miR-4286 is Involved in Connections Between IGF-1 and TGF-β Signaling for the Mesenchymal Transition and Invasion by Glioblastomas

Kuo Hao Ho; Peng Hsu Chen; Chwen Ming Shih; Yi Ting Lee; Chia Hsiung Cheng; Ann Jeng Liu; Chin Cheng Lee; Ku Chung Chen

doi:10.1007/s10571-020-00977-1

miR-4286 is Involved in Connections Between IGF-1 and TGF-β Signaling for the Mesenchymal Transition and Invasion by Glioblastomas

Kuo Hao Ho, Peng Hsu Chen, Chwen Ming Shih, Yi Ting Lee, Chia Hsiung Cheng, Ann Jeng Liu, Chin Cheng Lee, Ku Chung Chen

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

11 Citations (Scopus)

Abstract

The insulin-like growth factor (IGF)-1 and transforming growth factor (TGF)-β signal pathways are both recognized as important in regulating cancer prognosis, such as the epithelial-to-mesenchymal transition (EMT) and cell invasion. However, cross-talk between these two signal pathways in glioblastoma multiforme (GBM) is still unclear. In the present study, by analyzing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GSE) 4412, GBM patients with higher IGF-1 levels exhibited poorer survival. Genes positively correlated with IGF-1 were enriched in EMT and TGF-β signal pathways. IGF-1 treatment enhanced mesenchymal marker expressions and GBM cell invasion. A significant positive correlation was observed for IGF-1 with TGF-β1 (TGFB1) or TGF-β receptor 2 (TGFBR2), both of which participate in TGF-β signaling and are risk genes in the GBM process. IGF-1 stimulation promoted both TGFB1 and TGFBR2 expressions. LY2157299, a TGF-β signaling inhibitor, attenuated IGF-1-enhanced GBM cell invasion and mesenchymal transition. By analyzing IGF-1-regulated microRNA (miR) profiles, miR-4286 was found to be significantly downregulated in IGF-1-treated cells and could be targeted to both TGFB1 and TGFBR2. Overexpression of miR-4286 significantly attenuated expressions of the IGF-1-mediated mesenchymal markers, TGFB1 and TGFBR2. Using kinase inhibitors, only U0126 treatment showed an inhibitory effect on IGF-1-reduced miR-4286 and IGF-1-induced TGFB1/TGFBR2 expressions, suggesting that MEK/ERK signaling is involved in the IGF-1/miR-4286/TGF-β signaling axis. Finally, our results suggested that miR-4286 might act as a tumor suppressive microRNA in inhibiting IGF-1-enhanced GBM cell invasion. In conclusion, IGF-1 is connected to TGF-β signaling in regulating the mesenchymal transition and cell invasion of GBM through inhibition of miR-4286. Our findings provide new directions and mechanisms for exploring GBM progression.

Original language	English
Pages (from-to)	791-806
Number of pages	16
Journal	Cellular and Molecular Neurobiology
Volume	42
Issue number	3
DOIs	https://doi.org/10.1007/s10571-020-00977-1
Publication status	Published - Apr 2022

Keywords

Epithelial-to-mesenchymal transition (EMT)
IGF-1
miR-4286
TGF-β
TGFBR2

ASJC Scopus subject areas

Cellular and Molecular Neuroscience
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s10571-020-00977-1

Cite this

@article{471e03cc3165402da17c5020320c5ca1,

title = "miR-4286 is Involved in Connections Between IGF-1 and TGF-β Signaling for the Mesenchymal Transition and Invasion by Glioblastomas",

abstract = "The insulin-like growth factor (IGF)-1 and transforming growth factor (TGF)-β signal pathways are both recognized as important in regulating cancer prognosis, such as the epithelial-to-mesenchymal transition (EMT) and cell invasion. However, cross-talk between these two signal pathways in glioblastoma multiforme (GBM) is still unclear. In the present study, by analyzing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GSE) 4412, GBM patients with higher IGF-1 levels exhibited poorer survival. Genes positively correlated with IGF-1 were enriched in EMT and TGF-β signal pathways. IGF-1 treatment enhanced mesenchymal marker expressions and GBM cell invasion. A significant positive correlation was observed for IGF-1 with TGF-β1 (TGFB1) or TGF-β receptor 2 (TGFBR2), both of which participate in TGF-β signaling and are risk genes in the GBM process. IGF-1 stimulation promoted both TGFB1 and TGFBR2 expressions. LY2157299, a TGF-β signaling inhibitor, attenuated IGF-1-enhanced GBM cell invasion and mesenchymal transition. By analyzing IGF-1-regulated microRNA (miR) profiles, miR-4286 was found to be significantly downregulated in IGF-1-treated cells and could be targeted to both TGFB1 and TGFBR2. Overexpression of miR-4286 significantly attenuated expressions of the IGF-1-mediated mesenchymal markers, TGFB1 and TGFBR2. Using kinase inhibitors, only U0126 treatment showed an inhibitory effect on IGF-1-reduced miR-4286 and IGF-1-induced TGFB1/TGFBR2 expressions, suggesting that MEK/ERK signaling is involved in the IGF-1/miR-4286/TGF-β signaling axis. Finally, our results suggested that miR-4286 might act as a tumor suppressive microRNA in inhibiting IGF-1-enhanced GBM cell invasion. In conclusion, IGF-1 is connected to TGF-β signaling in regulating the mesenchymal transition and cell invasion of GBM through inhibition of miR-4286. Our findings provide new directions and mechanisms for exploring GBM progression.",

