MicroRNA-575 acts as a novel oncogene via targeting multiple signaling pathways in glioblastoma

Ashley Gray; Tiantian Cui; Erica Hlavin Bell; Joseph McElroy; Ebin Sebastian; Fuhai Li; Marjolein Geurts; Kevin Liu; Pierre Robe; S. Jaharul Haque; Arnab Chakravarti

doi:10.1016/j.yexmp.2022.104813

MicroRNA-575 acts as a novel oncogene via targeting multiple signaling pathways in glioblastoma

Ashley Gray, Tiantian Cui, Erica Hlavin Bell, Joseph McElroy, Ebin Sebastian, Fuhai Li, Marjolein Geurts, Kevin Liu, Pierre Robe, S. Jaharul Haque, Arnab Chakravarti

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

PURPOSE: Glioblastoma (GBM) patients currently face poor survival outcomes with an average survival period of <15 months, while only 3-5% of patients survive longer than 36 months. Although the mechanisms of tumorigenesis are still being elucidated, miRNAs are promising candidates to explore as novel and prognostic biomarkers in GBM. In this study, we identified the association between miR-575 expression and overall survival (OS) of primary GBM patients and undertook functional studies to discern the contribution of miR-575 to GBM tumorigenesis.

METHODS: Total RNAs were isolated from 254 FFPE GBM tumor samples and miR expression was assayed (simultaneously) using NanoString Technologies. To determine the association between miR-575 and patients' prognosis, Kaplan-Meier, univariable and multivariable Cox regression analyses were performed. Cell proliferation, colony formation, migration assays were conducted to investigate the function of miR-575 in vitro and in vivo. In silico target gene network analysis was performed to identify the putative targets of miR-575 in GBM, which were further verified by luciferase reporter assay, as well as qPCR and immunoblotting.

RESULTS: Our clinical data (n = 254) show that miR-575 is associated with worse GBM OS by univariable analysis (UVA, HR = 1.27, p-value<0.001) and multivariable (MVA, HR = 1.23, p = 0.007) analysis incorporating critical clinical variables. Functional studies indicated that overexpression of miR-575 significantly increased cell proliferation and migration of GBM cells in vitro, as well as tumor growth in vivo. Subsequent in silico target gene network and mechanistic studies identified CDKN1B/p27 and PTEN, as potential targets of miR-575 in GBM. MicroRNA-575 can also regulate the activity of AKT and ERK pathways in GBM.

CONCLUSION: miR-575 has prognostic value in GBM, with higher expression associating with worse OS of patients, and contributes to GBM tumorigenesis by regulating multiple signaling pathways in GBM.

Original language	English (US)
Article number	104813
Pages (from-to)	104813
Journal	Experimental and Molecular Pathology
Volume	128
DOIs	https://doi.org/10.1016/j.yexmp.2022.104813
State	Published - Oct 2022

Keywords

CDKN1B/p27
Glioblastoma
MicroRNA-575
Oncogene
PTEN
Tumor progression
Cell Movement/genetics
MicroRNAs/genetics
Humans
Signal Transduction/genetics
Proto-Oncogene Proteins c-akt/metabolism
Glioblastoma/pathology
Brain Neoplasms/pathology
Cell Line, Tumor
Biomarkers
Cell Proliferation/genetics
Gene Expression Regulation, Neoplastic/genetics
Luciferases/genetics
Oncogenes
Carcinogenesis/genetics

ASJC Scopus subject areas

Molecular Biology
Clinical Biochemistry
Pathology and Forensic Medicine

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10.1016/j.yexmp.2022.104813

Cite this

@article{9ad155a29f214baaac77668417ffcf46,

title = "MicroRNA-575 acts as a novel oncogene via targeting multiple signaling pathways in glioblastoma",

abstract = "PURPOSE: Glioblastoma (GBM) patients currently face poor survival outcomes with an average survival period of <15 months, while only 3-5% of patients survive longer than 36 months. Although the mechanisms of tumorigenesis are still being elucidated, miRNAs are promising candidates to explore as novel and prognostic biomarkers in GBM. In this study, we identified the association between miR-575 expression and overall survival (OS) of primary GBM patients and undertook functional studies to discern the contribution of miR-575 to GBM tumorigenesis.METHODS: Total RNAs were isolated from 254 FFPE GBM tumor samples and miR expression was assayed (simultaneously) using NanoString Technologies. To determine the association between miR-575 and patients' prognosis, Kaplan-Meier, univariable and multivariable Cox regression analyses were performed. Cell proliferation, colony formation, migration assays were conducted to investigate the function of miR-575 in vitro and in vivo. In silico target gene network analysis was performed to identify the putative targets of miR-575 in GBM, which were further verified by luciferase reporter assay, as well as qPCR and immunoblotting.RESULTS: Our clinical data (n = 254) show that miR-575 is associated with worse GBM OS by univariable analysis (UVA, HR = 1.27, p-value<0.001) and multivariable (MVA, HR = 1.23, p = 0.007) analysis incorporating critical clinical variables. Functional studies indicated that overexpression of miR-575 significantly increased cell proliferation and migration of GBM cells in vitro, as well as tumor growth in vivo. Subsequent in silico target gene network and mechanistic studies identified CDKN1B/p27 and PTEN, as potential targets of miR-575 in GBM. MicroRNA-575 can also regulate the activity of AKT and ERK pathways in GBM.CONCLUSION: miR-575 has prognostic value in GBM, with higher expression associating with worse OS of patients, and contributes to GBM tumorigenesis by regulating multiple signaling pathways in GBM.",

