MicroRNA-195 reverses the resistance to temozolomide through targeting cyclin E1 in glioma cells

Abstract

Glioma is the most common malignant tumor of the central nervous system with poor survival. Temozolomide (TMZ) is the first-line chemotherapy drug for initial and recurrent glioma treatment with a relatively good efficacy, which exerts its antitumor effects mainly through cell death induced by DNA double-strand breaks in the G1 and S phases. However, endogenous or acquired resistance to TMZ limits glioma patients’ clinical outcome and is also an important cause of glioma replase. MicroRNA-195 (miR-195) plays an important role in the regulation of G1-phase/S-phase transition, DNA damage repair, and apoptosis of tumor cells. We found that miR-195 expression was significantly decreased in TMZ-resistant glioma cells induced with TMZ and correlated to the resistance index negatively. Also, the exogenous expression of miR-195 reversed TMZ resistance and induced the apoptosis of TMZ-resistant glioblastoma cells. Further bioinformatics analysis showed cyclin E1 (CCNE1) was a potential target gene of miR-195. Knockdown of CCNE1 partially reversed the effect of decreased miR-195 on TMZ resistance. The data from The Cancer Genome Atlas – Cancer Genome further suggested that hsa-miR-195 could negatively regulate the expression of CCNE1 in glioma. In conclusion, miR-195 reverses the resistance to TMZ by targeting CCNE1 in glioma cells and it could act as a potential target for treatment in glioma with TMZ resistance.

The Significance of MicroRNAs Expression in Regulation of Extracellular Matrix and Other Drug Resistant Genes in Drug Resistant Ovarian Cancer Cell Lines

“…Changes in miRNAs expression were also noted in another cancer. miR-195 expression was downregulated in temozolomid-resistant glioma cells [36], and miR-203 was downregulated in prostate cancer cells resistant to doxorubicin (DOX) [37]. The use of miRNA microarrays to analyze changes in miRNAs expression is an effective molecular tool for discovering new miRNAs involved in drug resistance processes.…”

Long non‑coding RNA LINC00473/miR‑195‑5p promotes glioma progression via YAP1‑TEAD1‑Hippo signaling

“…In particular, miR-195-5p may inhibit cell proliferation and induce apoptosis in glioma cells through the regulation of cell apoptosis-related proteins including Caspase-3, -8, -9 and Bcl-2 (34). Direct targets of miR-195 in glioma cells were identified as Sal-like protein 4 (35), cyclin E1 (36) to affect cell cycle (37) in the previous studies. The present study also demonstrated that miR-195-5p expression is reduced in glioma tissues and cells, and inhibition of miR-195-5p promoted cell proliferation, migration and invasion of glioma cells, and inhibited apoptosis.…”

Enhanced Inhibition of Tumorigenesis Using Combinations of miRNA-Targeted Therapeutics

“…A plethora of evidence highlights the essential role of miRNAs in the development of resistant tumor cell phenotypes. A lack of sensitivity to several chemotherapeutics may be a consequence of the hyperfunction of oncogenic miRNAs such as miRNA-26a, miRNA-18a, miRNA-29b-1, miRNA-431, miRNA-4521, and miRNA-155, or may be the result of a significant decrease in the activity of tumor suppressor miRNAs, including miRNA-575, miRNA-642b, miRNA-4430, miRNA-203a, and miRNA-203b (Mikamori et al, 2017; Yamaguchi et al, 2017; Ge et al, 2018; Aako et al, 2019; Wang H. et al, 2019; Wang M. et al, 2019). Aberrant functions of miRNAs may impede the interactions between miRNAs and their mRNA targets, a few examples of which are miRNA-210-3p and the multidrug efflux transporter ABCC5 (also known as MRP5; Amponsah et al, 2017); miRNA-101 and DNA-dependent protein kinases (Hu et al, 2017); miRNA-125a and the pro-apoptotic protein A20 (Yao et al, 2016); miR-145 and the ribosomal protein S6 kinase p70S6K1 (Lin et al, 2016); miRNA-181b and the cylindromatosis protein CYDL (Takiuchi et al, 2013); miRNA-144-3p and the AT-rich interactive domain 1A protein ARD1A (Xiao et al, 2017); and miRNA-199a-5p and miRNA-375 with the PH domain and leucine-rich repeat protein phosphatase 1 PHLPP1 (Mussnich et al, 2015).…”

“…Application of the first approach involves preliminary treatment with miRNA mimics that leads to the restoration of sensitivity of cells to chemotherapeutic agents and considerable enhancement of the effectiveness of subsequent chemotherapy. For instance, transfection with mimics of miRNA-429, miRNA-383, miRNA-101-3p, miRNA-195, miRNA-634, or miRNA-1294 results in a two- to 5-fold decrease in the values of EC 50 and IC 50 for gemcitabine, temozolomide, and paclitaxel (Fan et al, 2016; Yu et al, 2017; Chen et al, 2018; Tan et al, 2018; Jiang et al, 2019; Tu et al, 2019; Wang H. et al, 2019; Supplementary Table S1). A preparatory increase in cell sensitivity to gemcitabine by transfection with the synthetic tumor suppressor miRNA-205 has been shown to promote a two-fold decrease in the migratory potential of pancreatic cancer cells (Mittal et al, 2014; Supplementary Table S1).…”