Exosomal transfer of miR-151a enhances chemosensitivity to temozolomide in drug-resistant glioblastoma

Zeng, Ailiang; Wei, Zhiyun; Yan, Wei; Yin, Jianxing; Huang, Xiaoxu; Zhou, Xu; Li, Rui; Shen, Feng; Wu, Weining; Wang, Xiefeng; You, Yongping

doi:10.1016/j.canlet.2018.08.004

Cited by 159 publications

(139 citation statements)

References 26 publications

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“…N3 patient-derived cells were obtained from the China National Clinical Research Center for Neurological Diseases, Beijing Tian Tan Hospital. Six drug-related cell lines (Pri GBM, Rec GBM, N3S, N3T3rd, U251, and U251T3rd) were as described in our previous report [13]. All cells were cultured in high-glucose Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS) at 37°C with 5% CO 2 .…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

DNA-methylation-mediated activating of lncRNA SNHG12 promotes temozolomide resistance in glioblastoma

et al. 2020

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Background: Accumulating evidence shows that long noncoding RNAs (lncRNAs) are important regulator molecules involved in diverse biological processes. Acquired drug resistance is a major challenge in the clinical treatment of glioblastoma (GBM), and lncRNAs have been shown to play a role in chemotherapy resistance. However, the underlying mechanisms by which lncRNA mediates TMZ resistance in GBM remain poorly characterized. Methods: Quantitative reverse transcription PCR (qRT-PCR) and fluorescence in situ hybridization assays were used to detect small nucleolar RNA host gene 12 (SNHG12) levels in TMZ-sensitive and TMZ-resistant GBM cells and tissues. The effects of SNHG12 on TMZ resistance were investigated through in vitro assays (western blots, colony formation assays, flow cytometry assays, and TUNEL assays). The mechanism mediating the high expression of SNHG12 in TMZ-resistant cells and its relationships with miR-129-5p, mitogen-activated protein kinase 1 (MAPK1), and E2F transcription factor 7 (E2F7) were determined by bioinformatic analysis, bisulfite amplicon sequencing, methylation-specific PCR, dual luciferase reporter assays, chromatin immunoprecipitation assays, RNA immunoprecipitation assays, immunofluorescence, qRT-PCR, and western blot. For in vivo experiments, an intracranial xenograft tumor mouse model was used to investigate SNHG12 function. Results: SNHG12 was upregulated in TMZ-resistant cells and tissues. Overexpression of SNHG12 led to the development of acquired TMZ resistance, while knockdown of SNHG12 restored TMZ sensitivity. An abnormally low level of DNA methylation was detected within the promoter region of SNHG12, and loss of DNA methylation made this region more accessible to the Sp1 transcription factor (SP1); this indicated that methylation and SP1 work together to regulate SNHG12 expression. In the cytoplasm, SNHG12 served as a sponge for miR-129-5p, leading to upregulation of MAPK1 and E2F7 and endowing the GBM cells with TMZ resistance. Disinhibition of MAPK1 regulated TMZ-induced cell apoptosis and the G1/S cell cycle transition by activating the MAPK/ERK pathway, while E2F7 dysregulation was primarily associated with G1/S cell cycle transition. Clinically, SNHG12 overexpression was associated with poor survival of GBM patients undergoing TMZ treatment. Conclusion: Our results suggest that SNHG12 could serve as a promising therapeutic target to surmount TMZ resistance, thereby improving the clinical efficacy of TMZ chemotherapy.

