MiR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma

Foteini Kouri, Lisa A. Hurley, Weston L. Daniel, Emily S. Day, Youjia Hua, Liangliang Hao, Chian-Yu Peng, Timothy J. Merkel, Markus A. Queisser, Carissa Ritner, Hailei Zhang, Charles David James, Jacob I Sznajder, Lynda Chin, David A. Giljohann, John Kessler, Marcus Ernst Peter, Chad A Mirkin, Alexander H Stegh*

*Corresponding author for this work

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Glioblastoma multiforme (GBM) is a lethal, therapy-resistant brain cancer consisting of numerous tumor cell subpopulations, including stem-like glioma-initiating cells (GICs), which contribute to tumor recurrence following initial response to therapy. Here, we identified miR-182 as a regulator of apoptosis, growth, and differentiation programs whose expression level is correlated with GBM patient survival. Repression of Bcl2-like12 (Bcl2L12), c- Met, and hypoxia-inducible factor 2α (HIF2A) is of central importance to miR-182 anti-tumor activity, as it results in enhanced therapy susceptibility, decreased GIC sphere size, expansion, and stemness in vitro. To evaluate the tumor-suppressive function of miR-182 in vivo, we synthesized miR-182-based spherical nucleic acids (182-SNAs); i.e., gold nanoparticles covalently functionalized with mature miR-182 duplexes. Intravenously administered 182- SNAs penetrated the blood–brain/blood–tumor barriers (BBB/BTB) in orthotopic GBM xenografts and selectively disseminated throughout extravascular glioma parenchyma, causing reduced tumor burden and increased animal survival. Our results indicate that harnessing the anti-tumor activities of miR-182 via safe and robust delivery of 182-SNAs represents a novel strategy for therapeutic intervention in GBM.

Original languageEnglish (US)
Pages (from-to)732-745
Number of pages14
JournalGenes and Development
Volume29
Issue number7
DOIs
StatePublished - Jan 1 2015

Fingerprint

Glioblastoma
Apoptosis
Glioma
Growth
Neoplasms
Nucleic Acids
Therapeutics
Tumor Burden
Cell Size
Heterografts
Brain Neoplasms
Gold
Nanoparticles
Recurrence
Survival

Keywords

  • Bcl2L12
  • Glioblastoma
  • HIF2A
  • Nanotechnology
  • Spherical nucleic acids
  • c-Met
  • miR-182

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Kouri, Foteini ; Hurley, Lisa A. ; Daniel, Weston L. ; Day, Emily S. ; Hua, Youjia ; Hao, Liangliang ; Peng, Chian-Yu ; Merkel, Timothy J. ; Queisser, Markus A. ; Ritner, Carissa ; Zhang, Hailei ; James, Charles David ; Sznajder, Jacob I ; Chin, Lynda ; Giljohann, David A. ; Kessler, John ; Peter, Marcus Ernst ; Mirkin, Chad A ; Stegh, Alexander H. / MiR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma. In: Genes and Development. 2015 ; Vol. 29, No. 7. pp. 732-745.
@article{aa78e8c7a5084f599aeeb8aa888000cb,
title = "MiR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma",
abstract = "Glioblastoma multiforme (GBM) is a lethal, therapy-resistant brain cancer consisting of numerous tumor cell subpopulations, including stem-like glioma-initiating cells (GICs), which contribute to tumor recurrence following initial response to therapy. Here, we identified miR-182 as a regulator of apoptosis, growth, and differentiation programs whose expression level is correlated with GBM patient survival. Repression of Bcl2-like12 (Bcl2L12), c- Met, and hypoxia-inducible factor 2α (HIF2A) is of central importance to miR-182 anti-tumor activity, as it results in enhanced therapy susceptibility, decreased GIC sphere size, expansion, and stemness in vitro. To evaluate the tumor-suppressive function of miR-182 in vivo, we synthesized miR-182-based spherical nucleic acids (182-SNAs); i.e., gold nanoparticles covalently functionalized with mature miR-182 duplexes. Intravenously administered 182- SNAs penetrated the blood–brain/blood–tumor barriers (BBB/BTB) in orthotopic GBM xenografts and selectively disseminated throughout extravascular glioma parenchyma, causing reduced tumor burden and increased animal survival. Our results indicate that harnessing the anti-tumor activities of miR-182 via safe and robust delivery of 182-SNAs represents a novel strategy for therapeutic intervention in GBM.",
keywords = "Bcl2L12, Glioblastoma, HIF2A, Nanotechnology, Spherical nucleic acids, c-Met, miR-182",
author = "Foteini Kouri and Hurley, {Lisa A.} and Daniel, {Weston L.} and Day, {Emily S.} and Youjia Hua and Liangliang Hao and Chian-Yu Peng and Merkel, {Timothy J.} and Queisser, {Markus A.} and Carissa Ritner and Hailei Zhang and James, {Charles David} and Sznajder, {Jacob I} and Lynda Chin and Giljohann, {David A.} and John Kessler and Peter, {Marcus Ernst} and Mirkin, {Chad A} and Stegh, {Alexander H}",
year = "2015",
month = "1",
day = "1",
doi = "10.1101/gad.257394.114",
language = "English (US)",
volume = "29",
pages = "732--745",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "7",

