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. 2025 Mar;132(4):340-353.
doi: 10.1038/s41416-024-02923-0. Epub 2025 Jan 11.

Sodium nitrite orchestrates macrophage mimicry of tongue squamous carcinoma cells to drive lymphatic metastasis

Xiangwan Lu  1 , Weifan Lin  1 , Junheng Zheng  1 , Wuheng Huang  1 , Shuyi Yu  1 , Haoxiang Chen  1 , Hua Wang  2 , Yan Zhang  3
Affiliations

Sodium nitrite orchestrates macrophage mimicry of tongue squamous carcinoma cells to drive lymphatic metastasis

Xiangwan Lu et al. Br J Cancer. 2025 Mar.

Abstract

Background: Tongue squamous cell carcinoma (TSCC) is a malignant oral cancer with unclear pathogenesis that shows a tendency for early-stage lymphatic metastasis. This results in a poor prognosis, with a low 5-year survival rate. Dietary sodium nitrite (NaNO2) has proposed associations with disease, including cancer. However, a direct relationship between NaNO2 and TSCC has not been established.

Methods: In vitro and in vivo assays were used to investigate the role of NaNO2 in TSCC. Protein expression in TSCC specimens was detected by immunohistochemistry and immunofluorescence. The molecular mechanism was determined using RT-qPCR, western blot, RNA-seq, luciferase reporter assays, migration assays, and FACS analysis. More detail of methods can be found in the Materials and methods section.

Results: The data in this study showed that NaNO2 did not initiate carcinogenesis in the tongue but improved the lymphatic metastatic potential of TSCC cells in the specified experimental period. During metastasis to lymph nodes, monocyte-macrophage markers were upregulated in TSCC cells, whereas keratin markers were downregulated. Specifically, expression of the CD68 gene was high in TSCC cells following NaNO2-induced TSCC phenotypic switching. These phenotypic changes were associated with activation of transcription factor cyclic-AMP response binding protein (CREB1), which directly targets CD68 transcription. Furthermore, blocking CREB1 activity either through gene knockout or specific inhibitor treatment decreased the migration ability of TSCC cells and suppressed CD68 expression.

Conclusions: Our findings highlight the role of NaNO2 in enabling macrophage mimicry in TSCC cells through the CREB1-CD68 signaling pathway, which promotes lymphatic metastasis. Shedding light on drivers of lymphatic metastasis in TSCC and providing a new perspective on dietary strategies to improve outcomes of patients with TSCC.

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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethics approval and consent to participate:: The human specimen collection in this study was followed the protocol approved by the ethics committee of Guanghua Hospital, Sun Yat-sen University (approval No. 2010-9), and written informed consent was obtained from the patient in accordance with ethical guidelines. All animal experimental protocols were performed following by the Animal Ethics Committee of Sun Yat-sen University (approval No. 2022002118).

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