N-cadherin upregulation mediates adaptive radioresistance in glioblastoma

Osuka, Satoru; Zhu, Dan; Zhang, Zhaobin; Li, Chaoxi; Stackhouse, Christian T.; Sampetrean, Oltea; Olson, Jeffrey J.; Gillespie, G. Yancey; Saya, Hideyuki; Willey, Christopher D.; Meir, Erwin G. Van

doi:10.1172/jci136098

Cited by 62 publications

(43 citation statements)

References 72 publications

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“…Gliomas account for more than 60% of primary intracranial tumors [ 35 ]. Due to its aggressive nature and unclear boundaries, it is difficult to remove completely these tumors with surgery alone [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: N(6)-adenosine-methyltransferase-14 promotes glioma tumorigenesis by repressing argininosuccinate synthase 1 expression in an m6A-dependent manner

et al. 2022

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Glioma is one of the leading causes of tumor-related deaths worldwide, but its potential mechanism remains unclear. This study aimed to explore the biological role and potential mechanism of argininosuccinate synthase 1 (ASS1) in glioma. The relative expression levels of ASS1 in glioma specimens and cell lines were calculated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting. The biological functions of ASS1 were demonstrated using the 5-ethynyl-2ʹ-deoxyuridine (EdU) assay, transwell assay, and in vivo experiments. In addition, methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), and luciferase reporter assays were performed to explore the molecular mechanism of ASS1 in glioma. ASS1 expression levels were found to be downregulated in glioma specimens and cell lines. Functionally, we confirmed that ASS1 inhibited glioma cell proliferation, migration, invasion, and growth both. Furthermore, we found that ASS1 was a target of N(6)-adenosine-methyltransferase-14 (METTL14)-mediated N 6 -methyladenosine (m 6 A) modification. Overexpression of METTL14 markedly elevated ASS1 mRNA m 6 A modification and suppressed ASS1 mRNA expression. We also revealed that METTL14-mediated ASS1 mRNA degradation relied on the YTH m6A RNA-binding protein 2 (YTHDF2)-dependent pathway. We confirmed that decreased ASS1 expression promoted the cell proliferation, migration, and invasion in glioma, and that the METTL14/ASS1/YTHDF2 regulatory axis may be an effective therapeutic target for glioma.

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Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: N(6)-adenosine-methyltransferase-14 promotes glioma tumorigenesis by repressing argininosuccinate synthase 1 expression in an m6A-dependent manner

et al. 2022

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“…We showed that the proneural-to-mesenchymal transition is independent of histological feature composition and reflects transcriptional changes in the cellular tumor. Mesenchymal transitions have been shown to associate with several factors, including increased myeloid cell infiltration, radiation-induced NF-κB activation, altered tumor metabolism, and hypoxia (Bhat et al, 2013;Garofano et al, 2021;Kim et al, 2021;Mao et al, 2013;Osuka et al, 2021;Schmitt et al, 2021;Wang et al, 2017). Our results indicate that the proneural-tomesenchymal transition is likely influenced by tumor-wide changes, supporting the hypothesis that this transition is involved in therapy resistance.…”

Section: Discussionsupporting

confidence: 77%

Longitudinal analysis of diffuse glioma reveals cell state dynamics at recurrence associated with changes in genetics and the microenvironment

Varn

Johnson

Wade

et al. 2021

Preprint

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To interrogate the factors driving therapy resistance in diffuse glioma, we collected and analyzed RNA and/or DNA sequencing data from temporally separated tumor pairs of 292 adult patients with IDH-wild-type or IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions associated with an increase in proliferating stem-like malignant cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their malignant cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a specific myeloid cell state defined by unique ligand-receptor interactions with malignant cells. Collectively, our results uncover recurrence-associated changes that could be targetable to shape disease progression following initial diagnosis.

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“…They proposed an AJ-mediated mechanism for glioma migration and progression, dependent on N-cadherin and p120-catenin complex [142]. Similarly, Osuka et al showed an N-cadherin expression increase among the population of radioresistant glioma stem cells (GSC), with increased stemness and reduced proliferation [143]. E-cadherin expression has been more commonly described as scarce or absent in gliomas [120,125,131,141] while contradicting results regarding its role in disease progression have been hypothesized.…”

Section: Gliomasmentioning

confidence: 99%

Cadherin Expression and EMT: A Focus on Gliomas

et al. 2021

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Cadherins are calcium-binding proteins with a pivotal role in cell adhesion and tissue homeostasis. The cadherin-dependent mechanisms of cell adhesion and migration are exploited by cancer cells, contributing to tumor invasiveness and dissemination. In particular, cadherin switch is a hallmark of epithelial to mesenchymal transition, a complex development process vastly described in the progression of most epithelial cancers. This is characterized by drastic changes in cell polarity, adhesion, and motility, which lead from an E-cadherin positive differentiated epithelial state into a dedifferentiated mesenchymal-like state, prone to metastization and defined by N-cadherin expression. Although vastly explored in epithelial cancers, how these mechanisms contribute to the pathogenesis of other non-epithelial tumor types is poorly understood. Herein, the current knowledge on cadherin expression in normal development in parallel to tumor pathogenesis is reviewed, focusing on epithelial to mesenchymal transition. Emphasis is taken in the unascertained cadherin expression in CNS tumors, particularly in gliomas, where the potential contribution of an epithelial-to-mesenchymal-like process to glioma genesis and how this may be associated with changes in cadherin expression is discussed.

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N-cadherin upregulation mediates adaptive radioresistance in glioblastoma

Cited by 62 publications

References 72 publications

RETRACTED ARTICLE: N(6)-adenosine-methyltransferase-14 promotes glioma tumorigenesis by repressing argininosuccinate synthase 1 expression in an m6A-dependent manner

RETRACTED ARTICLE: N(6)-adenosine-methyltransferase-14 promotes glioma tumorigenesis by repressing argininosuccinate synthase 1 expression in an m6A-dependent manner

Longitudinal analysis of diffuse glioma reveals cell state dynamics at recurrence associated with changes in genetics and the microenvironment

Cadherin Expression and EMT: A Focus on Gliomas

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