p53 and miR‐210 regulated NeuroD2, a neuronal basic helix–loop–helix transcription factor, is downregulated in glioblastoma patients and functions as a tumor suppressor under hypoxic microenvironment

Agrawal, Rahul; Garg, Ankita; Malgulwar, Prit Benny; Sharma, Vikas; Sarkar, Chitra; Kulshreshtha, Ritu

doi:10.1002/ijc.31209

Cited by 25 publications

(17 citation statements)

References 31 publications

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“…We found that expressions of a set of neurogenic transcription factors, such as Neurod2, Ascl1 and Myt1l, were increased during GBM-neuron cell conversion. Neurod2 is significantly downregulated in GBM patients, which is involved in the p53 pathway [ 63 ]. Ascl1 and Myt1l suppress GBM tumorigenicity and are required for glioblastoma stem cells to undergo neuronal lineage differentiation [ 64 – 66 ].…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: Reprogramming glioblastoma multiforme cells into neurons by protein kinase inhibitors

Yuan

Zhang

Hallahan

et al. 2018

J Exp Clin Cancer Res

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BackgroundReprogramming of cancers into normal-like tissues is an innovative strategy for cancer treatment. Recent reports demonstrate that defined factors can reprogram cancer cells into pluripotent stem cells. Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor in humans. Despite multimodal therapy, the outcome for patients with GBM is still poor. Therefore, developing novel therapeutic strategy is a critical requirement.MethodsWe have developed a novel reprogramming method that uses a conceptually unique strategy for GBM treatment. We screened a kinase inhibitor library to find which candidate inhibitors under reprogramming condition can reprogram GBM cells into neurons. The induced neurons are identified whether functional and loss of tumorigenicity.ResultsWe have found that mTOR and ROCK kinase inhibitors are sufficient to reprogram GBM cells into neural-like cells and “normal” neurons. The induced neurons expressed neuron-specific proteins, generated action potentials and neurotransmitter receptor-mediated currents. Genome-wide transcriptional analysis showed that the induced neurons had a profile different from GBM cells and were similar to that of control neurons induced by established methods. In vitro and in vivo tumorigenesis assays showed that induced neurons lost their proliferation ability and tumorigenicity. Moreover, reprogramming treatment with ROCK-mTOR inhibitors prevented GBM local recurrence in mice.ConclusionThis study indicates that ROCK and mTOR inhibitors-based reprogramming treatment prevents GBM local recurrence. Currently ROCK-mTOR inhibitors are used as anti-tumor drugs in patients, so this reprogramming strategy has significant potential to move rapidly toward clinical trials.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0857-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: Reprogramming glioblastoma multiforme cells into neurons by protein kinase inhibitors

Yuan

Zhang

Hallahan

et al. 2018

J Exp Clin Cancer Res

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“…It has been reported that miR‐145 inhibits non‐small‐cell lung cancer growth by targeting RIOK2 31 . NeuroD2 is post‐transcriptionally targeted by miR‐210, overexpression of NeuroD2 diminishes glioma cell proliferation, migration, and promotes apoptosis under hypoxia 18 . MiR‐4744 was originally identified by second‐generation sequencing in breast cancer tissues 20 .…”

Section: Discussionmentioning

confidence: 99%

“…Extensive studies have revealed the dysregulation of miRNAs in the progression of gliomas. For example, miR‐210 strictly regulates the expression of NeuroD2, and overexpression of NeuroD2 reduces the invasiveness of glioblastoma under hypoxia conditions 18 . The level of miRNAs in cerebrospinal fluid and brain tissue of glioma patients is a reliable marker and may have diagnostic value for glioma 19 .…”

Section: Introductionmentioning

confidence: 99%

RIOK2 is negatively regulated by miR‐4744 and promotes glioma cell migration/invasion through epithelial‐mesenchymal transition

