DRR1 promotes glioblastoma cell invasion and epithelial-mesenchymal transition via regulating AKT activation

Ma, Yu‐Shui; Wu, Zhijun; Bai, Ruizhen; Hua, Dong; Xie, Bingxue; Wu, Xiaohong; Hang, Xiao-Sheng; Liu, Ai-Ning; Jiang, Xiaohui; Gaoren, Wang; Jiang, Junjian; Xu, Wei; Chen, Xiaoping; Tan, Guangming; Fu, Da; Liu, Ji‐Bin; Liu, Quan

doi:10.1016/j.canlet.2018.03.015

Cited by 26 publications

(20 citation statements)

References 42 publications

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“…Similarly, Illumina’s TruSeq small RNA library preparation kit was used to prepare the miRNA library from samples. 52 Libraries were pooled and sequenced in a single lane of Illumina HiSeq 2000 sequencing platform.…”

Section: Methodsmentioning

confidence: 99%

Whole-Transcriptome Sequencing Identifies Key Differentially Expressed mRNAs, miRNAs, lncRNAs, and circRNAs Associated with CHOL

Chu

Jiang

et al. 2020

Molecular Therapy - Nucleic Acids

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To systematically evaluate the whole-transcriptome sequencing data of cholangiocarcinoma (CHOL) to gain more insights into the transcriptomic landscape and molecular mechanism of this cancer, we performed whole-transcriptome sequencing based on the tumorous (C) and their corresponding non-tumorous adjacent to the tumors (CP) from eight CHOL patients. Subsequently, differential expression analysis was performed on the C and CP groups, followed by functional interaction prediction analysis to investigate gene-regulatory circuits in CHOL. In addition, The Cancer Genome Atlas (TCGA) for CHOL data was used to validate the results. In total, 2,895 differentially expressed messenger RNAs (dif-mRNAs), 56 differentially expressed microRNAs (dif-miRNAs), 151 differentially expressed long non-coding RNAs (dif-lncRNAs), and 110 differentially expressed circular RNAs (dif-circRNAs) were found in CHOL samples compared with controls. Enrichment analysis on those differentially expressed genes (DEGs) related to miRNA, lncRNA, and circRNA also identified the function of spliceosome. The downregulated hsa-miR-144-3p were significantly enriched in the competing endogenous RNA (ceRNA) complex network, which also included 7 upregulated and 13 downregulated circRNAs, 7 upregulated lncRNAs, and 90 upregulated and 40 downregulated mRNAs. Moreover, most of the DEGs and a few of the miRNAs (such as hsa-miR-144-3p) were successfully validated by TCGA data. The genes involved in RNA splicing and protein degradation processes and miR-144-3p may play fundamental roles in the pathogenesis of CHOL.

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Section: Methodsmentioning

confidence: 99%

Whole-Transcriptome Sequencing Identifies Key Differentially Expressed mRNAs, miRNAs, lncRNAs, and circRNAs Associated with CHOL

Chu

Jiang

et al. 2020

Molecular Therapy - Nucleic Acids

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“…However, the effects of HMGB1 on the invasion and EMT of GBM cells remain unclear. Zinc-finger transcription factor Snail, a transcriptional regulator for EMT, represses the expression of epithelial markers (occludin, claudins and cytokeratin) and increases the expression of mesenchymal markers (fibronectin and vimentin) 17, 18. Snail has been emerged as a master regulator of cell migration and invasion, as well as irradiation-induced EMT in GBM cells 19.…”

Section: Introductionmentioning

confidence: 99%

HMGB1-Induced p62 Overexpression Promotes Snail-Mediated Epithelial-Mesenchymal Transition in Glioblastoma Cells via the Degradation of GSK-3β

