MicroRNAs in neuroblastoma tumorigenesis, therapy resistance, and disease evolution

Aravindan, Natarajan; Karthikeyan, S.; Somasundaram, Dinesh Babu; Herman, Terence S.; Aravindan, Sheeja

doi:10.20517/cdr.2019.68

Cited by 22 publications

(29 citation statements)

References 168 publications

(179 reference statements)

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“…Dysregulation of miRNAs has been reported in numerous cancers where individual miRNAs behave in an oncogenic or tumor suppressor manner [11][12][13][14]. To date, several profiling studies have reported that miRNAs are associated with clinical outcome in NB [15] and specific miRNAs have been identified to regulate key processes such as apoptosis, differentiation, cell proliferation and cell invasiveness in NB [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-145 overexpression inhibits neuroblastoma tumorigenesis in vitro and in vivo

Zhao

Zhou

et al. 2020

Bioengineered

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Neuroblastoma (NB) is responsible for 15% of all childhood cancer deaths. Despite advances in treatment and disease management, the overall 5-year survival rates remain poor in high-risk disease (25-40%). It is well known that miR-145 functions as a tumor suppressor in several types of cancer. However, the impact of miR-145 on NB is still ambiguous. Our aim was to investigate the potential tumor suppressive role and mechanisms of miR-145 in high-risk neuroblastoma. Expression levels of miR-145 in tissues and cells were determined using RT-qPCR. The effect of miR-145 on cell viability was evaluated using MTT assays, apoptosis levels were determined using TUNEL staining, and the MTDH protein expression was determined using western blot and RT-PCR. Luciferase reporter plasmids were constructed to confirm direct targeting for MTDH. The results showed that miR-145 expression was significantly lower in high-risk MYCN amplified (MNA) tumors and low miR-145 expression was associated with worse EFS and OS in our cohort. Over-expression of miR-145 reduced cell viability and increased apoptosis in SH-SY-5Y cells. We identified MTDH as a direct target for miR-145 in SH-SY-5Y cells. Targeting MTDH has the similar results as miR-145 overexpression. Our findings suggest that low miR-145 expression was associated with poor prognosis in patients with NB, and the overexpression of miR-145 inhibited NB cells growth by down-regulating MTDH, thus providing a potential target for the development of microRNA-based approach for NB therapy.

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Section: Introductionmentioning

confidence: 99%

MicroRNA-145 overexpression inhibits neuroblastoma tumorigenesis in vitro and in vivo

Zhao

Zhou

et al. 2020

Bioengineered

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“…Notably, almost 30% of neuroblastoma patients show the MYCN amplification [ 48 ]. The correlation between oncogene amplification and increased tumor aggressiveness has been extensively studied; nevertheless, since MYC is involved in several cellular pathways, the role of this oncogene in tumor progression has not yet been fully elucidated [ 49 , 50 ]. Accordingly, in this study we found that the autocrine response of MYCN -amplified SK-N-BE cells to EVs was similar or even greater than the one observed in SH-SY5Y cells.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Aravindan et al have published a comprehensive review on the key role of microRNAs-loaded exosomes in neuroblastoma multi-drug resistance [ 50 ]; other authors have investigated pathways in neuroblastoma cells that are important in determining radio-resistance [ 51 ]. Abramowicz et al reviewed the role of EVs released by cells subjected to environmental physicochemical stress in regulating proliferation, cell survival, migration, and angiogenesis [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Ionizing Radiation-Induced Extracellular Vesicle Release Promotes AKT-Associated Survival Response in SH-SY5Y Neuroblastoma Cells

