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TNFAIP3 Overexpression Inhibits Diffuse Large B-Cell Lymphoma Progression by Promoting Autophagy through

Fangying Ning^1,2, Huafang Wang², Zuyu Liang²

¹Suzhou Medical College of Soochow University, 215006 Suzhou, Jiangsu, China.

Discovery Medicine

|August 27, 2024

Abstract

Background:

Tumor necrosis factor alpha induced protein 3 (TNFAIP3) is reportedly to have significant implications for autophagy regulation in various cancers. The current study aimed to decipher the role and mechanism of TNFAIP3 in diffuse large B-cell lymphoma (DLBCL) by modulating autophagy.

Methods:

Information pertaining to the differential expression and prognostic role of TNFAIP3 in DLBCL was gleaned from the Gene Expression Omnibus (GEO) database. The TNFAIP3 expression levels in human DLBCL cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Cell counting kit-8 (CCK-8) and colony formation assays were employed to determine cell proliferation. Transwell assay and flow cytometry were applied to detect cell migration and apoptosis, respectively. Immunofluorescence and transmission electron microscope were used for the assessment of cell autophagy. The levels of apoptotic markers (caspase-3, cleaved-caspase-3, Bcl-2 Associated X (Bax), and B cell lymphoma-2 (Bcl-2)), autophagy indicators (the ratio of microtubule-associated proteins 1A/1B light chain 3 II and I (LC3II/LC3I), Sequestosome (p62)), and pathway proteins (toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), Transcription Factor NF-Kappa-B P65 Subunit (p65), and phosphorylated-p65 (p-p65)) were assessed via Western blotting. Immunohistochemistry was employed to detect Ki67 expression in tumor tissues.

Results:

TNFAIP3 expression in DLBCL samples was downregulated, correlating with poor prognosis. TNFAIP3 expression was also downregulated in DLBCL cells. It was found that TNFAIP3 impeded cell proliferation and migration, and enhanced apoptosis of OCI-LY3 cells. Intervention with autophagy inhibitor 3-methyladenine (3-MA) markedly reversed apoptosis of OCI-LY3 cells induced by TNFAIP3. Besides, TNFAIP3 induced autophagy via modulating the TLR4/MyD88/nuclear factor kappa B (NF-κB) signaling pathway. In vivo experiments showed that TNFAIP3 expression in DLBCL was downregulated, and upregulation of TNFAIP3 could inhibit tumor growth.

Conclusion:

TNFAIP3 inhibits DLBCL progression by inducing TLR4/MyD88/NF-κB pathway-mediated autophagy.

Insights

Tumor necrosis factor alpha induced protein 3 (TNFAIP3) inhibits diffuse large B-cell lymphoma (DLBCL) progression by inducing autophagy. This TNFAIP3-mediated autophagy suppresses tumor growth and enhances apoptosis in DLBCL cells.

Area of Science:

Oncology
Cell Biology
Immunology

Background:

Tumor necrosis factor alpha induced protein 3 (TNFAIP3) plays a role in autophagy regulation across various cancers.
Its specific function in diffuse large B-cell lymphoma (DLBCL) requires further elucidation.

Purpose of the Study:

To investigate the role and mechanism of TNFAIP3 in DLBCL.
To determine if TNFAIP3 modulates autophagy in DLBCL progression.

Main Methods:

Utilized Gene Expression Omnibus (GEO) database for differential expression and prognostic analysis of TNFAIP3 in DLBCL.
Employed qRT-PCR, Western blotting, CCK-8, colony formation, Transwell, and flow cytometry assays to assess TNFAIP3 expression, proliferation, migration, and apoptosis.
Investigated autophagy using immunofluorescence, transmission electron microscopy, and Western blotting for key markers (LC3II/LC3I, p62).
Analyzed the TLR4/MyD88/NF-κB signaling pathway and Ki67 expression.

Main Results:

TNFAIP3 expression was found to be downregulated in DLBCL samples and cells, correlating with poor prognosis.
TNFAIP3 suppressed proliferation and migration while enhancing apoptosis in DLBCL cells (OCI-LY3).
TNFAIP3 induced autophagy via the TLR4/MyD88/NF-κB pathway, and its upregulation inhibited tumor growth in vivo.

Conclusions:

TNFAIP3 acts as a tumor suppressor in DLBCL.
The inhibitory effect of TNFAIP3 on DLBCL progression is mediated by inducing autophagy through the TLR4/MyD88/NF-κB signaling pathway.

Read full analysis

Keywords:

TLR4/MyD88/NF-κB autophagy diffuse large B-cell lymphoma

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