Functional profiling of precursor MicroRNAs identifies MicroRNAs essential for glioma proliferation

Saija Haapa-Paananen (Corresponding Author), Ping Chen, Kirsi Hellström, Pekka Kohonen, Sampsa Hautaniemi, Olli Kallioniemi, Merja Perälä

Research output: Contribution to journalArticleScientificpeer-review

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Abstract

Cancer initiation and progression involve microRNAs that can function like tumor suppressors and oncogenes. The functional significance of most miRNAs is currently unknown. To determine systematically which microRNAs are essential for glioma growth, we screened a precursor microRNA library in three human glioblastoma and one astroglial cell line model systems. The most prominent and consistent cell proliferation–reducing hits were validated in secondary screening with an additional apoptosis endpoint. The functional screening data were integrated in the miRNA expression data to find underexpressed true functional tumor suppressor miRNAs. In addition, we used miRNA-target gene predictions and combined siRNA functional screening data to find the most probable miRNA-target gene pairs with a similar functional effect on proliferation. Nine novel functional miRNAs (hsa-miR-129, -136, -145, -155, -181b, -342-5p, -342-3p, -376a/b) in GBM cell lines were validated for their importance in glioma cell growth, and similar effects for six target genes (ROCK1, RHOA, MET, CSF1R, EIF2AK1, FGF7) of these miRNAs were shown functionally. The clinical significance of the functional hits was validated in miRNA expression data from the TCGA glioblastoma multiforme (GBM) tumor cohort. Five tumor suppressor miRNAs (hsa-miR-136, -145, -342, -129, -376a) showed significant underexpression in clinical GBM tumor samples from the TCGA GBM cohort further supporting the role of these miRNAs in vivo. Most importantly, higher hsa-miR-145 expression in GBM tumors yielded significantly better survival (p<0.005) in a subset of patients thus validating it as a genuine tumor suppressor miRNA. This systematic functional profiling provides important new knowledge about functionally relevant miRNAs in GBM biology and may offer new targets for treating glioma.
Original languageEnglish
Article numbere60930
Number of pages10
JournalPLoS ONE
Volume8
Issue number4
DOIs
Publication statusPublished - 2013
MoE publication typeA1 Journal article-refereed

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MicroRNAs
microRNA
Glioma
neoplasms
Glioblastoma
Tumors
screening
Neoplasms
cell lines
Screening
Genes
genes
oncogenes
small interfering RNA
endpoints
cell growth
Cells
apoptosis
Cell Line
Biological Sciences

Cite this

Haapa-Paananen, S., Chen, P., Hellström, K., Kohonen, P., Hautaniemi, S., Kallioniemi, O., & Perälä, M. (2013). Functional profiling of precursor MicroRNAs identifies MicroRNAs essential for glioma proliferation. PLoS ONE, 8(4), [e60930]. https://doi.org/10.1371/journal.pone.0060930
Haapa-Paananen, Saija ; Chen, Ping ; Hellström, Kirsi ; Kohonen, Pekka ; Hautaniemi, Sampsa ; Kallioniemi, Olli ; Perälä, Merja. / Functional profiling of precursor MicroRNAs identifies MicroRNAs essential for glioma proliferation. In: PLoS ONE. 2013 ; Vol. 8, No. 4.
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title = "Functional profiling of precursor MicroRNAs identifies MicroRNAs essential for glioma proliferation",
abstract = "Cancer initiation and progression involve microRNAs that can function like tumor suppressors and oncogenes. The functional significance of most miRNAs is currently unknown. To determine systematically which microRNAs are essential for glioma growth, we screened a precursor microRNA library in three human glioblastoma and one astroglial cell line model systems. The most prominent and consistent cell proliferation–reducing hits were validated in secondary screening with an additional apoptosis endpoint. The functional screening data were integrated in the miRNA expression data to find underexpressed true functional tumor suppressor miRNAs. In addition, we used miRNA-target gene predictions and combined siRNA functional screening data to find the most probable miRNA-target gene pairs with a similar functional effect on proliferation. Nine novel functional miRNAs (hsa-miR-129, -136, -145, -155, -181b, -342-5p, -342-3p, -376a/b) in GBM cell lines were validated for their importance in glioma cell growth, and similar effects for six target genes (ROCK1, RHOA, MET, CSF1R, EIF2AK1, FGF7) of these miRNAs were shown functionally. The clinical significance of the functional hits was validated in miRNA expression data from the TCGA glioblastoma multiforme (GBM) tumor cohort. Five tumor suppressor miRNAs (hsa-miR-136, -145, -342, -129, -376a) showed significant underexpression in clinical GBM tumor samples from the TCGA GBM cohort further supporting the role of these miRNAs in vivo. Most importantly, higher hsa-miR-145 expression in GBM tumors yielded significantly better survival (p<0.005) in a subset of patients thus validating it as a genuine tumor suppressor miRNA. This systematic functional profiling provides important new knowledge about functionally relevant miRNAs in GBM biology and may offer new targets for treating glioma.",
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Haapa-Paananen, S, Chen, P, Hellström, K, Kohonen, P, Hautaniemi, S, Kallioniemi, O & Perälä, M 2013, 'Functional profiling of precursor MicroRNAs identifies MicroRNAs essential for glioma proliferation', PLoS ONE, vol. 8, no. 4, e60930. https://doi.org/10.1371/journal.pone.0060930

Functional profiling of precursor MicroRNAs identifies MicroRNAs essential for glioma proliferation. / Haapa-Paananen, Saija (Corresponding Author); Chen, Ping; Hellström, Kirsi; Kohonen, Pekka; Hautaniemi, Sampsa; Kallioniemi, Olli; Perälä, Merja.

