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<i>FLI1</i> enhances the malignant phenotype of glioma cells and exerts immunomodulatory effects through feedback crosstalk with exonic circRNA <i>FECR1</i> and interferon‑induced <i>ISG15</i>.

Overview

Authors: Xue Wen1, Xiaoyi Gu1, Xu Yan1, Naifei Chen1, Lei Zhou1, Hui Li1, Andrew R. Hoffman2, Wei Li1, Ji-Fan Hu1,2, Jiuwei Cui1
  1. Cancer Center, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
  2. Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
Institutions: First Hospital of Jilin University (China); Stanford Medicine (United States); Stanford University (United States)
Journal: International journal of molecular medicine, volume 58, issue 3, article 241
Dates: received 21 January 2026; accepted 5 June 2026; published online 1 July 2026; in print September 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.3892/ijmm.2026.5912 · PMID 42396652 · PMCID PMC13354330 · OpenAlex W7166804838
Open access: hybrid, a free copy (OpenAlex)
Status: data only
Categories: human (organism), other condition (population), cellular / molecular (subfield)
Methods: Statistics
Keywords: FLI-1, ISG15, glioma, epigenetics, immunoregulatory, feedback circuitry
MeSH: Brain Neoplasms*, Cytokines*, Glioma*, Interferons*, Proto-Oncogene Protein c-fli-1*, RNA, Circular*, Ubiquitins*, Animals, Cell Line, Tumor, Feedback, Physiological, Gene Expression Regulation, Neoplastic, Humans, Phenotype (* major topic)
Topic: Circular RNAs in diseases (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: National Natural Science Foundation of China (82301885, 82371872, 32000431, 81874052, 82203312); National Key R&D Program of China (2020YFA0707704, 2018YFA0106902); Innovative Program of National Natural Science Foundation of China (82050003); Fund of Jilin Provincial Science and Technology Department (YDZJ202301ZYTS003, 20200602032ZP, YDZJ202202CXJD004, 20210303002SF, 20200201390JC, 20200201593JC); Youth Fund of the First Hospital of Jilin University (JDYY102019043, JDYY14202303); Fund of Jilin Province Labor Resources and Social Security Department (2023RY03); Fund of Jilin Provincial Development and Reform Commission (2021C010); Fund of Changchun Science and Technology Bureau (21ZGY28); California Institute of Regenerative Medicine (CIRM) (RT2-01942)
Citations: not cited yet (Europe PMC); 71 references in the paper

Abstract

Gliomas comprise a group of common primary brain tumors with a high degree of malignancy and a poor prognosis. There are currently no targeted therapeutics for glioma in clinical practice. The present study revealed a novel crosstalk circuitry mechanism that contributes to the overexpression of Friend leukemia virus integration 1 (FLI1) in glioma. FLI1, a member of the ETS transcription factor family, was upregulated in glioma and its expression was associated with malignant phenotype and poor prognosis of the disease. Notably, aberrant FLI1 expression in glioma was regulated by its exonic circRNA FECR1 through a positive feedback mechanism. FLI1 knockdown suppresses tumor phenotypes of glioma cells. Using RNA-seq and Co-IP assays, the present study identified interferon-stimulated gene 15 (ISG15), a paracrine factor known to reprogram the tumor immunosuppressive microenvironment, as a new molecular target of FLI1 in glioma. FLI1 coordinated with ISG15 to suppress immune function, including the secretion of the cytokines perforin, IFN-γ, TNF-α and IL2 from T cells, as well as perforin from γδ T cells. Mechanistically, FLI1 bound to the ISG15 promoter regulatory elements, where it activates the ISG15 gene by orchestrating an active intrachromosomal spatial loop with characteristic DNA hypomethylation and histone H3K9 and H3K27 acetylation. As a downstream target, ISG15 also participated in a positive feedback loop with FLI1 by enhancing its stability from ubiquitination-induced degradation. Thus, targeting this FLI1-ISG15 feedback circuitry may provide a novel strategy to develop therapeutics for gliomas.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

Availability of data and materials

The data generated in the present study may be requested from the corresponding author. RNA-seq data generated in the present study have been deposited in NIH GEO databases under accession number of GSE316716 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE316716). The data of LC-MS/MS have been deposited in the OMIX, China National Center for Bioinformation / Beijing Institute of Genomics, Chinese Academy of Sciences with the accession no. OMIX016920 (https://ngdc.cncb.ac.cn/omix/release/OMIX016920) (70,71).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 6 keywords, 13 MeSH terms, 9 funders, 69 references.

Cite

This paper

Wen, X., Gu, X., Yan, X., Chen, N., Zhou, L., Li, H., Hoffman, A. R., Li, W., Hu, J.-F., & Cui, J. (2026). <i>FLI1</i> enhances the malignant phenotype of glioma cells and exerts immunomodulatory effects through feedback crosstalk with exonic circRNA <i>FECR1</i> and interferon‑induced <i>ISG15</i>. International journal of molecular medicine, 58(3), 241. https://doi.org/10.3892/ijmm.2026.5912

BibTeX

@article{wen2026lt,
author = {Wen, Xue and Gu, Xiaoyi and Yan, Xu and Chen, Naifei and Zhou, Lei and Li, Hui and Hoffman, Andrew R. and Li, Wei and Hu, Ji-Fan and Cui, Jiuwei},
title = {{\<i\>FLI1\</i\> enhances the malignant phenotype of glioma cells and exerts immunomodulatory effects through feedback crosstalk with exonic circRNA \<i\>FECR1\</i\> and interferon‑induced \<i\>ISG15\</i\>}},
journal = {International journal of molecular medicine},
year = {2026},
month = jul,
volume = {58},
number = {3},
pages = {241},
publisher = {Spandidos Publications},
issn = {1107-3756},
doi = {10.3892/ijmm.2026.5912},
url = {https://doi.org/10.3892/ijmm.2026.5912},
pmid = {42396652},
pmcid = {PMC13354330}
}

RIS

TY - JOUR
AU - Wen, Xue
AU - Gu, Xiaoyi
AU - Yan, Xu
AU - Chen, Naifei
AU - Zhou, Lei
AU - Li, Hui
AU - Hoffman, Andrew R.
AU - Li, Wei
AU - Hu, Ji-Fan
AU - Cui, Jiuwei
TI - <i>FLI1</i> enhances the malignant phenotype of glioma cells and exerts immunomodulatory effects through feedback crosstalk with exonic circRNA <i>FECR1</i> and interferon‑induced <i>ISG15</i>
T2 - International journal of molecular medicine
J2 - Int J Mol Med
PY - 2026
DA - 2026/07/03
VL - 58
IS - 3
SP - 241
SN - 1107-3756
PB - Spandidos Publications
DO - 10.3892/ijmm.2026.5912
UR - https://doi.org/10.3892/ijmm.2026.5912
LA - en
ER -

CSL-JSON

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