Tortolici

Vumbaca

Incocciati

et al. 2021

Cells

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Radiation therapy is one of the most effective methods of tumor eradication; however, in some forms of neuroblastoma, radiation can increase the risk of secondary neoplasms, due to the ability of irradiated cells to transmit pro-survival signals to non-irradiated cells through vesicle secretion. The aims of this study were to characterize the vesicles released by the human neuroblastoma cell line SH-SY5Y following X-ray radiations and their ability to increase invasiveness in non-irradiated SH-SY5Y cells. We first purified the extracellular vesicles released by the SH-SY5Y cells following X-rays, and then determined their total amount, dimensions, membrane protein composition, and cellular uptake. We also examined the effects of these extracellular vesicles on viability, migration, and DNA damage in recipient SH-SY5Y cells. We found that exposure to X-rays increased the release of extracellular vesicles and altered their protein composition. These vesicles were readily uptaken by non-irradiated cells, inducing an increase in viability, migration, and radio-resistance. The same results were obtained in an MYCN-amplified SK-N-BE cell line. Our study demonstrates that vesicles released from irradiated neuroblastoma cells stimulate proliferation and invasiveness that correlate with the epithelial to mesenchymal transition in non-irradiated cells. Moreover, our results suggest that, at least in neuroblastomas, targeting the extracellular vesicles may represent a novel therapeutic approach to counteract the side effects associated with radiotherapy.

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“…miR126-3P suppresses SOX2 expressions in GBM patients sensitizing tumor cells to temozolomide (TMZ) treatment [20]. In NB, induced and upregulated expression of miR-340 inhibits SOX2 expressions implicating its role in countering therapy resistance [21]. All these facts indicate a critical role of SOX2 in initiation, progression, and sustenance of cancer, signifying the importance of exosomal SOX2 DNA analysis.…”

Section: Competing Interestsmentioning

confidence: 99%

Differential sequences and single nucleotide polymorphism of exosomal SOX2 DNA in cancer

Vaidya

Sugaya

2020

PLoS ONE

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Glioblastoma multiforme (GBM) is the most common form of brain cancer, with an average life expectancy of fewer than two years post-diagnosis. We have previously reported that cancer cell originated exosomes, including GBM, have NANOG and NANOGP8 DNA associated with them. The exosomal NANOG DNA has certain differences as compared to its normal counterpart that are of immense importance as a potential cancer biomarker. NANOG has been demonstrated to play an essential role in the maintenance of embryonic stem cells, and its pseudogene, NANOGP8, is suggested to promote the cancer stem cell phenotype. Similarly, SOX2 is another stemness gene highly expressed in cancer stem cells with an intimate involvement in GBM progression and metastasis as well as promotion of tumorigenicity in Neuroblastoma (NB). Since exosomes are critical in intercellular communication with a role in dissipating hallmark biomolecules responsible for cancer, we conducted a detailed analysis of the association of the SOX2 gene with exosomes whose sequence modulations with further research and appropriate sample size can help to identify diagnostic markers for cancer. We have detected SOX2 DNA associated with exosomes and have identified some of the SNPs and nucleotide variations in the sequences from a GBM and SH-SY5Y sample. Although a further systematic investigation of exosomal DNA from GBM and NB patient's blood is needed, finding of SOX2 DNA in exosomes in the current study may have value in clinical research. SOX2 is known to be misregulated in cancer cells by changes in miRNA function, such as SNPs in the binding sites. Our finding of cancer-specific SNPs in exosomal SOX2 DNA sequence may reflect those changes in the cancer stem cells as well as cancer cells. A series of our study on embryonic stem cell gene analysis in exosomal DNA may lead to a minimally invasive exosome-based diagnosis, and give us a key in understanding the mechanisms of cancer formation, progression, and metastasis.

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MicroRNAs in neuroblastoma tumorigenesis, therapy resistance, and disease evolution

Cited by 22 publications

References 168 publications

MicroRNA-145 overexpression inhibits neuroblastoma tumorigenesis in vitro and in vivo

MicroRNA-145 overexpression inhibits neuroblastoma tumorigenesis in vitro and in vivo

Ionizing Radiation-Induced Extracellular Vesicle Release Promotes AKT-Associated Survival Response in SH-SY5Y Neuroblastoma Cells

Differential sequences and single nucleotide polymorphism of exosomal SOX2 DNA in cancer

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