Silencing of ZFP36L2 increases sensitivity to temozolomide through G2/M cell cycle arrest and BAX mediated apoptosis in GBM cells

Mat, Mohd Firdaus Che; Hanif, Ezanee Azlina Mohamad; Murad, Nor Azian Abdul; Ibrahim, Kamariah; Harun, Roslan; Jamal, Rahman

doi:10.1007/s11033-021-06144-z

Cited by 7 publications

(6 citation statements)

References 45 publications

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“…Importantly, re-expression of ZFP36L2 overcame the inhibitory effects of miR-520d-3p on CC cells. Consistent with our data, ZFP36L2 protein expression was upregulated in glioblastoma and ZFP36L2 inhibition led to decreased cell proliferation in temozolomide-resistant LN18 cells [ 25 ]. Overexpression of ZFP36L2 was confirmed in PDAC clinical specimens and involved in tumor-suppressive miR-375-mediated PDAD molecular network [ 24 ].…”

Section: Discussionsupporting

confidence: 91%

“…Nevertheless, recent studies pointed the oncogenic role of ZFP36L2 as follows: Yonemori et al [ 24 ] confirmed the overexpression of ZFP36L2 in pancreatic ductal adenocarcinoma (PDAC) clinical specimens and demonstrated that silencing ZFP36L2 inhibited cancer cell aggressiveness. Moreover, ZFP36L2 has oncogenic and chemosensitive characteristics in glioblastoma through regulating cell proliferation, cell cycle arrest and apoptosis [ 25 ]. These findings indicate that the dysregulation of ZFP36L2 expression plays a key role in cancer development.…”

Section: Introductionmentioning

confidence: 99%

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MiR-520d-3p suppresses the proliferation and epithelial-mesenchymal transition of cervical cancer cells by targeting ZFP36L2

Zhang

Tian

Zhao

2023

Heliyon

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

MiR-520d-3p suppresses the proliferation and epithelial-mesenchymal transition of cervical cancer cells by targeting ZFP36L2

Zhang

Tian

Zhao

2023

Heliyon

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“…The result demonstrates that CD44 mainly distributes in the perinecrotic region within tumor ( Figure 8A ). Some of the top correlated genes are immune genes (e.g., TNC, CCL2, SOCS3, TNFRSF12A, PTX3 , and VAT1 ) ( 38 , 39 ), invasive genes (e.g., GBP2, EMP1, VIM, ANO6, RBM47, CHI3L1, HMOX1 , and ICAM1 ) ( 40 – 42 ), proliferative genes (e.g., ANXA2, ZFP36L2 , and CHI3L2 ) ( 43 , 44 ), and apoptotic genes (e.g., SOD2 ) ( 45 ). From the spatial-based correlated gene pattern, CD44 may take part in GBM immunity, invasion, and proliferation process.…”

Section: Resultsmentioning

confidence: 99%

CD44-Mediated Poor Prognosis in Glioma Is Associated With M2-Polarization of Tumor-Associated Macrophages and Immunosuppression

et al. 2022

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BackgroundGlioma is the most common primary brain tumor with a poor prognosis. Key genes that are negatively related to prognosis may provide the therapy targets to cure glioma. To clarify the role of CD44 in glioma, we explored its function at bulk-transcriptome, spatial and single-cell transcriptome levels.MethodsIn total, expression profiles with survival data of whole-grade glioma from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), RNA-seq data with anatomic information of glioblastoma (GBM) from the Ivy Glioblastoma Atlas Project, RNA-sequencing (RNA-seq) data from recurrent GBM receiving adjuvant anti-PD-1 immunotherapy accessed through GSE121810, and single-cell RNA-seq data of GBM under accession GSE103224 were enrolled in this study. CD44-specific findings were further analyzed by R language.ResultsCD44 is positively correlated with WHO grade of malignancy and is negatively related to prognosis in glioma. Meanwhile, CD44 predominantly expresses in GBM mesenchymal subtype, and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses reveal that CD44 positively coexpressed genes are closely related to glioma immunity. Moreover, CD44+ cells mainly distribute in perinecrotic region with high expression of immune factors. At single-cell resolution, only malignant tumor cells, tumor-associated macrophages (TAMs), and T cells express CD44 in GBM. CD44+ malignant tumor cells are in mesenchymal-1-like (MES1-like) cellular state, and CD44+ TAMs are in M2 phenotype. CD44+ T cells have high expression of both PD-1 and PD-L1. CD44 and its directly interacted inhibitory immunomodulators are upregulated in patients with nonresponder recurrent GBM treated with PD-1 blockade therapy.ConclusionOur work demonstrates that CD44, a new M2 TAM biomarker, is involved in immune suppressor and promote glioma progression in glioma microenvironment. These results expand our understanding of CD44-specific clinical and immune features in glioma.