keywords = "Epithelial-to-mesenchymal transition (EMT), IGF-1, miR-4286, TGF-β, TGFBR2",

author = "Ho, {Kuo Hao} and Chen, {Peng Hsu} and Shih, {Chwen Ming} and Lee, {Yi Ting} and Cheng, {Chia Hsiung} and Liu, {Ann Jeng} and Lee, {Chin Cheng} and Chen, {Ku Chung}",

note = "Funding Information: This study was sponsored by the Shin Kong Wu Ho-Su Memorial Hospital, Taiwan (2018SKHADR030 to Chin-Cheng Lee); the Ministry of Science and Technology, Taiwan (Contract Grant No. MOST 106-2320-B-038-051-MY3 to Ku-Chung Chen and MOST 108-2314-B-038-110 to Chwen-Ming Shih); Taipei City Government (Contract Grant No. 10801-62-082 to Ann-Jeng Liu); Taipei City Hospital Ren-Ai Branch (Contract Grant No. TPCH-109-10 to Ann-Jeng Liu); and Taipei Medical University-Shin Kong Wu Ho-Su Memorial Hospital, Taiwan (Intramural Grant No. SKH-TMU-107-03 to Ku-Chung Chen). Acknowledgements Funding Information: This study was sponsored by the Shin Kong Wu Ho-Su Memorial Hospital, Taiwan (2018SKHADR030 to Chin-Cheng Lee); the Ministry of Science and Technology, Taiwan (Contract Grant No. MOST 106-2320-B-038-051-MY3 to Ku-Chung Chen and MOST 108-2314-B-038-110 to Chwen-Ming Shih); Taipei City Government (Contract Grant No. 10801-62-082 to Ann-Jeng Liu); Taipei City Hospital Ren-Ai Branch (Contract Grant No. TPCH-109-10 to Ann-Jeng Liu); and Taipei Medical University-Shin Kong Wu Ho-Su Memorial Hospital, Taiwan (intramural grant no. SKH-TMU-107-03 to Ku-Chung Chen). We thank the National RNAi Core Facility at Academia Sinica, Taiwan for providing shRNA reagents and related services. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2020, Springer Science+Business Media, LLC, part of Springer Nature.",

year = "2022",

month = apr,

doi = "10.1007/s10571-020-00977-1",

language = "English",

volume = "42",

pages = "791--806",

journal = "Cellular and Molecular Neurobiology",

issn = "0272-4340",

publisher = "Springer New York",

number = "3",

}

TY - JOUR

T1 - miR-4286 is Involved in Connections Between IGF-1 and TGF-β Signaling for the Mesenchymal Transition and Invasion by Glioblastomas

AU - Ho, Kuo Hao

AU - Chen, Peng Hsu

AU - Shih, Chwen Ming

AU - Lee, Yi Ting

AU - Cheng, Chia Hsiung

AU - Liu, Ann Jeng

AU - Lee, Chin Cheng

AU - Chen, Ku Chung

N1 - Funding Information: This study was sponsored by the Shin Kong Wu Ho-Su Memorial Hospital, Taiwan (2018SKHADR030 to Chin-Cheng Lee); the Ministry of Science and Technology, Taiwan (Contract Grant No. MOST 106-2320-B-038-051-MY3 to Ku-Chung Chen and MOST 108-2314-B-038-110 to Chwen-Ming Shih); Taipei City Government (Contract Grant No. 10801-62-082 to Ann-Jeng Liu); Taipei City Hospital Ren-Ai Branch (Contract Grant No. TPCH-109-10 to Ann-Jeng Liu); and Taipei Medical University-Shin Kong Wu Ho-Su Memorial Hospital, Taiwan (Intramural Grant No. SKH-TMU-107-03 to Ku-Chung Chen). Acknowledgements Funding Information: This study was sponsored by the Shin Kong Wu Ho-Su Memorial Hospital, Taiwan (2018SKHADR030 to Chin-Cheng Lee); the Ministry of Science and Technology, Taiwan (Contract Grant No. MOST 106-2320-B-038-051-MY3 to Ku-Chung Chen and MOST 108-2314-B-038-110 to Chwen-Ming Shih); Taipei City Government (Contract Grant No. 10801-62-082 to Ann-Jeng Liu); Taipei City Hospital Ren-Ai Branch (Contract Grant No. TPCH-109-10 to Ann-Jeng Liu); and Taipei Medical University-Shin Kong Wu Ho-Su Memorial Hospital, Taiwan (intramural grant no. SKH-TMU-107-03 to Ku-Chung Chen). We thank the National RNAi Core Facility at Academia Sinica, Taiwan for providing shRNA reagents and related services. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