keywords = "CDKN1B/p27, Glioblastoma, MicroRNA-575, Oncogene, PTEN, Tumor progression, Cell Movement/genetics, MicroRNAs/genetics, Humans, Signal Transduction/genetics, Proto-Oncogene Proteins c-akt/metabolism, Glioblastoma/pathology, Brain Neoplasms/pathology, Cell Line, Tumor, Biomarkers, Cell Proliferation/genetics, Gene Expression Regulation, Neoplastic/genetics, Luciferases/genetics, Oncogenes, Carcinogenesis/genetics",

author = "Ashley Gray and Tiantian Cui and Bell, {Erica Hlavin} and Joseph McElroy and Ebin Sebastian and Fuhai Li and Marjolein Geurts and Kevin Liu and Pierre Robe and Haque, {S. Jaharul} and Arnab Chakravarti",

note = "Funding Information: This work was supported by National Cancer Institute [ R01CA169368 (to A.C.), R01CA11522358 (to A.C.), R01CA1145128 (to A.C.), R01CA108633 (to A.C.), R01CA188228 (to A.C., R.B., K.L., and J.B.), 1RC2CA148190 (to A.C.), and U10CA180850-01 (to A.C.)]; A Brain Tumor Funders Collaborative Grant (to A.C.); Ohio State University Comprehensive Cancer Center Award (to A.C.). The T&P Bohnenn Fund for Neuro-Oncology Research (grant to P.A.R.). Funding Information: We thank Dr. Jeremy Rich ( UC San Diego , USA) for providing primary GBM patient-derived cells. We also thank The Ohio State University (OSU) Comprehensive Cancer Center Small Animal Imaging Core, The Ohio State University (OSU) Genomics Shared Resource (GSR), The Ohio State University (OSU) Target Validation Shared Resource (TVSR), and The Ohio State University (OSU) Comprehensive Cancer Center Pathology Core Facility supported in part by grant no. P30 CA016058, NCI. Publisher Copyright: {\textcopyright} 2022",

year = "2022",

month = oct,

doi = "10.1016/j.yexmp.2022.104813",

language = "English (US)",

volume = "128",

pages = "104813",

journal = "Experimental and Molecular Pathology",

issn = "0014-4800",

publisher = "Academic Press",

}

TY - JOUR

T1 - MicroRNA-575 acts as a novel oncogene via targeting multiple signaling pathways in glioblastoma

AU - Gray, Ashley

AU - Cui, Tiantian

AU - Bell, Erica Hlavin

AU - McElroy, Joseph

AU - Sebastian, Ebin

AU - Li, Fuhai

AU - Geurts, Marjolein

AU - Liu, Kevin

AU - Robe, Pierre

AU - Haque, S. Jaharul

AU - Chakravarti, Arnab

N1 - Funding Information: This work was supported by National Cancer Institute [ R01CA169368 (to A.C.), R01CA11522358 (to A.C.), R01CA1145128 (to A.C.), R01CA108633 (to A.C.), R01CA188228 (to A.C., R.B., K.L., and J.B.), 1RC2CA148190 (to A.C.), and U10CA180850-01 (to A.C.)]; A Brain Tumor Funders Collaborative Grant (to A.C.); Ohio State University Comprehensive Cancer Center Award (to A.C.). The T&P Bohnenn Fund for Neuro-Oncology Research (grant to P.A.R.). Funding Information: We thank Dr. Jeremy Rich ( UC San Diego , USA) for providing primary GBM patient-derived cells. We also thank The Ohio State University (OSU) Comprehensive Cancer Center Small Animal Imaging Core, The Ohio State University (OSU) Genomics Shared Resource (GSR), The Ohio State University (OSU) Target Validation Shared Resource (TVSR), and The Ohio State University (OSU) Comprehensive Cancer Center Pathology Core Facility supported in part by grant no. P30 CA016058, NCI. Publisher Copyright: © 2022