In: PLoS ONE, Vol. 8, No. 4, e60930, 2013.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Functional profiling of precursor MicroRNAs identifies MicroRNAs essential for glioma proliferation

AU - Haapa-Paananen, Saija

AU - Chen, Ping

AU - Hellström, Kirsi

AU - Kohonen, Pekka

AU - Hautaniemi, Sampsa

AU - Kallioniemi, Olli

AU - Perälä, Merja

PY - 2013

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N2 - Cancer initiation and progression involve microRNAs that can function like tumor suppressors and oncogenes. The functional significance of most miRNAs is currently unknown. To determine systematically which microRNAs are essential for glioma growth, we screened a precursor microRNA library in three human glioblastoma and one astroglial cell line model systems. The most prominent and consistent cell proliferation–reducing hits were validated in secondary screening with an additional apoptosis endpoint. The functional screening data were integrated in the miRNA expression data to find underexpressed true functional tumor suppressor miRNAs. In addition, we used miRNA-target gene predictions and combined siRNA functional screening data to find the most probable miRNA-target gene pairs with a similar functional effect on proliferation. Nine novel functional miRNAs (hsa-miR-129, -136, -145, -155, -181b, -342-5p, -342-3p, -376a/b) in GBM cell lines were validated for their importance in glioma cell growth, and similar effects for six target genes (ROCK1, RHOA, MET, CSF1R, EIF2AK1, FGF7) of these miRNAs were shown functionally. The clinical significance of the functional hits was validated in miRNA expression data from the TCGA glioblastoma multiforme (GBM) tumor cohort. Five tumor suppressor miRNAs (hsa-miR-136, -145, -342, -129, -376a) showed significant underexpression in clinical GBM tumor samples from the TCGA GBM cohort further supporting the role of these miRNAs in vivo. Most importantly, higher hsa-miR-145 expression in GBM tumors yielded significantly better survival (p<0.005) in a subset of patients thus validating it as a genuine tumor suppressor miRNA. This systematic functional profiling provides important new knowledge about functionally relevant miRNAs in GBM biology and may offer new targets for treating glioma.

AB - Cancer initiation and progression involve microRNAs that can function like tumor suppressors and oncogenes. The functional significance of most miRNAs is currently unknown. To determine systematically which microRNAs are essential for glioma growth, we screened a precursor microRNA library in three human glioblastoma and one astroglial cell line model systems. The most prominent and consistent cell proliferation–reducing hits were validated in secondary screening with an additional apoptosis endpoint. The functional screening data were integrated in the miRNA expression data to find underexpressed true functional tumor suppressor miRNAs. In addition, we used miRNA-target gene predictions and combined siRNA functional screening data to find the most probable miRNA-target gene pairs with a similar functional effect on proliferation. Nine novel functional miRNAs (hsa-miR-129, -136, -145, -155, -181b, -342-5p, -342-3p, -376a/b) in GBM cell lines were validated for their importance in glioma cell growth, and similar effects for six target genes (ROCK1, RHOA, MET, CSF1R, EIF2AK1, FGF7) of these miRNAs were shown functionally. The clinical significance of the functional hits was validated in miRNA expression data from the TCGA glioblastoma multiforme (GBM) tumor cohort. Five tumor suppressor miRNAs (hsa-miR-136, -145, -342, -129, -376a) showed significant underexpression in clinical GBM tumor samples from the TCGA GBM cohort further supporting the role of these miRNAs in vivo. Most importantly, higher hsa-miR-145 expression in GBM tumors yielded significantly better survival (p<0.005) in a subset of patients thus validating it as a genuine tumor suppressor miRNA. This systematic functional profiling provides important new knowledge about functionally relevant miRNAs in GBM biology and may offer new targets for treating glioma.

U2 - 10.1371/journal.pone.0060930

DO - 10.1371/journal.pone.0060930

M3 - Article

VL - 8

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 4

M1 - e60930

ER -

Haapa-Paananen S, Chen P, Hellström K, Kohonen P, Hautaniemi S, Kallioniemi O et al. Functional profiling of precursor MicroRNAs identifies MicroRNAs essential for glioma proliferation. PLoS ONE. 2013;8(4). e60930. https://doi.org/10.1371/journal.pone.0060930