PY - 2022/4

Y1 - 2022/4

N2 - The insulin-like growth factor (IGF)-1 and transforming growth factor (TGF)-β signal pathways are both recognized as important in regulating cancer prognosis, such as the epithelial-to-mesenchymal transition (EMT) and cell invasion. However, cross-talk between these two signal pathways in glioblastoma multiforme (GBM) is still unclear. In the present study, by analyzing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GSE) 4412, GBM patients with higher IGF-1 levels exhibited poorer survival. Genes positively correlated with IGF-1 were enriched in EMT and TGF-β signal pathways. IGF-1 treatment enhanced mesenchymal marker expressions and GBM cell invasion. A significant positive correlation was observed for IGF-1 with TGF-β1 (TGFB1) or TGF-β receptor 2 (TGFBR2), both of which participate in TGF-β signaling and are risk genes in the GBM process. IGF-1 stimulation promoted both TGFB1 and TGFBR2 expressions. LY2157299, a TGF-β signaling inhibitor, attenuated IGF-1-enhanced GBM cell invasion and mesenchymal transition. By analyzing IGF-1-regulated microRNA (miR) profiles, miR-4286 was found to be significantly downregulated in IGF-1-treated cells and could be targeted to both TGFB1 and TGFBR2. Overexpression of miR-4286 significantly attenuated expressions of the IGF-1-mediated mesenchymal markers, TGFB1 and TGFBR2. Using kinase inhibitors, only U0126 treatment showed an inhibitory effect on IGF-1-reduced miR-4286 and IGF-1-induced TGFB1/TGFBR2 expressions, suggesting that MEK/ERK signaling is involved in the IGF-1/miR-4286/TGF-β signaling axis. Finally, our results suggested that miR-4286 might act as a tumor suppressive microRNA in inhibiting IGF-1-enhanced GBM cell invasion. In conclusion, IGF-1 is connected to TGF-β signaling in regulating the mesenchymal transition and cell invasion of GBM through inhibition of miR-4286. Our findings provide new directions and mechanisms for exploring GBM progression.

AB - The insulin-like growth factor (IGF)-1 and transforming growth factor (TGF)-β signal pathways are both recognized as important in regulating cancer prognosis, such as the epithelial-to-mesenchymal transition (EMT) and cell invasion. However, cross-talk between these two signal pathways in glioblastoma multiforme (GBM) is still unclear. In the present study, by analyzing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GSE) 4412, GBM patients with higher IGF-1 levels exhibited poorer survival. Genes positively correlated with IGF-1 were enriched in EMT and TGF-β signal pathways. IGF-1 treatment enhanced mesenchymal marker expressions and GBM cell invasion. A significant positive correlation was observed for IGF-1 with TGF-β1 (TGFB1) or TGF-β receptor 2 (TGFBR2), both of which participate in TGF-β signaling and are risk genes in the GBM process. IGF-1 stimulation promoted both TGFB1 and TGFBR2 expressions. LY2157299, a TGF-β signaling inhibitor, attenuated IGF-1-enhanced GBM cell invasion and mesenchymal transition. By analyzing IGF-1-regulated microRNA (miR) profiles, miR-4286 was found to be significantly downregulated in IGF-1-treated cells and could be targeted to both TGFB1 and TGFBR2. Overexpression of miR-4286 significantly attenuated expressions of the IGF-1-mediated mesenchymal markers, TGFB1 and TGFBR2. Using kinase inhibitors, only U0126 treatment showed an inhibitory effect on IGF-1-reduced miR-4286 and IGF-1-induced TGFB1/TGFBR2 expressions, suggesting that MEK/ERK signaling is involved in the IGF-1/miR-4286/TGF-β signaling axis. Finally, our results suggested that miR-4286 might act as a tumor suppressive microRNA in inhibiting IGF-1-enhanced GBM cell invasion. In conclusion, IGF-1 is connected to TGF-β signaling in regulating the mesenchymal transition and cell invasion of GBM through inhibition of miR-4286. Our findings provide new directions and mechanisms for exploring GBM progression.

KW - Epithelial-to-mesenchymal transition (EMT)

KW - IGF-1

KW - miR-4286

KW - TGF-β

KW - TGFBR2

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miR-4286 is Involved in Connections Between IGF-1 and TGF-β Signaling for the Mesenchymal Transition and Invasion by Glioblastomas

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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