miR-29a sensitizes the response of glioma cells to temozolomide by modulating the P53/MDM2 feedback loop

Abstract

Recently, pivotal functions of miRNAs in regulating common tumorigenic processes and manipulating signaling pathways in brain tumors have been recognized; notably, miR‐29a is closely associated with p53 signaling, contributing to the development of glioma. However, the molecular mechanism of the interaction between miR-29a and p53 signaling is still to be revealed. Herein, a total of 30 glioma tissues and 10 non-cancerous tissues were used to investigate the expression of miR‐29a. CCK-8 assay and Transwell assay were applied to identify the effects of miR-29a altered expression on the malignant biological behaviors of glioma cells in vitro, including proliferation, apoptosis, migration and invasion. A dual-luciferase reporter assay was used to further validate the regulatory effect of p53 or miR-29a on miR-29a or MDM2, respectively, at the transcriptional level. The results showed that miR-29a expression negatively correlated with tumor grade of human gliomas; at the same time it inhibited cell proliferation, migration, and invasion and promoted apoptosis of glioma cells in vitro. Mechanistically, miR-29a expression was induced by p53, leading to aberrant expression of MDM2 targeted by miR-29a, and finally imbalanced the activity of the p53-miR-29a-MDM2 feedback loop. Moreover, miR-29a regulating p53/MDM2 signaling sensitized the response of glioma cells to temozolomide treatment. Altogether, the study demonstrated a potential molecular mechanism in the tumorigenesis of glioma, while offering a possible target for treating human glioma in the future.

circSMARCA5 Is an Upstream Regulator of the Expression of miR-126-3p, miR-515-5p, and Their mRNA Targets, Insulin-like Growth Factor Binding Protein 2 (IGFBP2) and NRAS Proto-Oncogene, GTPase (NRAS) in Glioblastoma

“…The pathway leading to the expression of miRNAs is very complex and tightly regulated by several factors at different steps [ 64 ]. Altered expression of the microRNAome in GBM has been extensively studied, although the molecular mechanisms steering specific miRNA dysregulation have been elucidated only in a few cases [ 65 , 66 , 67 ]. Numerous RBPs play a crucial role in the post-transcriptional processing of pri-miRNAs and pre-miRNAs [ 68 ]: among them, the splicing factor SRSF1 has been demonstrated to regulate the expression of several mature miRNAs by a cross-talk with the enzymes involved in the processing of their precursors, through mechanisms that have been only partially explained to date [ 69 ].…”

Recent insights into the microRNA-dependent modulation of gliomas from pathogenesis to diagnosis and treatment

“…On the other hand, Chen et al. reported that miR-29a can also sensitize the response of glioma cells to TMZ through regulating the p53/MDM2 feedback loop [ 173 ]. Indeed, p53-induced expression of miR-29a can cause aberrant expression of MDM2 targeted by the corresponding miRNA, thereby affecting the activity of the p53-miR-29a-MDM2 loop [ 173 ].…”

Effects of TP53 Mutations and miRs on Immune Responses in the Tumor Microenvironment Important in Pancreatic Cancer Progression

“…It increased the expression of collagens, laminin and fibronectin, all components of the ECM [ 33 ]. Regulatory loops between TP53 and miR-29 exist, as TP53 can activate miR-29 expression and miR-29 can negatively regulate MDM2 expression, resulting in increased stability of TP53 [ 34 ]. The effects of multiple miRs, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) have been implicated in regulating the PDAC microenvironment and have recently been summarized [ 35 ].…”

“…This also increases the resistance to treatment with the chemotherapeutic drug temozolomide. TP53 can induce the expression of miR-29 in certain cancers [ 34 , 39 ].…”