Overexpression of Fli-1 in astrocytoma is associated with poor prognosis

Tsai, Hung-Pei; Tsai, Tai-Hsin; Hsieh, Ya-Ju; Chen, Yi-Ting; Lee, Chih-Ling; Tsai, Yi-Cheng; She, Ting-Chang; Lin, Chih-Lung; Chai, Chee‐Yin; Kwan, Aij‐Lie

doi:10.18632/oncotarget.16303

Cited by 14 publications

(14 citation statements)

References 44 publications

(43 reference statements)

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“…Aberrant expression of FLI1 is associated with hematological malignancies and solid tumors [61–63]. Altered expression of FLI1 is also linked with tumor aggressiveness [63] and poor prognosis [64]. In our study, we have observed higher levels of FLI1 expression with the concomitant upregulation of CCL5 and the increased number of macrophages in human AIP pos tumors, supporting a crucial role for FLI1 and CCL5 in macrophage recruitment.…”

Section: Discussionsupporting

confidence: 75%

Tumor microenvironment defines the invasive phenotype of AIP-mutation-positive pituitary tumors

Barry

Carlsen²,

Marques

et al. 2019

Oncogene

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The molecular mechanisms leading to aryl hydrocarbon receptor interacting protein (AIP) mutation-induced aggressive, young-onset growth hormone-secreting pituitary tumors are not fully understood. In this study, we have identified that AIP-mutation-positive tumors are infiltrated by a large number of macrophages compared to sporadic tumors. Tissue from pituitary-specific Aip-knockout (AipFlox/Flox;Hesx1Cre/+) mice recapitulated this phenotype. Our human pituitary tumor transcriptome data revealed the “epithelial-to-mesenchymal transition (EMT) pathway” as one of the most significantly altered pathways in AIPpos tumors. Our in vitro data suggest that bone marrow-derived macrophage-conditioned media induces more prominent EMT-like phenotype and enhanced migratory and invasive properties in Aip-knockdown somatomammotroph cells compared to non-targeting controls. We identified that tumor-derived cytokine CCL5 is upregulated in AIP-mutation-positive human adenomas. Aip-knockdown GH3 cell-conditioned media increases macrophage migration, which is inhibited by the CCL5/CCR5 antagonist maraviroc. Our results suggest that a crosstalk between the tumor and its microenvironment plays a key role in the invasive nature of AIP-mutation-positive tumors and the CCL5/CCR5 pathway is a novel potential therapeutic target.

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Section: Discussionsupporting

confidence: 75%

Tumor microenvironment defines the invasive phenotype of AIP-mutation-positive pituitary tumors

Barry

Carlsen²,

Marques

et al. 2019

Oncogene

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“…A reduction of FLI1 expression resulted in a reduction of h TERT , CCND1 and E2F2 transcript levels and less proliferation. Similar observations had already been made for CCND1 in astrocytoma . Strikingly, however, FLI1 knockdown in a normal lung cell line led to rapid progression through the cell cycle.…”

Section: Discussionsupporting

confidence: 84%

The transcription factor FLI1 promotes cancer progression by affecting cell cycle regulation

Miao

Bauer

Hufnagel

et al. 2020

Intl Journal of Cancer

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Binding of transcription factors to mutated DNA sequences is a likely regulator of cancer progression. Noncoding regulatory mutations such as those on the core promoter of the gene encoding human telomerase reverse transcriptase have been shown to affect gene expression in cancer. Using a protein microarray of 667 transcription factor DNA-binding domains and subsequent functional assays, we looked for transcription factors that preferentially bind the mutant hTERT promoter and characterized their downstream effects. One of them, friend leukemia integration 1 (FLI1), which belongs to the E26 transforming-specific family of transcription factors, exhibited particularly strong effects with respect to regulating hTERT expression, while the even better binding ELK3 did not. Depletion of FLI1 decreased expression of the genes for cyclin D1 (CCND1) and E2F transcription factor 2 (E2F2) resulting in a G1/S cell cycle arrest and in consequence a reduction of cell proliferation. FLI1 also affected CMTM7, another gene involved in G1/S transition, although by another process that suggests a balanced regulation of the tumor suppressor gene's activity via opposing regulation processes. FLI1 expression was found upregulated and correlated with an increase in CCND1 expression in pancreatic cancer and brain tumors. In non-neoplastic lung cells, however, FLI1 depletion led to rapid progression through the cell cycle. This coincides with the fact that FLI1 is downregulated in lung tumors. Taken together, our data indicate a cell cycle regulatory hub involving FLI1, hTERT, CCND1 and E2F2 in a tissue-and context-dependent manner. J.D.H. and S.L. contributed equally to this work Additional Supporting Information may be found in the online version of this article.

