MiR-592 activates the mTOR kinase, ERK1/ERK2 kinase signaling and imparts neuronal differentiation signature characteristic of Group 4 medulloblastoma

Abstract

Medulloblastoma, a common malignant brain tumor in children, consists of four molecular subgroups WNT, SHH, Group 3 and Group 4. Group 3, Group 4 tumors have an overlap in their expression profiles and genetic alterations but differ significantly in their clinical characteristics, with Group 3 having the worst five-year overall survival of less than 60%. MiR-592 is overexpressed predominantly in Group 4 tumors. MiR-592 expression reduced the anchorage-independent growth, invasion potential, and tumorigenicity of Group 3 medulloblastoma cells. DEPTOR, an endogenous inhibitor of the mTOR kinase, and EML1 were identified as novel targets of miR-592. The miR-592 mediated decrease in the DEPTOR expression levels activated both mTORC1 and mTORC2 complex in medulloblastoma cells. However, the miR-592 expression also decreased the AKT kinase activity, likely to be due to the activation of the inhibitory feedback of the mTOR signaling. MiR-592 expression upregulated several neuronal differentiation-related genes, a characteristic of Group 4 medulloblastoma in Group 3 cell lines. The expression of miR-592 also upregulated the activity of ERK1/ERK2 kinases indicating activation of the MAPK signaling pathway. The inhibition of MAPK signaling by the ERK1/ERK2 inhibitor and mTOR signaling by rapamycin abrogated the miR-592-mediated upregulation of neuronal differentiation-related genes. Group 4 medulloblastomas showed higher activity of the mTOR and MAPK signaling compared to Group 3 tumors. Thus, miR-592 overexpression appears to be a driver event and a determining factor of Group 4 biology, which activates the mTOR and MAPK signaling pathways and thereby imparts its characteristic expression profile of neuronal differentiation-related genes.

Deficiency in the Treatment Description of mTOR Inhibitor Resistance in Medulloblastoma, a Systematic Review

“…In addition to the contribution of genetic and epigenetic activation of The PI3K/Akt/mTOR pathway in medulloblastoma progression, aberrant constitutive activation of several growth factor receptors acting upstream of the PI3K/Akt/mTOR pathway has also been linked with the development and progression of some of the medulloblastoma subgroups. For instance, medulloblastoma group 4, which is considered the largest and the most diverse group, harbors multiple molecular alterations that constitutively activate several growth factor receptors, including the insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), epidermal endothelial growth factor (EGFR) and vascular endothelial growth factor (VEGF) among others [ 26 , 27 , 28 ]. It has been suggested that targeting cell membrane receptors that are highly expressed on medulloblastoma cells could be one of the effective therapeutic approaches to medulloblastoma treatment.…”

Identification of m7G Methylation-Related miRNA Signature Associated with Survival and Immune Microenvironment Regulation in Uterine Corpus Endometrial Carcinoma

“…MiR-592 suppresses the malignant phenotypes of thyroid cancer through the regulation of lncRNA NEAT1 and downregulation of NOVA1 [ 34 ]. A miR-592-mediated activation of mTOR (mammalian target of rapamycin), ERK1/ERK2 signaling, and neuronal differentiation impart group 4 medulloblastoma characteristics [ 35 ]. It has been found that lncRNA MEF2C-AS1 inhibits cervical cancer by targeting RSPO1 by suppressing miR-592 [ 36 ].…”

Cornerstone Cellular Pathways for Metabolic Disorders and Diabetes Mellitus: Non-Coding RNAs, Wnt Signaling, and AMPK

“…Wnt signaling and WISP1 are vital pathways during metabolic disorders and DM for the oversight of oxidative stress, programmed cell death, and non-coding RNA function (Figure 2). Wnt proteins, which are cysteine-rich glycosylated proteins, are part of the wingless pathway that can modulate cell development and survival during aging, cardiovascular disorders, tumorigenesis, organogenesis, neurodegeneration, vascular disease, inflammation, and DM [25,28,48,76,92,115,131,150,184,276,296,297,305,307,338,339,[457][458][459][460][461][462][463][464][465][466][467]. Wnt proteins that can involve Wnt1 oversee programmed cell death [105,219,278,299,339,362,387,[467][468][469][470][471][472], pancreatic β-cell development and growth [473], skeletal function [152,305,307], trophic factor protec...…”