMT in the future.…”

The Role of microRNAs in Gliomas and Their Potential Applications for Diagnosis and Treatment

“…The results showed that miR-195, miR-455-3p and miR-10a* were the three most upregulated miRNAs in the resistant cells. When miR-195 was reduced, the resistant cells displayed a moderate cell killing effect, and the combination with TMZ strongly enhanced this effect 25 . Another article examined the correlation between the expression levels of selected microRNAs in 22 primary glioblastomas with response to concomitant therapy (e.g., chemoradiotherapy with TMZ).…”

“…For example, high levels of miR-21, miR-182 and miR-196 as well as low expression of miR-181b and miR-106a are associated with poor overall survival in patients with malignant gliomas [22][23][24] , and these miRNAs might function as biomarkers of glioma progression. Furthermore, miR-195, miR-455-3p, miR-10a 25 and the miR-181 family 26 have been linked to treatment resistance, and assessing the relative expression levels of these miRNAs may assist with the design of personalized treatments.…”

MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics

“…To identify miRNAs involved in TMZ resistance in GBM, Ujifuku et al. 87 used miRNA microarrays to perform a comprehensive analysis of miRNA expression in a TMZ‐sensitive GBM cell line. They found that miR‐195, miR‐455‐3p, and miR‐10a ∗ were the three most upregulated miRNAs in resistant cells.…”