miR-7 inhibits glioblastoma growth by simultaneously interfering with the PI3K/ATK and Raf/MEK/ERK pathways

Abstract

Abstract. Epidermal growth factor receptor (EGFR) signaling regulates glioblastoma cell proliferation, survival, migration and invasion and plays a key role in tumor progression. We show that microRNA-7 (miR-7) is a common regulator of the phosphoinositide-3-kinase (PI3K)/ATK and Raf/ mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways, both of which are launched by EGFR through its two direct targets, the transcription factors PI3K and Raf-1, respectively. Enforced expression of miR-7 markedly decreased expression of PI3K, phosphorylated Akt, Raf-1, phosphorylated MEK 1/2, and cyclin D1, as well as slightly reduced expression of EGFR. Forced expression of PI3K or Raf-1 transcripts lacking the 3'-untranslated region (3'-UTR) partially reversed the effects of miR-7 on cell growth inhibition and cell cycle arrest in glioma cells. Additionally, transient expression of miR-7 in glioblastoma cells strongly inhibited in vivo glioblastoma xenograft growth. We conclude that miR-7 is a potential tumor suppressor in glioblastoma that acts by targeting multiple oncogenes related to the downstream pathway of EGFR and may serve as a novel therapeutic target for malignant gliomas.

MiRNAs Mediate GDNF-Induced Proliferation and Migration of Glioma Cells

“…However, the molecular mechanisms underlying these observations remain unclear. Recent reports indicate miRNAs as an important factor, and the abnormal expression of some miRNAs are involved in GDNF-mediated signaling pathways [31-34]. We tested the hypothesis that GDNF promotes glioma cell proliferation and migration by modulating the expression of specific miRNAs.…”

“…Recent studies have shown abnormal miRNA expression in malignant glioma [28, 29], and these miRNAs can be useful biomarkers [30]. Moreover, some are involved in signaling pathways activated by GDNF, such as c-Jun N terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK-1/2), and p38 MAPK signaling pathways, to promote malignant glioma metastasis and invasive growth [31-34]. Therefore, we hypothesized that high GDNF expression promotes glioma cell proliferation and migration by modulating the expression of specific miRNAs.…”

Circular RNA participates in the carcinogenesis and the malignant behavior of cancer

“…Microarrays showed that miR-7 inhibits multiple oncogenic pathways to suppress HER2-mediated breast cancer and reverse trastuzumab resistance in vitro. [54][55][56] Moreover, miR-7 is reported to inhibit cell growth and invasion in pancreatic cancer cells, and could sensitize non-small cell lung cancer cells to paclitaxel. 57,58 A study in cervical cancer found that miR-7 inhibited the metastasis and invasion of cervical cancer by targeting focal adhesion kinase (FAK) at the transcriptional and translational levels.…”

Role of microRNA-7 in digestive system malignancy

“…Also, miR-7 is expressed abundantly in human pancreas and endocrine cells and has a specific role in endocrine cell differentiation and function [10] . It has been demonstrated that miR-7 is a tumor suppressor in breast, lung and ovarian cancers, and glioblastoma, mainly focusing on its relationship with EGFR [11][12][13][14][15] . Accumulating evidence shows that miR-7 can simultaneously target a variety of mRNAs involved in diverse signaling pathways in different tumors.…”