}

Kouri, F, Hurley, LA, Daniel, WL, Day, ES, Hua, Y, Hao, L, Peng, C-Y, Merkel, TJ, Queisser, MA, Ritner, C, Zhang, H, James, CD, Sznajder, JI, Chin, L, Giljohann, DA, Kessler, J, Peter, ME, Mirkin, CA & Stegh, AH 2015, 'MiR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma', Genes and Development, vol. 29, no. 7, pp. 732-745. https://doi.org/10.1101/gad.257394.114

MiR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma. / Kouri, Foteini; Hurley, Lisa A.; Daniel, Weston L.; Day, Emily S.; Hua, Youjia; Hao, Liangliang; Peng, Chian-Yu; Merkel, Timothy J.; Queisser, Markus A.; Ritner, Carissa; Zhang, Hailei; James, Charles David; Sznajder, Jacob I; Chin, Lynda; Giljohann, David A.; Kessler, John; Peter, Marcus Ernst; Mirkin, Chad A; Stegh, Alexander H.

In: Genes and Development, Vol. 29, No. 7, 01.01.2015, p. 732-745.

Research output: Contribution to journalArticle

TY - JOUR

T1 - MiR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma

AU - Kouri, Foteini

AU - Hurley, Lisa A.

AU - Daniel, Weston L.

AU - Day, Emily S.

AU - Hua, Youjia

AU - Hao, Liangliang

AU - Peng, Chian-Yu

AU - Merkel, Timothy J.

AU - Queisser, Markus A.

AU - Ritner, Carissa

AU - Zhang, Hailei

AU - James, Charles David

AU - Sznajder, Jacob I

AU - Chin, Lynda

AU - Giljohann, David A.

AU - Kessler, John

AU - Peter, Marcus Ernst

AU - Mirkin, Chad A

AU - Stegh, Alexander H

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Glioblastoma multiforme (GBM) is a lethal, therapy-resistant brain cancer consisting of numerous tumor cell subpopulations, including stem-like glioma-initiating cells (GICs), which contribute to tumor recurrence following initial response to therapy. Here, we identified miR-182 as a regulator of apoptosis, growth, and differentiation programs whose expression level is correlated with GBM patient survival. Repression of Bcl2-like12 (Bcl2L12), c- Met, and hypoxia-inducible factor 2α (HIF2A) is of central importance to miR-182 anti-tumor activity, as it results in enhanced therapy susceptibility, decreased GIC sphere size, expansion, and stemness in vitro. To evaluate the tumor-suppressive function of miR-182 in vivo, we synthesized miR-182-based spherical nucleic acids (182-SNAs); i.e., gold nanoparticles covalently functionalized with mature miR-182 duplexes. Intravenously administered 182- SNAs penetrated the blood–brain/blood–tumor barriers (BBB/BTB) in orthotopic GBM xenografts and selectively disseminated throughout extravascular glioma parenchyma, causing reduced tumor burden and increased animal survival. Our results indicate that harnessing the anti-tumor activities of miR-182 via safe and robust delivery of 182-SNAs represents a novel strategy for therapeutic intervention in GBM.

AB - Glioblastoma multiforme (GBM) is a lethal, therapy-resistant brain cancer consisting of numerous tumor cell subpopulations, including stem-like glioma-initiating cells (GICs), which contribute to tumor recurrence following initial response to therapy. Here, we identified miR-182 as a regulator of apoptosis, growth, and differentiation programs whose expression level is correlated with GBM patient survival. Repression of Bcl2-like12 (Bcl2L12), c- Met, and hypoxia-inducible factor 2α (HIF2A) is of central importance to miR-182 anti-tumor activity, as it results in enhanced therapy susceptibility, decreased GIC sphere size, expansion, and stemness in vitro. To evaluate the tumor-suppressive function of miR-182 in vivo, we synthesized miR-182-based spherical nucleic acids (182-SNAs); i.e., gold nanoparticles covalently functionalized with mature miR-182 duplexes. Intravenously administered 182- SNAs penetrated the blood–brain/blood–tumor barriers (BBB/BTB) in orthotopic GBM xenografts and selectively disseminated throughout extravascular glioma parenchyma, causing reduced tumor burden and increased animal survival. Our results indicate that harnessing the anti-tumor activities of miR-182 via safe and robust delivery of 182-SNAs represents a novel strategy for therapeutic intervention in GBM.

KW - Bcl2L12

KW - Glioblastoma

KW - HIF2A

KW - Nanotechnology

KW - Spherical nucleic acids

KW - c-Met

KW - miR-182

UR - http://www.scopus.com/inward/record.url?scp=84926392353&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84926392353&partnerID=8YFLogxK

U2 - 10.1101/gad.257394.114

DO - 10.1101/gad.257394.114

M3 - Article

C2 - 25838542

AN - SCOPUS:84926392353

VL - 29

SP - 732

EP - 745

JO - Genes and Development

JF - Genes and Development

SN - 0890-9369

IS - 7

ER -