Li¹,

Li²,

Zhang³

et al. 2019

Theranostics

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Rationale: Glioblastoma (GBM) is the most common and aggressive brain tumor, characterized by its propensity to invade the surrounding brain parenchyma. The effect of extracellular high-mobility group box 1 (HMGB1) protein on glioblastoma (GBM) progression is still controversial. p62 is overexpressed in glioma cells, and has been associated with the malignant features and poor prognosis of GBM patients. Hence, this study aimed to clarify the role of p62 in HMGB1-induced epithelial-mesenchymal transition (EMT) of GBM both in vitro and in vivo . Methods: Immunoblotting, immunofluorescence and qRT-PCR were performed to evaluate EMT progression in both human GBM cell line and primary GBM cells. Transwell and wound healing assays were used to assess the invasion and migration of GBM cells. shRNA technique was used to investigate the role of p62 in HMGB1-induced EMT both in vitro and in vivo orthotopic tumor model. Co-immunoprecipitation assay was used to reveal the interaction between p62 and GSK-3β (glycogen synthase kinase 3 beta). Immunohistochemistry was performed to detect the expression levels of proteins in human GBM tissues. Results: In this study, GBM cells treated with recombinant human HMGB1 (rhHMGB1) underwent spontaneous EMT through GSK-3β/Snail signaling pathway. In addition, our study revealed that rhHMGB1-induced EMT of GBM cells was accompanied by p62 overexpression, which was mediated by the activation of TLR4-p38-Nrf2 signaling pathway. Moreover, the results demonstrated that p62 knockdown impaired rhHMGB1-induced EMT both in vitro and in vivo . Subsequent mechanistic investigations showed that p62 served as a shuttling factor for the interaction of GSK-3β with proteasome, and ultimately activated GSK-3β/Snail signaling pathway by augmenting the degradation of GSK-3β. Furthermore, immunohistochemistry analysis revealed a significant inverse correlation between p62 and GSK-3β, and a combination of the both might serve as a more powerful predictor of poor survival in GBM patients. Conclusions: This study suggests that p62 is an effector for HMGB1-induced EMT, and may represent a novel therapeutic target in GBM.

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“…DRR1 is downregulated in various cancer cell lines, including renal cell, ovarian, cervical, laryngeal, gastric, prostate, liver, lymph, and non-small cell lung cancer and is associated with the progression of neuroblastoma, meningioma and malignant glioma [26,27,28,29,30,31,32,33,34,35,36]. On the other hand, DRR1 is highly expressed in outer radial glial cells [37] and in the invasive component of glioblastoma [38,39]. Lately, DRR1 has been associated to several brain disorders.…”

Section: Introductionmentioning

confidence: 99%

The Stress-Inducible Protein DRR1 Exerts Distinct Effects on Actin Dynamics

Kretzschmar

Schülke

Masana

et al. 2018

IJMS

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Cytoskeletal dynamics are pivotal to memory, learning, and stress physiology, and thus psychiatric diseases. Downregulated in renal cell carcinoma 1 (DRR1) protein was characterized as the link between stress, actin dynamics, neuronal function, and cognition. To elucidate the underlying molecular mechanisms, we undertook a domain analysis of DRR1 and probed the effects on actin binding, polymerization, and bundling, as well as on actin-dependent cellular processes. Methods: DRR1 domains were cloned and expressed as recombinant proteins to perform in vitro analysis of actin dynamics (binding, bundling, polymerization, and nucleation). Cellular actin-dependent processes were analyzed in transfected HeLa cells with fluorescence recovery after photobleaching (FRAP) and confocal microscopy. Results: DRR1 features an actin binding site at each terminus, separated by a coiled coil domain. DRR1 enhances actin bundling, the cellular F-actin content, and serum response factor (SRF)-dependent transcription, while it diminishes actin filament elongation, cell spreading, and actin treadmilling. We also provide evidence for a nucleation effect of DRR1. Blocking of pointed end elongation by addition of profilin indicates DRR1 as a novel barbed end capping factor. Conclusions: DRR1 impacts actin dynamics in several ways with implications for cytoskeletal dynamics in stress physiology and pathophysiology.

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DRR1 promotes glioblastoma cell invasion and epithelial-mesenchymal transition via regulating AKT activation

Cited by 26 publications

References 42 publications

Whole-Transcriptome Sequencing Identifies Key Differentially Expressed mRNAs, miRNAs, lncRNAs, and circRNAs Associated with CHOL

Whole-Transcriptome Sequencing Identifies Key Differentially Expressed mRNAs, miRNAs, lncRNAs, and circRNAs Associated with CHOL

HMGB1-Induced p62 Overexpression Promotes Snail-Mediated Epithelial-Mesenchymal Transition in Glioblastoma Cells via the Degradation of GSK-3β

The Stress-Inducible Protein DRR1 Exerts Distinct Effects on Actin Dynamics

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