The positive feedback loop of NHE1-ERK phosphorylation mediated by BRAFV600E mutation contributes to tumorigenesis and development of glioblastoma

Li, Yuhui; Li, Dan; Liu, Yankun; Wang, Shuqing; Sun, Mingyang; Zhang, Zhongyuan; Zheng, Xuan; Li, Jingwu

doi:10.1016/j.bbrc.2021.11.104

Cited by 5 publications

(4 citation statements)

References 33 publications

(29 reference statements)

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“…As for proliferation, it was found to be reduced in U87MG and T98G cells but elevated in DBTRG-05MG. Discrepancies for DBTRG-05MG might be attributed to the specific features of these cells (among four investigated cell lines), e.g., the presence of a BRAF V600E mutation [ 73 , 74 ]. It is known that this alteration can lead to the maintenance of proliferation, transformation, and tumorigenicity [ 75 ] and that multiple proliferation-related signaling pathways are simultaneously active when V600E is present [ 76 ].…”

Section: Discussionmentioning

confidence: 99%

Antineoplastic Nature of WWOX in Glioblastoma Is Mainly a Consequence of Reduced Cell Viability and Invasion

Kałuzińska

Kośla

Kołat

et al. 2023

Biology

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Following the discovery of WWOX, research has moved in many directions, including the role of this putative tumor suppressor in the central nervous system and related diseases. The task of determining the nature of WWOX in glioblastoma (GBM) is still considered to be at the initial stage; however, the influence of this gene on the GBM malignant phenotype has already been reported. Because most of the available in vitro research does not consider several cellular GBM models or a wide range of investigated biological assays, the present study aimed to determine the main processes by which WWOX exhibits anticancer properties in GBM, while taking into account the phenotypic heterogeneity between cell lines. Ectopic WWOX overexpression was studied in T98G, DBTRG-05MG, U251MG, and U87MG cell lines that were compared with the use of assays investigating cell viability, proliferation, apoptosis, adhesion, clonogenicity, three-dimensional and anchorage-independent growth, and invasiveness. Observations presenting the antineoplastic properties of WWOX were consistent for T98G, U251MG, and U87MG. Increased proliferation and tumor growth were noted in WWOX-overexpressing DBTRG-05MG cells. A possible explanation for this, arrived at via bioinformatics tools, was linked to the TARDBP transcription factor and expression differences of USP25 and CPNE2 that regulate EGFR surface abundance. Collectively, and despite various cell line-specific circumstances, WWOX exhibits its anticancer nature mainly via a reduction of cell viability and invasiveness of glioblastoma.

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Section: Discussionmentioning

confidence: 99%

Antineoplastic Nature of WWOX in Glioblastoma Is Mainly a Consequence of Reduced Cell Viability and Invasion

Kałuzińska

Kośla

Kołat

et al. 2023

Biology

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“…Gene mutations are a common tumorigenic mechanism in liver cancer ( 31 – 34 ). In this study, it was found that CLGN was rarely mutated in HCC patients, which suggests that the pathological effects of CLGN may not be exerted through genetic mutations.…”

Section: Discussionmentioning

confidence: 99%

The upregulation of CLGN in hepatocellular carcinoma is potentially regulated by hsa-miR-194-3p and associated with patient progression

Cui

Wang²,

Chen³

et al. 2023

Front. Oncol.

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BackgroundPatients with hepatocellular carcinoma (HCC) have poor prognosis, especially in advanced stages. Targeted therapy is the main treatment for advanced HCC patients, but the optimal targets for HCC remain poorly understood. The main purpose of this study was to identify potential novel prognostic markers and therapeutic targets.MethodsFirstly, differentially expressed genes (DEGs) in HCC were identified from the Gene Expression Omnibus (GEO) database. The expression, significance in prognosis, and potential mechanisms of DEGs were analyzed using GEPIA, TIMER, HPA, Kaplan Meier Plotter, CBioPortal, miRWalk, TargetScan, and ENCORI databases. Immunohistochemical staining was used to determine the protein expression levels of potential candidate genes.ResultsThe mRNA levels of MND1, STXBP6, and CLGN were significantly increased in HCC (p< 0.01). HCC patients with elevated CLGN mRNA levels had poorer overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and disease-specific survival (DSS) (p < 0.05). Higher MND1 mRNA levels significantly correlated with poorer DFS in HCC patients (p< 0.05). However, there was no significant correlation between STXBP6 expression and prognosis of HCC (p> 0.05). Further analysis revealed that patients with elevated CLGN mRNA expression in advanced pathology stages had poorer prognosis (p< 0.01). In addition, CLGN protein levels were elevated in HCC compared to their levels in normal tissues. The mRNA levels of CLGN had no significant correlation with the abundance of six common tumor infiltrating lymphocytes in HCC (COR < 0.5). Moreover, the mutation rate of CLGN was less than 1% in HCC patients (10/1089). Finally, the expression level of hsa-miR-194-3p in HCC was significantly lower than that in normal tissues (p < 0.05), and prognosis of HCC with low expression of hsa-miR-194 was poor (p < 0.05).ConclusionThe upregulation of CLGN in HCC is significantly associated with poor patient prognosis, especially in the advanced stages, and may be regulated by hsa-miR-194-3p. These findings suggest that CLGN may be closely related to the progression of HCC, and is a potential therapeutic target and prognostic indicator for patients with advanced HCC.