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“…As a member of the ETS transcription factor family, FLI1 was known to regulate the expression of oncogenes, tumour suppressor genes, and some genes involved in maintaining vascular homoeostasis such as VE-cadherin, platelet endothelial cell adhesion molecule 1. 26,28,45 In GECs, we found that FLI1 was highly expressed and knockdown of FLI1 downregulated claudin-5, occludin and ZO-1 expression, which increased BTB permeability. Similarly, knockdown of FLI1 and ETS-related gene, its closest homolog, increased human pulmonary endothelial cell monolayer permeability with capacity like that of vascular endothelial growth factor.…”

Section: Combined Treatment Of Circ-usp1 and Mir-194-5p Promoted Domentioning

confidence: 87%

“…23 In human tissues, FLI1 is abnormally expressed in some solid tumours, including Ewing sarcoma, breast cancer and astrocytoma. [24][25][26] In endothelial cells, FLI1 is a regulator of vessel maturation and stabilization via modulating expressions of genes involved in maintaining vascular homoeostasis and integrity. 27,28 However, a little attention has been directed to clarify the possible role of FLI1 in GECs and BTB permeability.…”

mentioning

confidence: 99%

Circular RNA USP1 regulates the permeability of blood‐tumour barrier via miR‐194‐5p/FLI1 axis

Gao

et al. 2019

J Cellular Molecular Medi

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Recent studies indicate circular RNAs are related to dysregulation of vascular endothelial cell function, yet the underlying mechanisms have remained elusive. Here, we characterized the functional role of circular RNA USP1 (circ‐USP1) in the regulation of the blood‐tumour barrier (BTB) permeability and the potential mechanisms. In the current study, the circ‐USP1 expressing level was up‐regulated in glioma cerebral microvascular endothelial cells (GECs) of the BTB model in vitro. Knockdown of circ‐USP1 disrupted the barrier integrity, increased its permeability as well as reduced tight junction‐related protein claudin‐5, occludin and ZO‐1 expressions in GECs. Bioinformatic prediction and luciferase assay indicated that circ‐USP1 bound to miR‐194‐5p and suppressed its activity. MiR‐194‐5p contributed to circ‐USP1 knockdown‐induced increase of BTB permeability via targeting and down‐regulating transcription factor FLI1. Furthermore, FLI1 regulated the expressions of claudin‐5, occludin and ZO‐1 in GECs through binding to their promoter regions. Single or combined treatment of circ‐USP1 and miR‐194‐5p effectively promoted anti‐tumour drug doxorubicin across BTB to induce apoptosis of glioma cells. Overall, this present study identified the crucial regulation of circ‐USP1 on BTB permeability via miR‐194‐5p/FLI1 axis‐mediated regulation of tight junction proteins, which might facilitate the development of therapeutics against human gliomas.

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Overexpression of Fli-1 in astrocytoma is associated with poor prognosis

Cited by 14 publications

References 44 publications

Tumor microenvironment defines the invasive phenotype of AIP-mutation-positive pituitary tumors

Tumor microenvironment defines the invasive phenotype of AIP-mutation-positive pituitary tumors

The transcription factor FLI1 promotes cancer progression by affecting cell cycle regulation

Circular RNA USP1 regulates the permeability of blood‐tumour barrier via miR‐194‐5p/FLI1 axis

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