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circNOX4 activates an inflammatory fibroblast niche to promote tumor growth and metastasis in NSCLC via FAP/IL-6 axis

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机构： [1]Department of Tumor Immunotherapy, The Fourth Hospital of Hebei Medical University and Hebei Provincial Tumor Hospital, Shijiazhuang, 050035, China. [2]Department of Oncology, The Fourth Hospital of Hebei Medical University and Hebei Provincial Tumor Hospital, Shijiazhuang, 050011, China. [3]Department of Nuclear Medicine, The Fourth Hospital of Hebei Medical University and Hebei Provincial Tumor Hospital, Shijiazhuang, 050011, China. [4]Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University and Hebei Provincial Tumor Hospital, Shijiazhuang, 050011, China. [5]Departments of Oncology, The Affiliated Hospital of Chengde Medical University, Chengde, 067000, China. [6]Department of Nuclear Medicine, The Fourth Hospital of Hebei Medical University and Hebei Provincial Tumor Hospital, Shijiazhuang, 050011, China. [7]Hebei Provincial Key Laboratory of Tumor Microenvironment and Drug Resistance, Shijiazhuang, 050011, China. [8]Department of Tumor Immunotherapy, The Fourth Hospital of Hebei Medical University and Hebei Provincial Tumor Hospital, Shijiazhuang, 050035, China. [9]Cancer Research Institute of Hebei Province, Shijiazhuang, 050011, China. [10]International Cooperation Laboratory of Stem Cell Research, Hebei Medical University, Shijiazhuang, 050011, China.

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关键词： NSCLC CAFs circNOX4 FAP IL-6 Metastasis

摘要：

Cancer-associated fibroblasts (CAFs) orchestrate a supportive niche that fuels cancer metastatic development in non-small cell lung cancer (NSCLC). Due to the heterogeneity and plasticity of CAFs, manipulating the activated phenotype of fibroblasts is a promising strategy for cancer therapy. However, the underlying mechanisms of fibroblast activation and phenotype switching that drive metastasis remain elusive.The clinical implications of fibroblast activation protein (FAP)-positive CAFs (FAP+CAFs) were evaluated based on tumor specimens from NSCLC patients and bioinformatic analysis of online databases. CAF-specific circular RNAs (circRNAs) were screened by circRNA microarrays of primary human CAFs and matched normal fibroblasts (NFs). Survival analyses were performed to assess the prognostic value of circNOX4 in NSCLC clinical samples. The biological effects of circNOX4 were investigated by gain- and loss-of-function experiments in vitro and in vivo. Fluorescence in situ hybridization, luciferase reporter assays, RNA immunoprecipitation, and miRNA rescue experiments were conducted to elucidate the underlying mechanisms of fibroblast activation. Cytokine antibody array, transwell coculture system, and enzyme-linked immunosorbent assay (ELISA) were performed to investigate the downstream effectors that promote cancer metastasis.FAP+CAFs were significantly enriched in metastatic cancer samples, and their higher abundance was correlated with the worse overall survival in NSCLC patients. A novel CAF-specific circRNA, circNOX4 (hsa_circ_0023988), evoked the phenotypic transition from NFs into CAFs and promoted the migration and invasion of NSCLC in vitro and in vivo. Clinically, circNOX4 correlated with the poor prognosis of advanced NSCLC patients. Mechanistically, circNOX4 upregulated FAP by sponging miR-329-5p, which led to fibroblast activation. Furthermore, the circNOX4/miR-329-5p/FAP axis activated an inflammatory fibroblast niche by preferentially inducing interleukin-6 (IL-6) and eventually promoting NSCLC progression. Disruption of the intercellular circNOX4/IL-6 axis significantly suppressed tumor growth and metastatic colonization in vivo.Our study reveals a role of the circRNA-induced fibroblast niche in tumor metastasis and highlights that targeting the circNOX4/FAP/IL-6 axis is a promising strategy for the intervention of NSCLC metastasis.© 2024. The Author(s).

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中科院分区：

出版当年[2025]版：

大类 | 1 区

医学

小类 | 1 区生化与分子生物学 1 区肿瘤学

最新[2025]版：

大类 | 1 区

医学

小类 | 1 区生化与分子生物学 1 区肿瘤学

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出版当年[2024]版：

Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Q1 ONCOLOGY

最新[2024]版：

Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Q1 ONCOLOGY

影响因子： 33.9 最新[2024版] 35.9 最新五年平均 33.9 出版当年[2024版] 35.9 出版当年五年平均 27.7 出版前一年[2023版]

第一作者：

第一作者机构： [1]Department of Tumor Immunotherapy, The Fourth Hospital of Hebei Medical University and Hebei Provincial Tumor Hospital, Shijiazhuang, 050035, China. [2]Department of Oncology, The Fourth Hospital of Hebei Medical University and Hebei Provincial Tumor Hospital, Shijiazhuang, 050011, China.

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通讯作者：

通讯机构： [6]Department of Nuclear Medicine, The Fourth Hospital of Hebei Medical University and Hebei Provincial Tumor Hospital, Shijiazhuang, 050011, China. [7]Hebei Provincial Key Laboratory of Tumor Microenvironment and Drug Resistance, Shijiazhuang, 050011, China. [8]Department of Tumor Immunotherapy, The Fourth Hospital of Hebei Medical University and Hebei Provincial Tumor Hospital, Shijiazhuang, 050035, China. [9]Cancer Research Institute of Hebei Province, Shijiazhuang, 050011, China. [10]International Cooperation Laboratory of Stem Cell Research, Hebei Medical University, Shijiazhuang, 050011, China.

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circNOX4 activates an inflammatory fibroblast niche to promote tumor growth and metastasis in NSCLC via FAP/IL-6 axis

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