Hypoxia-Induced miR-137 Inhibition Increased Glioblastoma Multiforme Growth and Chemoresistance Through LRP6
PurposeGlioblastoma multiforme (GBM) is one of the deadliest tumors, which is involved in numerous dysregulated microRNAs including miR-137. However, the mechanism of how miR-137 suppression associated with cancer progression and chemoresistance still remains to be elucidated.MethodsQuantitative rev...
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Frontiers Media S.A.
2021-02-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2020.611699/full |
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| author | Dong-Mei Li Dong-Mei Li Qiu-Dan Chen Gui-Ning Wei Jie Wei Jian-Xing Yin Jian-Xing Yin Jun-Hui He Xin Ge Xin Ge Zhu-Mei Shi Zhu-Mei Shi |
| author_facet | Dong-Mei Li Dong-Mei Li Qiu-Dan Chen Gui-Ning Wei Jie Wei Jian-Xing Yin Jian-Xing Yin Jun-Hui He Xin Ge Xin Ge Zhu-Mei Shi Zhu-Mei Shi |
| author_sort | Dong-Mei Li |
| collection | DOAJ |
| description | PurposeGlioblastoma multiforme (GBM) is one of the deadliest tumors, which is involved in numerous dysregulated microRNAs including miR-137. However, the mechanism of how miR-137 suppression associated with cancer progression and chemoresistance still remains to be elucidated.MethodsQuantitative reverse transcriptase-PCR (qRT-PCR), DNA methylation analysis, cell proliferation assay, flow cytometric analysis, invasion assay, in situ tumor formation experiment were performed to test the expression levels and functions of miR-137 in GBM. Bioinformatics analysis, luciferase reporter assay, qRT-PCR, immunoblotting, immunofluorescence, and immunohistochemistry assay were used to identify and verify the target of miR-137.ResultsWe found that miR-137 was downregulated in primary and recurrent GBM compared with normal brain tissues. Overexpression of miR-137 inhibited cell invasion and enhanced cell chemosensitivity to temozolomide (TMZ) by directly targeting low-density lipoprotein receptor-related protein 6 (LRP6) in GBM. Forced expression of LRP6 cDNA without its 3’-UTR region partly restored the effects of miR-137 in vitro and in vivo. Hypoxia-induced miR-137 methylation was responsible for the miR-137 suppression, leading to the cell chemoresistance and poor prognosis of GBM.ConclusionsThese findings demonstrated the detailed molecular mechanism of miR-137 in regulating GBM growth and chemoresistance in hypoxia microenvironment, suggesting the potentiality of miR-137 as a therapeutic target for GBM. |
| first_indexed | 2024-12-22T19:46:23Z |
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| language | English |
| last_indexed | 2024-12-22T19:46:23Z |
| publishDate | 2021-02-01 |
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| series | Frontiers in Oncology |
| spelling | doaj.art-bb153e90822c44d380bd0488781df9f72022-12-21T18:14:41ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-02-011010.3389/fonc.2020.611699611699Hypoxia-Induced miR-137 Inhibition Increased Glioblastoma Multiforme Growth and Chemoresistance Through LRP6Dong-Mei Li0Dong-Mei Li1Qiu-Dan Chen2Gui-Ning Wei3Jie Wei4Jian-Xing Yin5Jian-Xing Yin6Jun-Hui He7Xin Ge8Xin Ge9Zhu-Mei Shi10Zhu-Mei Shi11Department of Pharmacology, Guangxi Institute of Chinese Medicine & Pharmaceutical Science, Nanning, ChinaInstitute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, ChinaThe Department of Central Laboratory, Clinical Laboratory, Jing’an District Center Hospital of Shanghai, Fudan University, Shanghai, ChinaDepartment of Pharmacology, Guangxi Institute of Chinese Medicine & Pharmaceutical Science, Nanning, ChinaDepartment of Pharmacology, Guangxi Institute of Chinese Medicine & Pharmaceutical Science, Nanning, ChinaInstitute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, ChinaDepartment of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Pharmacology, Guangxi Institute of Chinese Medicine & Pharmaceutical Science, Nanning, ChinaInstitute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, ChinaDepartment of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, ChinaInstitute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, ChinaDepartment of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaPurposeGlioblastoma multiforme (GBM) is one of the deadliest tumors, which is involved in numerous dysregulated microRNAs including miR-137. However, the mechanism of how miR-137 suppression associated with cancer progression and chemoresistance still remains to be elucidated.MethodsQuantitative reverse transcriptase-PCR (qRT-PCR), DNA methylation analysis, cell proliferation assay, flow cytometric analysis, invasion assay, in situ tumor formation experiment were performed to test the expression levels and functions of miR-137 in GBM. Bioinformatics analysis, luciferase reporter assay, qRT-PCR, immunoblotting, immunofluorescence, and immunohistochemistry assay were used to identify and verify the target of miR-137.ResultsWe found that miR-137 was downregulated in primary and recurrent GBM compared with normal brain tissues. Overexpression of miR-137 inhibited cell invasion and enhanced cell chemosensitivity to temozolomide (TMZ) by directly targeting low-density lipoprotein receptor-related protein 6 (LRP6) in GBM. Forced expression of LRP6 cDNA without its 3’-UTR region partly restored the effects of miR-137 in vitro and in vivo. Hypoxia-induced miR-137 methylation was responsible for the miR-137 suppression, leading to the cell chemoresistance and poor prognosis of GBM.ConclusionsThese findings demonstrated the detailed molecular mechanism of miR-137 in regulating GBM growth and chemoresistance in hypoxia microenvironment, suggesting the potentiality of miR-137 as a therapeutic target for GBM.https://www.frontiersin.org/articles/10.3389/fonc.2020.611699/fullglioblastoma multiformemiR-137chemoresistanceLRP6epithelial-mesenchymal transition-related genes |
| spellingShingle | Dong-Mei Li Dong-Mei Li Qiu-Dan Chen Gui-Ning Wei Jie Wei Jian-Xing Yin Jian-Xing Yin Jun-Hui He Xin Ge Xin Ge Zhu-Mei Shi Zhu-Mei Shi Hypoxia-Induced miR-137 Inhibition Increased Glioblastoma Multiforme Growth and Chemoresistance Through LRP6 Frontiers in Oncology glioblastoma multiforme miR-137 chemoresistance LRP6 epithelial-mesenchymal transition-related genes |
| title | Hypoxia-Induced miR-137 Inhibition Increased Glioblastoma Multiforme Growth and Chemoresistance Through LRP6 |
| title_full | Hypoxia-Induced miR-137 Inhibition Increased Glioblastoma Multiforme Growth and Chemoresistance Through LRP6 |
| title_fullStr | Hypoxia-Induced miR-137 Inhibition Increased Glioblastoma Multiforme Growth and Chemoresistance Through LRP6 |
| title_full_unstemmed | Hypoxia-Induced miR-137 Inhibition Increased Glioblastoma Multiforme Growth and Chemoresistance Through LRP6 |
| title_short | Hypoxia-Induced miR-137 Inhibition Increased Glioblastoma Multiforme Growth and Chemoresistance Through LRP6 |
| title_sort | hypoxia induced mir 137 inhibition increased glioblastoma multiforme growth and chemoresistance through lrp6 |
| topic | glioblastoma multiforme miR-137 chemoresistance LRP6 epithelial-mesenchymal transition-related genes |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2020.611699/full |
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