PY - 2022/10

Y1 - 2022/10

N2 - PURPOSE: Glioblastoma (GBM) patients currently face poor survival outcomes with an average survival period of <15 months, while only 3-5% of patients survive longer than 36 months. Although the mechanisms of tumorigenesis are still being elucidated, miRNAs are promising candidates to explore as novel and prognostic biomarkers in GBM. In this study, we identified the association between miR-575 expression and overall survival (OS) of primary GBM patients and undertook functional studies to discern the contribution of miR-575 to GBM tumorigenesis.METHODS: Total RNAs were isolated from 254 FFPE GBM tumor samples and miR expression was assayed (simultaneously) using NanoString Technologies. To determine the association between miR-575 and patients' prognosis, Kaplan-Meier, univariable and multivariable Cox regression analyses were performed. Cell proliferation, colony formation, migration assays were conducted to investigate the function of miR-575 in vitro and in vivo. In silico target gene network analysis was performed to identify the putative targets of miR-575 in GBM, which were further verified by luciferase reporter assay, as well as qPCR and immunoblotting.RESULTS: Our clinical data (n = 254) show that miR-575 is associated with worse GBM OS by univariable analysis (UVA, HR = 1.27, p-value<0.001) and multivariable (MVA, HR = 1.23, p = 0.007) analysis incorporating critical clinical variables. Functional studies indicated that overexpression of miR-575 significantly increased cell proliferation and migration of GBM cells in vitro, as well as tumor growth in vivo. Subsequent in silico target gene network and mechanistic studies identified CDKN1B/p27 and PTEN, as potential targets of miR-575 in GBM. MicroRNA-575 can also regulate the activity of AKT and ERK pathways in GBM.CONCLUSION: miR-575 has prognostic value in GBM, with higher expression associating with worse OS of patients, and contributes to GBM tumorigenesis by regulating multiple signaling pathways in GBM.

AB - PURPOSE: Glioblastoma (GBM) patients currently face poor survival outcomes with an average survival period of <15 months, while only 3-5% of patients survive longer than 36 months. Although the mechanisms of tumorigenesis are still being elucidated, miRNAs are promising candidates to explore as novel and prognostic biomarkers in GBM. In this study, we identified the association between miR-575 expression and overall survival (OS) of primary GBM patients and undertook functional studies to discern the contribution of miR-575 to GBM tumorigenesis.METHODS: Total RNAs were isolated from 254 FFPE GBM tumor samples and miR expression was assayed (simultaneously) using NanoString Technologies. To determine the association between miR-575 and patients' prognosis, Kaplan-Meier, univariable and multivariable Cox regression analyses were performed. Cell proliferation, colony formation, migration assays were conducted to investigate the function of miR-575 in vitro and in vivo. In silico target gene network analysis was performed to identify the putative targets of miR-575 in GBM, which were further verified by luciferase reporter assay, as well as qPCR and immunoblotting.RESULTS: Our clinical data (n = 254) show that miR-575 is associated with worse GBM OS by univariable analysis (UVA, HR = 1.27, p-value<0.001) and multivariable (MVA, HR = 1.23, p = 0.007) analysis incorporating critical clinical variables. Functional studies indicated that overexpression of miR-575 significantly increased cell proliferation and migration of GBM cells in vitro, as well as tumor growth in vivo. Subsequent in silico target gene network and mechanistic studies identified CDKN1B/p27 and PTEN, as potential targets of miR-575 in GBM. MicroRNA-575 can also regulate the activity of AKT and ERK pathways in GBM.CONCLUSION: miR-575 has prognostic value in GBM, with higher expression associating with worse OS of patients, and contributes to GBM tumorigenesis by regulating multiple signaling pathways in GBM.

KW - CDKN1B/p27

KW - Glioblastoma

KW - MicroRNA-575

KW - Oncogene

KW - PTEN

KW - Tumor progression

KW - Cell Movement/genetics

KW - MicroRNAs/genetics

KW - Humans

KW - Signal Transduction/genetics

KW - Proto-Oncogene Proteins c-akt/metabolism

KW - Glioblastoma/pathology

KW - Brain Neoplasms/pathology

KW - Cell Line, Tumor

KW - Biomarkers

KW - Cell Proliferation/genetics

KW - Gene Expression Regulation, Neoplastic/genetics

KW - Luciferases/genetics

KW - Oncogenes

KW - Carcinogenesis/genetics

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UR - http://www.scopus.com/inward/citedby.url?scp=85136502413&partnerID=8YFLogxK

U2 - 10.1016/j.yexmp.2022.104813

DO - 10.1016/j.yexmp.2022.104813

M3 - Article

C2 - 35901926

AN - SCOPUS:85136502413

SN - 0014-4800

VL - 128

SP - 104813

JO - Experimental and Molecular Pathology

JF - Experimental and Molecular Pathology

M1 - 104813

ER -

MicroRNA-575 acts as a novel oncogene via targeting multiple signaling pathways in glioblastoma

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ASJC Scopus subject areas

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