Activation of STAT1 by the FRK tyrosine kinase is associated with human glioma growth

Liu, Hua; Wang, Guanghui; Wang, Zhen; Fu, Jiale; Fang, Zhen; Zhuang, Ting; Zhao, Liang; Zong, Zhenkun; Ye, Chengkun; Liu, Hongmei; Zhu, Y.; Yu, Rutong

doi:10.1007/s11060-019-03143-w

Cited by 10 publications

(9 citation statements)

References 48 publications

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“…YY1 or Yin Yang 1 transcription factor is known to regulate a number of proteins associated with cell division, differentiation, and DNA repair; and a number of evidences indicate its role in the progression of glioma (36). Conversely, STAT1 or Signal Transducer and Activator of Transcription controls the expression of different proteins involved in cell viability, and its activation has been previously reported to be involved in suppression of glioma carcinogenesis (37)(38)(39).…”

Section: Circulating Extracellular Vesicle Proteins Distinguish Patients With Glioma From Healthy Controlsmentioning

confidence: 99%

Plasma-Derived Extracellular Vesicles Reveal Galectin-3 Binding Protein as Potential Biomarker for Early Detection of Glioma

et al. 2021

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Gliomas are the most common type of the malignant brain tumor, which arise from glial cells. They make up about 40% of all primary brain tumors and around 70% of all primary malignant brain tumors. They can occur anywhere in the central nervous system (CNS) and have a poor prognosis. The average survival of glioma patients is approximately 6–15 months with poor aspects of life. In this edge, identification of proteins secreted by cancer cells is of special interest because it may provide a better understanding of tumor progression and provide early diagnosis of the diseases. Extracellular vesicles (EVs) were isolated from pooled plasma of healthy controls (n=03) and patients with different grades of glioma (Grade I or II or III, n=03 each). Nanoparticle tracking analysis, western blot, and flow cytometry were performed to determine the size, morphology, the concentration of glioma-derived vesicles and EV marker, CD63. Further, iTRAQ-based LC-MS/MS analysis of EV protein was performed to determine the differential protein abundance in extracellular vesicles across different glioma grades. We further verified galectin-3 binding protein (LGALS3BP) by ELISA in individual blood plasma and plasma-derived vesicles from control and glioma patients (n=40 each). Analysis by Max Quant identified 123 proteins from the pooled patient exosomes, out of which 34, 21, and 14 proteins were found to be differentially abundant by more than 1.3-fold in the different grades of glioma grade I, pilocytic astrocytoma; grade II, diffuse astrocytoma; grade III, anaplastic astrocytoma, respectively, in comparison with the control samples. A total of seven proteins—namely, CRP, SAA2, SERPINA3, SAA1, C4A, LV211, and KV112—showed differential abundance in all the three grades. LGALS3BP was seen to be upregulated across the different grades, and ELISA analysis from individual blood plasma and plasma-derived extracellular vesicles confirmed the increased expression of LGALS3BP in glioma patients (p<0.001). The present study provides LGALS3BP as a potential biomarker for early detection of glioma and improve survival outcome of the patient. The present study further provides the information of progression and monitoring the tumor grades (grade 1, grade II, grade III).

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Section: Circulating Extracellular Vesicle Proteins Distinguish Patients With Glioma From Healthy Controlsmentioning

confidence: 99%

Plasma-Derived Extracellular Vesicles Reveal Galectin-3 Binding Protein as Potential Biomarker for Early Detection of Glioma

et al. 2021

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“…Wu et al reported that miRNA-181 could inhibit the proliferation of OA chondrocytes and induce apoptosis by targeting phosphatase and tensin homolog (PTEN) [ 44 ]. As a member of the Src kinase family, FRK is involved in the progression of liver cancer, pancreatic cancer and breast cancer [ 27 , 45 ]. In this study, there was a potential target binding site of miR-663a in FRK predicted by biological information software TargetScan.…”

Section: Discussionmentioning

confidence: 99%

“…Fyn-related kinase (FRK) is a member of the Src kinase family and plays a role in promoting or inhibiting tumor growth in different types of tumors [ 24 ]. Studies have shown that FRK can promote the invasion of liver cancer and pancreatic cancer cells, and inhibit the metastasis of breast cancer and glioma cells [ 25 – 27 ]. However, there are no studies on the mechanism of miRNA-663a and FRK in the occurrence and development of OA.…”

Section: Introductionmentioning

confidence: 99%

LncRNA HOTTIP leads to osteoarthritis progression via regulating miR-663a/ Fyn-related kinase axis