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Section: Cell Lines and Cell Culturementioning

confidence: 99%

DNA-methylation-mediated activating of lncRNA SNHG12 promotes temozolomide resistance in glioblastoma

et al. 2020

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“…From an application standpoint, active drug encapsulation methods such as via electroporation, are advantageous compared with passive methods (incubation of either exosomes or exosome‐producing cells with drugs) because they offer much greater loading efficiency albeit at the slight risk of compromising exosome membrane integrity. Many studies have validated the ability of exosomes not only to protect their therapeutic cargo, which may include small molecules inhibitors, therapeutic siRNAs, or even peptides, but to increase their bioavailability and overall efficacy . P‐glycoprotein (P‐gp) overexpression is one of the major means by which cancer cells become resistant to multiple drugs, and this is a key factor in the acquirement of TMZ resistance by glioblastoma cells .…”

Section: Genetically Tailored Exosomes: the Future Of Glioma Therapy?mentioning

confidence: 99%

Extracellular Vesicles in Glioma: From Diagnosis to Therapy

Basu

Ghosh

2019

BioEssays

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Increasing evidence indicates that extracellular vesicles (EVs) secreted from tumor cells play a key role in the overall progression of the disease state. EVs such as exosomes are secreted by a wide variety of cells and transport a varied population of proteins, lipids, DNA, and RNA species within the body. Gliomas constitute a significant proportion of all primary brain tumors and majority of brain malignancies. Glioblastoma multiforme (GBM) represents grade IV glioma and is associated with very poor prognosis despite the cumulative advances in diagnostic procedures and treatment strategies. Here, the authors describe the progress in understanding the role of EVs, especially exosomes, in overall glioma progression, and how new research is unraveling the utilities of exosomes in glioma diagnostics and development of next-generation therapeutic systems. Finally, based on an understanding of the latest scientific literature, a model for the possible working of therapeutic exosomes in glioma treatment is proposed.

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“…Higher levels of tumor‐derived exosomes are prone to affect therapy resistance, and exosomal RNAs regulate major tumor therapy resistance, especially noncoding RNAs. Zeng et al . tested and identified miR‐151a loss pathway was key element of temozolomide‐resistant glioblastoma multiforme, and miR‐151a also provided a potential avenue for therapy‐refractory GBMs (Table ).…”

Section: Exosome and Tumor Developmentmentioning

confidence: 99%

“…6 Higher levels of tumor-derived exosomes are prone to affect therapy resistance, and exosomal RNAs regulate major tumor therapy resistance, especially noncoding RNAs. Zeng et al 7 tested and identified miR-151a loss pathway was key element of temozolomide-resistant glioblastoma multiforme, and miR-151a also provided a potential avenue for therapy-refractory GBMs (Table 1). Moreover, exosomal long-noncoding RNA (lncRNA) SBF2-AS1 (lncSBF2-AS1), could also increase temozolomide tolerance to glioblastoma mainly via exerting reconstructive action to tumor microenvironment ( Table 1).…”

Section: Therapy Resistancementioning

confidence: 99%

The cancer exosomes: Clinical implications, applications and challenges

Tang

Hou

et al. 2019

Intl Journal of Cancer

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The exosome is a small functional vesicle enriched in selected proteins, lipids and nucleic acids, displaying distinct molecular heterogeneity. Exosomes released can transform the extracellular matrix microenvironments, transmit signals and molecules to recipient cells and trigger changes in their pathophysiological functions. Tumor‐derived exosomes mediate the interactions of tumor cells and microenvironment significantly, and they stimulate tumor growth and development through specific signaling pathways related to metastasis, therapeutic resistance and immunosuppression. Exosome biogenesis from tumors often represents abundant biological information, and novel and efficient isolation and detection methods of exosomes provide a promising approach for tumor diagnosis and prognosis estimation. Moreover, exosome can even be developed as therapeutic agents for multiple disease models based on effective material transport characteristics and biofilm specificity. This review reports the clinical implications and challenges of exosomes in cancer progression, therapy resistance, metastasis and immune escape, and underlying cancerogenic pathological phenotypes including fibrosis and viral infection.

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Exosomal transfer of miR-151a enhances chemosensitivity to temozolomide in drug-resistant glioblastoma

Cited by 159 publications

References 26 publications

DNA-methylation-mediated activating of lncRNA SNHG12 promotes temozolomide resistance in glioblastoma

DNA-methylation-mediated activating of lncRNA SNHG12 promotes temozolomide resistance in glioblastoma

Extracellular Vesicles in Glioma: From Diagnosis to Therapy

The cancer exosomes: Clinical implications, applications and challenges

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