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Molecular mechanisms of transcription factor KLF4-mediated immune infiltration influencing lung adenocarcinoma
Kaining Jia1, Yiwen Na2, Qiang Lin2
1Clinical Trials Center, Huabei Petroleum Administration Bureau General Hospital, 062550, Hebei, China.
Background:
Lung adenocarcinoma (LUAD) is associated with an increasing incidence and mortality rate while existing treatment strategies continue to exhibit considerable limitation. Studies have demonstrated that upregulation of KLF4 gene inhibits LUAD progression, but its underlying mechanisms remain elusive. The present research explored roles and mechanisms of KLF4 and the NF-κB pathway in LUAD.
Methods:
Lentiviral vectors encoding KLF4 were constructed and transduced into H1299 and A549 cells to generate stable cell lines. These stable cell lines were then injected into BALB/c mice to establish a LUAD model. Subsequently, RNA sequencing, HE staining, immunohistochemistry, ELISA, Western blotting, and flow cytometry were employed to investigate the effects of KLF4 on tumor growth, invasion, immune cell infiltration, and related signaling pathways. Finally, dual-luciferase and in vivo mouse experiments were conducted to validate the molecular mechanisms.
Results:
KLF4 significantly reduced tumor cell invasion while promoted tumor cell necrosis. Transcriptomic sequencing identified CXCR2 as a target gene and the NF-κB signaling pathway associated with immune infiltration regulation. KLF4 downregulated NF-κB2 and CXCR2 expression, concomitantly decreasing tumor cell invasiveness but increasing levels of CD4+ and CD8+ T cells and macrophages.
Conclusion:
NF-κB and CXCR2 play an important role in KLF4-mediated immune infiltration, thereby inhibiting tumor invasion and promoting tumor cell apoptosis in mice.
Insights
The Kruppel-like factor 4 (KLF4) gene inhibits lung adenocarcinoma (LUAD) progression by downregulating NF-κB and CXCR2. This mechanism enhances anti-tumor immune cell infiltration, reducing tumor invasion and promoting apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Lung adenocarcinoma (LUAD) presents a growing health challenge with limited treatment options.
- The tumor-suppressive role of Kruppel-like factor 4 (KLF4) in LUAD is recognized, yet its precise mechanisms require elucidation.
- This study investigates the interplay between KLF4, the NF-κB pathway, and immune responses in LUAD.
Purpose of the Study:
- To explore the functional roles of KLF4 in LUAD progression.
- To elucidate the molecular mechanisms underlying KLF4's effects, focusing on the NF-κB pathway and immune infiltration.
- To validate the therapeutic potential of KLF4 in a LUAD mouse model.
Main Methods:
- Generation of stable LUAD cell lines overexpressing KLF4 using lentiviral vectors.
- Establishment of a LUAD mouse model via xenotransplantation of engineered cells.
- Comprehensive analysis using RNA sequencing, immunohistochemistry, ELISA, Western blotting, and flow cytometry.
Main Results:
- KLF4 overexpression significantly reduced tumor invasion and increased tumor cell necrosis.
- Transcriptomic analysis identified CXCR2 as a downstream target gene regulated by KLF4.
- KLF4 downregulated NF-κB2 and CXCR2, leading to decreased tumor invasiveness and enhanced infiltration of CD4+, CD8+ T cells, and macrophages.
Conclusions:
- The NF-κB signaling pathway and its target gene CXCR2 are critical mediators of KLF4's anti-tumor effects in LUAD.
- KLF4 promotes anti-tumor immunity by modulating the tumor microenvironment through the NF-κB/CXCR2 axis.
- Targeting KLF4 offers a promising strategy for inhibiting LUAD invasion and enhancing immune-mediated tumor suppression.
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