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<p>Lung adenocarcinoma (LUAD) is an exceptionally aggressive malignancy characterized by high mortality rates. Neutrophils fulfill dual roles in cancer, demonstrating the capacity to both inhibit and facilitate tumor development. This study aimed to delineate the functional contributions and mechanistic underpinnings of Homo sapiens circular RNA 0000376 (hsa_circ_0000376) in LUAD progression and neutrophil polarization. Quantitative real-time polymerase chain reaction (RT-qPCR) was utilized to determine the expression levels of hsa_circ_0000376 in LUAD clinical specimens and established cell lines. A comprehensive set of experimental techniques was applied to evaluate its influence on LUAD cellular phenotypes: the Cell Counting Kit-8 (CCK-8) assay for assessing proliferation, colony formation assay for clonogenic potential, flow cytometry for detecting apoptosis, the scratch wound assay for evaluating migration, and the Transwell assay for quantifying invasive capacity. Flow cytometric analysis was additionally employed to measure neutrophil polarization towards the N1 (inducible nitric oxide synthase [iNOS]<sup>+</sup>/CD16b<sup>+</sup>) and N2 (Arginase-1 [Arg1]<sup>+</sup>/CD16b<sup>+</sup>) subtypes. Bioinformatics analyses combined with RNA immunoprecipitation (RIP) assays were performed to validate molecular interactions involving insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), hsa_circ_0000376, and solute carrier family 2 member 1 (SLC2A1). The expression of hsa_circ_0000376 was found to be significantly upregulated in both LUAD tissues and cultured cell lines. Genetic silencing of hsa_circ_0000376 effectively impeded cellular proliferation, migration, and invasion while simultaneously promoting apoptotic cell death in LUAD cells. Moreover, conditioned medium collected from hsa_circ_0000376-depleted LUAD cells stimulated a shift towards N1 polarization and concurrently restrained N2 polarization in treated neutrophils. Mechanistically, hsa_circ_0000376 was demonstrated to physically interact with IGF2BP3, leading to enhanced stability of SLC2A1 mRNA. Exogenous overexpression of SLC2A1 successfully reversed the phenotypic consequences arising from hsa_circ_0000376 knockdown. These collective findings illustrate that hsa_circ_0000376 accelerates malignant progression and promotes neutrophil N2 polarization in LUAD by associating with IGF2BP3 to form a complex that stabilizes SLC2A1 mRNA.</p>

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The IGF2BP3/SLC2A1 axis mediates hsa_circ_0000376-Induced malignant progression and neutrophil N2 polarization in the lung adenocarcinoma microenvironment

  • 期刊论文

  • 发表日期：

    2026年2月23日

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  • ZhiBin Lu,
  • Yi Chen,
  • ZhiChao Xiao,
  • SiDong He,
  • YinPing Huo,
  • Hui Sun,
  • Qiang Cai

摘要

Lung adenocarcinoma (LUAD) is an exceptionally aggressive malignancy characterized by high mortality rates. Neutrophils fulfill dual roles in cancer, demonstrating the capacity to both inhibit and facilitate tumor development. This study aimed to delineate the functional contributions and mechanistic underpinnings of Homo sapiens circular RNA 0000376 (hsa_circ_0000376) in LUAD progression and neutrophil polarization. Quantitative real-time polymerase chain reaction (RT-qPCR) was utilized to determine the expression levels of hsa_circ_0000376 in LUAD clinical specimens and established cell lines. A comprehensive set of experimental techniques was applied to evaluate its influence on LUAD cellular phenotypes: the Cell Counting Kit-8 (CCK-8) assay for assessing proliferation, colony formation assay for clonogenic potential, flow cytometry for detecting apoptosis, the scratch wound assay for evaluating migration, and the Transwell assay for quantifying invasive capacity. Flow cytometric analysis was additionally employed to measure neutrophil polarization towards the N1 (inducible nitric oxide synthase [iNOS]+/CD16b+) and N2 (Arginase-1 [Arg1]+/CD16b+) subtypes. Bioinformatics analyses combined with RNA immunoprecipitation (RIP) assays were performed to validate molecular interactions involving insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), hsa_circ_0000376, and solute carrier family 2 member 1 (SLC2A1). The expression of hsa_circ_0000376 was found to be significantly upregulated in both LUAD tissues and cultured cell lines. Genetic silencing of hsa_circ_0000376 effectively impeded cellular proliferation, migration, and invasion while simultaneously promoting apoptotic cell death in LUAD cells. Moreover, conditioned medium collected from hsa_circ_0000376-depleted LUAD cells stimulated a shift towards N1 polarization and concurrently restrained N2 polarization in treated neutrophils. Mechanistically, hsa_circ_0000376 was demonstrated to physically interact with IGF2BP3, leading to enhanced stability of SLC2A1 mRNA. Exogenous overexpression of SLC2A1 successfully reversed the phenotypic consequences arising from hsa_circ_0000376 knockdown. These collective findings illustrate that hsa_circ_0000376 accelerates malignant progression and promotes neutrophil N2 polarization in LUAD by associating with IGF2BP3 to form a complex that stabilizes SLC2A1 mRNA.