Extracellular vesicles derived from hypoxic glioma stem-like cells confer temozolomide resistance on glioblastoma by delivering miR-30b-3p

Yin, Jianxing; Ge, Xin; Shi, Zhumei; Yu, Chen; Lu, Chenfei; Wei, Yutian; Zeng, Ailiang; Wang, Xiefeng; Yan, Wei; Zhang, Junxia; You, Yongping

doi:10.7150/thno.47057

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Theranostics 2021; 11(4):1763-1779. doi:10.7150/thno.47057 This issue Cite

Research Paper

Extracellular vesicles derived from hypoxic glioma stem-like cells confer temozolomide resistance on glioblastoma by delivering miR-30b-3p

Jianxing Yin^1,2*, Xin Ge^3*, Zhumei Shi^1,2*, Chen Yu^1,2, Chenfei Lu^1,2, Yutian Wei^1,2, Ailiang Zeng⁴, Xiefeng Wang^1,2, Wei Yan^1,2, Junxia Zhang^1,2✉, Yongping You^1,2✉

1. Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
2. Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
3. Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
4. Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
*These authors contributed equally to this work.

Citation:

Yin J, Ge X, Shi Z, Yu C, Lu C, Wei Y, Zeng A, Wang X, Yan W, Zhang J, You Y. Extracellular vesicles derived from hypoxic glioma stem-like cells confer temozolomide resistance on glioblastoma by delivering miR-30b-3p. Theranostics 2021; 11(4):1763-1779. doi:10.7150/thno.47057. https://www.thno.org/v11p1763.htm

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Abstract

Rationale: Glioma stem-like cells (GSCs) contribute to temozolomide (TMZ) resistance in gliomas, although the mechanisms have not been delineated.

Methods: In vitro functional experiments (colony formation assay, flow cytometric analysis, TUNEL assay) were used to assess the ability of extracellular vesicles (EVs) from hypoxic GSCs to promote TMZ resistance in glioblastoma (GBM) cells. RNA sequencing and quantitative Reverse Transcription-PCR were employed to identify the functional miRNA in hypoxic EVs. Chromatin immunoprecipitation assays were performed to analyze the transcriptional regulation of miRNAs by HIF1α and STAT3. RIP and RNA pull-down assays were used to validate the hnRNPA2B1-mediated packaging of miRNA into EVs. The function of EV miR-30b-3p from hypoxic GSCs was verified by in vivo experiments and analysis of clinical samples.

Results: Hypoxic GSC-derived EVs exerted a greater effect on GBM chemoresistance than those from normoxic GSCs. The miRNA profiling revealed that miR-30b-3p was significantly upregulated in the EVs from hypoxic GSCs. Further, HIF1α and STAT3 transcriptionally induced miR-30b-3p expression. RNA immunoprecipitation and RNA-pull down assays revealed that binding of miR-30b-3p with hnRNPA2B1 facilitated its transfer into EVs. EV-packaged miR-30b-3p (EV-miR-30b-3p) directly targeted RHOB, resulting in decreased apoptosis and increased proliferation in vitro and in vivo. Our results provided evidence that miR-30b-3p in CSF could be a potential biomarker predicting resistance to TMZ.

Conclusion: Our findings indicated that targeting EV-miR-30b-3p could provide a potential treatment strategy for GBM.

Keywords: GSCs, extracellular vesicles, miR-30b-3p, hypoxia, TMZ, chemoresistance

Citation styles

APA

Yin, J., Ge, X., Shi, Z., Yu, C., Lu, C., Wei, Y., Zeng, A., Wang, X., Yan, W., Zhang, J., You, Y. (2021). Extracellular vesicles derived from hypoxic glioma stem-like cells confer temozolomide resistance on glioblastoma by delivering miR-30b-3p. Theranostics, 11(4), 1763-1779. https://doi.org/10.7150/thno.47057.

ACS

Yin, J.; Ge, X.; Shi, Z.; Yu, C.; Lu, C.; Wei, Y.; Zeng, A.; Wang, X.; Yan, W.; Zhang, J.; You, Y. Extracellular vesicles derived from hypoxic glioma stem-like cells confer temozolomide resistance on glioblastoma by delivering miR-30b-3p. Theranostics 2021, 11 (4), 1763-1779. DOI: 10.7150/thno.47057.

NLM

CSE

Yin J, Ge X, Shi Z, Yu C, Lu C, Wei Y, Zeng A, Wang X, Yan W, Zhang J, You Y. 2021. Extracellular vesicles derived from hypoxic glioma stem-like cells confer temozolomide resistance on glioblastoma by delivering miR-30b-3p. Theranostics. 11(4):1763-1779.

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