口腔白斑病癌变过程中缺氧对巨噬细胞极化的影响

doi:10.19439/j.sjos.2026.03.005

上海口腔医学 ›› 2026, Vol. 35 ›› Issue (3): 252-257.doi: 10.19439/j.sjos.2026.03.005

口腔白斑病癌变过程中缺氧对巨噬细胞极化的影响

赵晓娴^1,2, 张春叶^2,3, 赵峥岩^1,3, 张颖^1,3, 吴岚^1,3

1.上海交通大学医学院附属第九人民医院口腔黏膜病科, 2.口腔病理科; 3.上海交通大学口腔医学院,国家口腔医学中心,口腔疾病国家临床医学研究中心,上海市口腔医学重点实验室,上海市口腔医学研究所,上海 200011

收稿日期:2025-03-03 修回日期:2025-05-12 发布日期:2026-07-02
通讯作者: 吴岚,E-mail: teana_wu@sina.com
作者简介:赵晓娴（1999—）,女,硕士研究生,E-mail: zhaoxiaoxian1999@163.com
基金资助:
上海市科委基金 (21S21902000); 上海市卫健委、上海市中医药管理局重大疑难疾病中西医协同诊疗示范项目 [ZY (2021-2023)-0207-01-04]; 上海市卫健委中医药科研项目 (2022CX009); 上海交通大学医学院附属第九人民医院交叉基金 (JYJC202111)

Research on hypoxia-mediated macrophage polarization during the carcinogenesis of oral leukoplakia

Zhao Xiaoxian^1,3, Zhang Chunye^2,3, Zhao Zhengyan^1,3, Zhang Ying^1,3, Wu Lan^1,3

1. Department of Oral Mucosal Diseases, 2. Department of Oral Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; 3. College of Stomatology, Shanghai Jiao Tong University, Shanghai Key Laboratory of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Research Institution of Stomatology. Shanghai 200011, China

Received:2025-03-03 Revised:2025-05-12 Published:2026-07-02

摘要/Abstract

摘要： 目的: 探讨口腔白斑病（oral leukoplakia, OLK）癌变过程中,缺氧诱导因子1α（hypoxia-inducible factors-1α, HIF-1α）表达变化及其对免疫微环境中巨噬细胞极化的影响。方法: 采用多重免疫荧光检测技术,回顾性分析25例不同异常增生程度的OLK及正常黏膜组织样本中HIF-1α、诱导型一氧化氮合酶（inducible nitric oxide synthase,iNOS）及CD206的表达水平。体外构建缺氧的人口腔白斑细胞与Raw 264.7细胞共培养模型,分析不同缺氧程度下巨噬细胞HIF-1α、iNOS及CD206表达水平的变化;抑制HIF-1α表达后,进一步验证结果。结果: 在 25 例OLK及正常黏膜组织样本中,iNOS⁺细胞在轻度异常增生时增多,重度及口腔鳞癌阶段显著下降;CD206⁺和 HIF-1α⁺细胞随OLK进展持续上升。巨噬细胞极化在轻-中度异常增生以M1为主[CD206/iNOS 为（0.68±0.22）~（0.69±0.41）],重度及 OSCC 阶段 M2 极化显著[（3.27±1.64）~（5.82±1.32）]。HIF-1α与CD206、iNOS及M2极化在疾病进展中相关性逐渐增强。体外实验表明,模拟缺氧条件下 HIF-1α与CD206、iNOS表达及M2极化呈正相关,抑制HIF-1α表达可显著降低 M2极化。结论: 在OLK癌变过程中,HIF-1α表达持续上调,驱动组织内巨噬细胞从促炎型M1极化向促瘤型M2极化转变。

Abstract: PURPOSE: To investigate the expression level of hypoxia-inducible factor-1α (HIF-1α) and its impact on macrophage polarization in the immune microenvironment during carcinogenesis of oral leukoplakia (OLK). METHODS: This study employed multiplex immunofluorescence to retrospectively analyze HIF-1α, inducible nitric oxide synthase (iNOS), and CD206 expression in 25 OLK and normal mucosal tissue samples. An in vitro co-culture system was conducted under hypoxic conditions with Leuk-1 and Raw 264.7 cells. Macrophage polarization dynamics were quantitatively assessed by detection of HIF-1α, iNOS, and CD206 expression levels. Subsequently, inhibitor of HIF-1α was used to validate its regulatory role. RESULTS: In a cohort of 25 OLK and normal mucosal tissue samples, iNOS⁺ cells demonstrated initial elevation during mild dysplasia but significantly decreased in severe dysplasia and oral squamous cell carcinoma (OSCC). Conversely, CD206⁺ and HIF-1α⁺ cells exhibited progressive accumulation throughout OLK malignant transformation. Macrophage polarization analysis revealed M1 polarization (CD206/iNOS ratio: 0.68±0.22 to 0.69±0.41) was presented in mild-to-moderate dysplasia, with marked M2 polarization emerging in advanced stages (3.27±1.64 to 5.82±1.32). Correlation analyses identified progressively strengthened associations between HIF-1α and CD206, iNOS, and M2 polarization during disease progression. In vitro experiments under hypoxic conditions confirmed positive correlations between HIF-1α expression and CD206/iNOS levels as well as M2 polarization, while HIF-1α inhibition significantly attenuated M2 polarization. These findings suggest hypoxia-mediated HIF-1α signaling may orchestrate macrophage phenotypic switching during oral carcinogenesis. CONCLUSIONS: During OLK malignant transformation, HIF-1α expression is progressively upregulated, driving the polarization shift of tissue macrophages from pro-inflammatory M1 to pro-tumorigenic M2 phenotypes.

Key words: Oral leukoplakia, Tumor-associated macrophages, Hypoxia-inducible factor-1α, Macrophage polarization, Hypoxic microenvironment

中图分类号:

R785.1

赵晓娴, 张春叶, 赵峥岩, 张颖, 吴岚. 口腔白斑病癌变过程中缺氧对巨噬细胞极化的影响[J]. 上海口腔医学, 2026, 35(3): 252-257.

Zhao Xiaoxian, Zhang Chunye, Zhao Zhengyan, Zhang Ying, Wu Lan. Research on hypoxia-mediated macrophage polarization during the carcinogenesis of oral leukoplakia[J]. Shanghai Journal of Stomatology, 2026, 35(3): 252-257.

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口腔白斑病癌变过程中缺氧对巨噬细胞极化的影响

Research on hypoxia-mediated macrophage polarization during the carcinogenesis of oral leukoplakia

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