Gao²,

Lu³

et al. 2021

BMC Musculoskelet Disord

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Background Long non-coding RNA (lncRNA) has been implicated in the progression of osteoarthritis (OA). This study was aimed to explore the role and molecular mechanism of lncRNA HOXA terminal transcriptional RNA (HOTTIP) in the development of OA. Methods The expression of HOTTIP, miR-663a and Fyn-related kinase (FRK) in the OA articular cartilage and OA chondrocyte model induced by IL-1β was determined by qRT-PCR. CCK-8, colony formation and flow cytometry were used to determine the cell proliferation and apoptosis of OA chondrocytes. The specific molecular mechanism of HOTTIP in OA chondrocytes was determined by dual luciferase reporter assay, qRT-PCR, western blotting and RNA pull-down. Results The expression of HOTTIP and FRK were up-regulated, while miR-663a was down-regulated in OA cartilage tissues. Knockdown of HOTTIP decreased the proliferation and induced the apoptosis of OA cartilage model cells, while overexpression of HOTTIP increased the proliferation and reduced the apoptosis of OA cartilage model cells. Moreover, HOTTIP could bind to miR-663a as competitive endogenous RNA. Inhibition of miR-663a expression could alleviate the effect of HOTTIP knockdown on the proliferation and apoptosis of OA cartilage model cells. Furthermore, FRK was found to be a direct target of miR-663a, which could markedly down-regulate the expression of FRK in OA chondrocytes, while HOTTIP could remarkably up-regulate the expression of FRK. In addition, miR-663a inhibition increased the proliferation and reduced the apoptosis of OA cells, while FRK knockdown reversed the effect of miR-663a inhibition on the proliferation and apoptosis of OA cells. Meanwhile, overexpression of miR-663a decreased the proliferation and induced the apoptosis of OA cells, while overexpression of FRK reversed the effect of miR-663a overexpression on the proliferation and apoptosis of OA cells. Conclusion HOTTIP was involved in the proliferation and apoptosis of OA chondrocytes via miR-663a/ FRK axis, and HOTTIP/miR-663a/FRK might be a potential target for the treatment of OA.

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“…While there is still controversy concerning the actual role of STAT1 in carcinogenesis, the majority of studies recognize STAT1 as a tumor suppressor. For instance, activation of STAT1 was reported to suppress the proliferation of glioma cells [ 35 ]. A more convincing evidence is that STAT1 knockout mice are highly susceptible to some tumours [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

An insertion variant of MGMT disrupts a STAT1 binding site and confers susceptibility to glioma

Huang

Yan

et al. 2021

Cancer Cell Int

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Background O6-methylguanine-DNA methyltransferase (MGMT) is a pivotal enzyme for repairing DNA alkylation damage. Epigenetic modification of MGMT has been well known as a promising prognostic biomarker for glioma. However, the significance of genetic variations of MGMT in glioma carcinogenesis has not been fully elucidated. Methods The associations between expression quantitative trait loci (eQTLs) of MGMT and glioma susceptibility were evaluated in a case–control study of 1056 individuals. The function of susceptibility locus for glioma was explored with a set of biochemical assays, including luciferase reporter gene, EMSA and supershift EMSA, ChIP, and siRNA knockdown. Results We found that rs11016798 TT genotype was associated with a significantly decreased risk of glioma (OR = 0.57, 95% CI 0.39–0.85; P = 0.006). Stratification analyses indicated that the association between rs11016798 and glioma was more pronounced in males (OR = 0.62, 95% CI 0.40–0.97; P = 0.035), older subjects (OR = 0.46, 95% CI 0.27–0.80; P = 0.006), WHO grade IV glioma (OR = 0.58, 95% CI 0.35–0.96; P = 0.033), and IDH wildtype glioma (OR = 0.43, 95% CI 0.21–0.88; P = 0.022). We characterized an insertion variant rs10659396 in the upstream of MGMT as a causative variant. The risk allele rs10659396 ins allele was demonstrated to downregulate MGMT expression by disrupting a STAT1 binding site. Knockdown of STAT1 remarkably attenuated MGMT expression. Moreover, the rs10659396 allele-specific positive correlation was observed between the expression of STAT1 and MGMT in population. Conclusions The study demonstrates that an insertion variant of MGMT rs10659396 confers susceptibility to glioma by downregulating MGMT expression through disrupting a STAT1 binding site. Graphic abstract

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Activation of STAT1 by the FRK tyrosine kinase is associated with human glioma growth

Cited by 10 publications

References 48 publications

Plasma-Derived Extracellular Vesicles Reveal Galectin-3 Binding Protein as Potential Biomarker for Early Detection of Glioma

Plasma-Derived Extracellular Vesicles Reveal Galectin-3 Binding Protein as Potential Biomarker for Early Detection of Glioma

LncRNA HOTTIP leads to osteoarthritis progression via regulating miR-663a/ Fyn-related kinase axis

An insertion variant of MGMT disrupts a STAT1 binding site and confers susceptibility to glioma

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