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“…Temozolomide, a type of alkylating drug authorized for glioblastoma anticancer therapy, is able to cross the blood–brain barrier damaging DNA and initiating cellular suicide 23 . Mat et al observed that temozolomide treatment could repress cell cycle arrest in G2/M cells in glioblastoma 24 . A number of previous articles proposed that temozolomide treatment could induce apoptosis and autophagy of glioblastoma cells 25,26 .…”

Section: Discussionmentioning

confidence: 99%

Temozolomide protects against the progression of glioblastoma via SOX4 downregulation by inhibiting the LINC00470‐mediated transcription factor EGR2

Wang

et al. 2023

CNS Neurosci Ther

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Objective: Temozolomide is extensively applied in chemotherapy for glioblastoma with unclear exact action mechanisms. This article seeks to address the potential molecular mechanisms in temozolomide therapy for glioblastoma involving LINC00470.Methods: Bioinformatics analysis was conducted to predict the potential mechanism of LINC00470 in glioblastoma, which was validated by dual-luciferase reporter, RIP, ChIP, and RNA pull-down assays. LINC00470 expression and the predicted downstream transcription factor early growth response 2 (EGR2) were detected in the collected brain tissues from glioblastoma patients. Following temozolomide treatment and/or gain-and loss-of-function approaches in glioblastoma cells, cell viability, invasion, migration, cycle distribution, angiogenesis, autophagy, and apoptosis were measured. In addition, the expression of mesenchymal surface marker proteins was assessed by western blot. Tumor xenograft in nude mice was conducted for in vivo validation.Results: Mechanistic analysis and bioinformatics analysis revealed that LINC00470 transcriptionally activated SRY-related high-mobility-group box 4 (SOX4) through the transcription factor EGR2. LINC00470 and EGR2 were highly expressed in brain tissues of glioblastoma patients. LINC00470 and EGR2 mRNA expression gradually decreased with increasing concentrations of temozolomide in glioblastoma cells, and SOX4 expression was reduced in cells by temozolomide and LINC00470 knockdown.Temozolomide treatment induced cell cycle arrest, diminished cell viability, migration, invasion, and angiogenesis, and increased apoptosis and autophagy in glioblastoma, which was counteracted by overexpressing LINC00470 or SOX4 but was further promoted by LINC00470 knockdown. Temozolomide restrained glioblastoma growth and angiogenesis in vivo, while LINC00470 or SOX4 overexpression nullified but LINC00470 knockdown further facilitated these trends. Conclusion:Conclusively, temozolomide repressed glioblastoma progression by repressing the LINC00470/EGR2/SOX4 axis.

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Silencing of ZFP36L2 increases sensitivity to temozolomide through G2/M cell cycle arrest and BAX mediated apoptosis in GBM cells

Cited by 7 publications

References 45 publications

MiR-520d-3p suppresses the proliferation and epithelial-mesenchymal transition of cervical cancer cells by targeting ZFP36L2

MiR-520d-3p suppresses the proliferation and epithelial-mesenchymal transition of cervical cancer cells by targeting ZFP36L2

CD44-Mediated Poor Prognosis in Glioma Is Associated With M2-Polarization of Tumor-Associated Macrophages and Immunosuppression

Temozolomide protects against the progression of glioblastoma via SOX4 downregulation by inhibiting the LINC00470‐mediated transcription factor EGR2

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