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“…Additionally, NHE1 protein blockade promoted an immunogenic tumor microenvironment by inducing the accumulation of CD8 T cells, enhancing interferon-gamma (IFN-γ) expression, and rendering animals sensitive to anti-PD-1 treatment [66]. Another study demonstrated that NHE1 is an upstream factor of the extracellular signal-regulated kinase (ERK) and a downstream target of the BRAFV600E mutation, while a positive feedback loop between NHE1-ERK phosphorylation under the regulation of the BRAFV600E mutation seems to contribute to GB cell proliferation and invasion [67]. The proliferative and invasive properties of BRAFV600E-mutant and -wild-type GB cells were suppressed by an NHE1 and/or BRAFV600E inhibitor, with the combination of both resulting in more effective inhibition, suggesting a promising new therapeutic option for GB, especially when BRAF is mutated [67].…”

Section: Slc Implication In Glioma Proliferation and Progressionmentioning

confidence: 99%

“…Another study demonstrated that NHE1 is an upstream factor of the extracellular signal-regulated kinase (ERK) and a downstream target of the BRAFV600E mutation, while a positive feedback loop between NHE1-ERK phosphorylation under the regulation of the BRAFV600E mutation seems to contribute to GB cell proliferation and invasion [67]. The proliferative and invasive properties of BRAFV600E-mutant and -wild-type GB cells were suppressed by an NHE1 and/or BRAFV600E inhibitor, with the combination of both resulting in more effective inhibition, suggesting a promising new therapeutic option for GB, especially when BRAF is mutated [67]. Although the abovementioned findings show that NHE1 might be a novel treatment target against brain tumorigenesis and progression, there are no clinical studies to date evaluating the pharmacological inhibition of NHE1 protein in brain tumors [68].…”

Section: Slc Implication In Glioma Proliferation and Progressionmentioning

confidence: 99%

Impact of Solute Carrier Transporters in Glioma Pathology: A Comprehensive Review

Anagnostakis,

Kokkorakis,

Markouli

et al. 2023

IJMS

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Solute carriers (SLCs) are essential for brain physiology and homeostasis due to their role in transporting necessary substances across cell membranes. There is an increasing need to further unravel their pathophysiological implications since they have been proposed to play a pivotal role in brain tumor development, progression, and the formation of the tumor microenvironment (TME) through the upregulation and downregulation of various amino acid transporters. Due to their implication in malignancy and tumor progression, SLCs are currently positioned at the center of novel pharmacological targeting strategies and drug development. In this review, we discuss the key structural and functional characteristics of the main SLC family members involved in glioma pathogenesis, along with their potential targeting options to provide new opportunities for CNS drug design and more effective glioma management.

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The positive feedback loop of NHE1-ERK phosphorylation mediated by BRAFV600E mutation contributes to tumorigenesis and development of glioblastoma

Cited by 5 publications

References 33 publications

Antineoplastic Nature of WWOX in Glioblastoma Is Mainly a Consequence of Reduced Cell Viability and Invasion

Antineoplastic Nature of WWOX in Glioblastoma Is Mainly a Consequence of Reduced Cell Viability and Invasion

The upregulation of CLGN in hepatocellular carcinoma is potentially regulated by hsa-miR-194-3p and associated with patient progression

Impact of Solute Carrier Transporters in Glioma Pathology: A Comprehensive Review

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