Song

Cheng

Jin

et al. 2020

J Cellular Molecular Medi

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RIOK2 is a member of RIO (right open reading frame) kinase family. Recent studies have revealed the involvement of RIO kinases in glioma cell growth and expansion. However, the role and mechanism of RIOK2 in glioma cell migration and invasion remain unclear. Wound healing assay, Transwell assay and real-time quantitative PCR (qRT-PCR) detection of matrix metalloproteinases (MMPs) were used to evaluate the migration/invasion of glioma cells. Western blot and qRT-PCR were employed to measure the expression of epithelial-mesenchymal transition (EMT) markers. Dual luciferase reporter assay was performed to determine the binding between RIOK2 and miR-4744. In addition, RIOK2 and miR-4744 levels were quantified by qRT-PCR and/ or immunohistochemistry in glioma tissues. Transfection of RIOK2 siRNAs significantly inhibited glioma cell migration and invasion and down-regulated the expression of MMPs (MMP2 and MMP9) and mesenchymal markers (N-cadherin, β-catenin, Twist1, fibronectin, ZEB-1) in glioma cells. Overexpression of RIOK2 showed the opposite effects. MiR-4744 directly bound to the 3'-untranslated region of RIOK2 and negatively regulated the expression of RIOK2. Up-regulation of miR-4744 inhibited the migration and invasion of glioma cells. Overexpression of RIOK2 could reverse the effects of miR-4744 up-regulation on the migration, invasion and EMT process in glioma cells. Moreover, RIOK2 was high, while miR-4744 was low in glioma tissues, and a negative correlation was found between them. These results suggest that RIOK2 is post-transcriptionally targeted by miR-4744, the low miR-4744 and high RIOK2 levels in glioma may contribute to tumour cell infiltration through promoting the EMT. K E Y W O R D S fibronectin, glioma, miR-4744, N-cadherin, RIOK2, β-catenin | 4495 SONG et al. S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Song Y, Li C, Jin L, et al. RIOK2 is negatively regulated by miR-4744 and promotes glioma cell migration/invasion through epithelial-mesenchymal transition.

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“…Clinically, inhibition of this pathway could be a potential strategy to enhance sustained TMZ-response in this malignancy. Agrawal et al identified a novel role of NeuroD2 as a tumor suppressor and prognostic biomarker in GBM the levels of which are tightly regulated by p53 and miR-210 [20]. Overexpressing NeuroD2 may potentially be a simple and efficient therapeutic strategy to inhibit the malignant phenotype of GBM cells [20].…”

Section: Discussionmentioning

confidence: 99%

Knockdown of DEPDC1B inhibits the development of glioblastoma

Guo

Cao

et al. 2020

Cancer Cell Int

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Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis. DEPDC1B (DEP domain-containing protein 1B) has been shown to be associated with some types of malignancies. However, the role and underlying regulatory mechanisms of DEPDC1B in GBM remain elusive. Methods: In this research, the expression level of DEPDC1B in GBM tissues was detected by IHC. The DEPDC1B knockdown cell line was constructed, identified by qRT-PCR and western blot and used to construct the xenotransplantation mice model and intracranial xenograft model. MTT assay, colony formation assay, flow cytometry, and Transwell assay were used to detected cell proliferation, apoptosis and migration. Results: The results proved that DEPDC1B was significantly upregulated in tumor tissues, and silencing DEPDC1B could inhibit proliferation, migration and promote apoptosis of GBM cell. In addition, human apoptosis antibody array detection showed that after DEPDC1B knockdown, the expression of apoptosis-related proteins was downregulated, such as IGFBP-2, Survivin, N-cadherin, Vimentin and Snail. Finally, we indicated that knockdown of DEPDC1B significantly inhibited tumor growth in vivo. Conclusions: In summary, DEPDC1B was involved in the development and progression of GBM, which may be a potential therapeutic target and bring a breakthrough in the treatment.

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p53 and miR‐210 regulated NeuroD2, a neuronal basic helix–loop–helix transcription factor, is downregulated in glioblastoma patients and functions as a tumor suppressor under hypoxic microenvironment

Cited by 25 publications

References 31 publications

RETRACTED ARTICLE: Reprogramming glioblastoma multiforme cells into neurons by protein kinase inhibitors

RETRACTED ARTICLE: Reprogramming glioblastoma multiforme cells into neurons by protein kinase inhibitors

RIOK2 is negatively regulated by miR‐4744 and promotes glioma cell migration/invasion through epithelial‐mesenchymal transition

Knockdown of DEPDC1B inhibits the development of glioblastoma

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