Yamaguchi Hana, Hiroi Miki, Mori Kazumasa, Ushio Ryosuke, Matsumoto Ari, Yamamoto Nobuharu, Shimada Jun, Ohmori Yoshihiro
Division of Microbiology and Immunology, Department of Oral Biology and Tissue Engineering, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado, Saitama 350-0283, Japan.
First Division of Oral and Maxillofacial Surgery, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado, Saitama 350-0283, Japan.
Cancers (Basel). 2021 Apr 12;13(8):1835. doi: 10.3390/cancers13081835.
Chemokines and cytokines in the tumor microenvironment influence immune cell infiltration and activation. To elucidate their role in immune cell recruitment during oral cancer development, we generated a mouse tongue cancer model using the carcinogen 4-nitroquinoline 1-oxide (4NQO) and investigated the carcinogenetic process and chemokine/cytokine gene expression kinetics in the mouse tongue. C57/BL6 mice were administered 4NQO in drinking water, after which tongues were dissected at 16 and 28 weeks and subjected to analysis using the RT Profiler PCR Array, qRT-PCR, and pathologic and immunohistochemical analyses. We found that Th1-associated chemokine/cytokine (, , , and ) and Treg-associated chemokine/cytokine (, , and ) mRNA levels were simultaneously increased in premalignant lesions of 4NQO-treated mice at 16 weeks. Additionally, although levels of , a Th2 marker, were not upregulated, those of , , and were upregulated in the tongue tissue. Furthermore, immunohistochemical analysis confirmed the infiltration of CD4, CD8, and Foxp3 cells in the tongue tissue of 4NQO-treated mice, as well as significant correlations between Th1- or Treg-associated chemokine/cytokine mRNA expression and T cell infiltration. These results indicate that CD4, CD8, and Foxp3 cells were simultaneously recruited through the expression of Th1- and Treg-associated chemokines in premalignant lesions of 4NQO-induced mouse tongue tissue.
肿瘤微环境中的趋化因子和细胞因子会影响免疫细胞的浸润和激活。为了阐明它们在口腔癌发生过程中免疫细胞招募中的作用，我们使用致癌物4-硝基喹啉1-氧化物（4NQO）建立了小鼠舌癌模型，并研究了小鼠舌部的致癌过程以及趋化因子/细胞因子基因表达动力学。给C57/BL6小鼠饮用含4NQO的水，16周和28周后解剖舌头，并用RT Profiler PCR Array、qRT-PCR以及病理和免疫组织化学分析进行检测。我们发现，在16周时，4NQO处理小鼠的癌前病变中，与Th1相关的趋化因子/细胞因子（、、、和）以及与Treg相关的趋化因子/细胞因子（、和）的mRNA水平同时升高。此外，虽然Th2标志物的水平没有上调，但、和在舌组织中的水平上调。此外，免疫组织化学分析证实，4NQO处理小鼠的舌组织中有CD4、CD8和Foxp3细胞浸润，并且Th1或Treg相关趋化因子/细胞因子mRNA表达与T细胞浸润之间存在显著相关性。这些结果表明，在4NQO诱导的小鼠舌组织癌前病变中，通过Th1和Treg相关趋化因子的表达同时招募了CD4、CD8和Foxp3细胞。
