4-硝基喹啉-1-氧化物与乙醇诱导的口腔鳞状细胞癌小鼠模型中组蛋白乙酰化与肿瘤发展的性别差异

Sex-Related Differences in Histone Acetylation and Tumor Development in a 4-Nitroquinoline 1-Oxide and Ethanol-Induced Oral Squamous Cell Carcinoma Mouse Model.

作者信息

Nazário Wender Rodrigues, Costa Anaíra Ribeiro Guedes Fonseca, de Oliveira Santos Débora, Del Nero Nayara Rúbio Diniz, Rodrigues Tamiris Sabrina, Borges Luiza Diniz Ferreira, Ueira-Vieira Carlos, Cardoso Sérgio Vitorino, Loyola Adriano Mota, de Faria Paulo Rogério

机构信息

Department of Oral and Maxillofacial Pathology, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.

Applied Immunology and Parasitology Postgraduate Program, Biomedical Sciences Institute, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.

出版信息

J Oral Pathol Med. 2025 Sep 10. doi: 10.1111/jop.70062.

DOI:10.1111/jop.70062

PMID:40928052

Abstract

BACKGROUND

Oral squamous cell carcinoma (OSCC) is one of the most frequent head and neck cancers. The 4-nitroquinoline 1-oxide (4NQO) mouse model of oral carcinogenesis is a well-established model to investigate the mechanism behind OSCC development, including epigenetic alterations. Studies have shown that histone acetylation is a key regulator of gene expression and may play a role in such a tumor. This study investigates the acetylation of H3K9, H3K14, and H3K27 and the KAT2A gene expression in a sex-based approach in a 4NQO/ethanol (EtOH)-induced OSCC mouse model.

METHODS

A total of 120 C57Bl/6J mice (60 males and 60 females) were divided into four groups (n = 15). In the first 10 weeks, they were treated with 5 mg/mL propylene glycol (PPG) or 100 μg/mL 4NQO in drinking water, followed by either sterilized water or 8% EtOH for 15 weeks. After euthanasia, tongues were analyzed histopathologically. Immunohistochemistry and qPCR were also employed to study the histones and gene expression.

RESULTS

Female mice showed increased H3K9ac and H3K14ac expression from normal mucosa to dysplasia, followed by decreased expression in OSCC. H3K9ac and H3K14ac expression in males was lower in the 4NQO/EtOH group. H3K27ac was higher in dysplastic lesions compared to OSCC, particularly in females. Comparatively, females had higher H3K9ac and H3K14ac expression in the 4NQO/EtOH group than males. KAT2A expression was lower in females treated with PPG/EtOH and 4NQO/HO than in males.

CONCLUSION

Our results indicate that H3 acetylation and KAT2A gene expression may play a key role in oral carcinogenesis on a sex-related basis.

摘要

背景

口腔鳞状细胞癌（OSCC）是最常见的头颈癌之一。4-硝基喹啉-1-氧化物（4NQO）诱导的口腔癌发生小鼠模型是研究OSCC发生机制（包括表观遗传改变）的成熟模型。研究表明，组蛋白乙酰化是基因表达的关键调节因子，可能在这类肿瘤中发挥作用。本研究采用基于性别的方法，在4NQO/乙醇（EtOH）诱导的OSCC小鼠模型中，研究H3K9、H3K14和H3K27的乙酰化以及KAT2A基因表达情况。

方法

总共120只C57Bl/6J小鼠（60只雄性和60只雌性）被分为四组（每组n = 15）。在最初的10周里，给它们饮用含5 mg/mL丙二醇（PPG）或100 μg/mL 4NQO的水，随后15周给予无菌水或8% EtOH。安乐死后，对舌头进行组织病理学分析。还采用免疫组织化学和定量聚合酶链反应（qPCR）研究组蛋白和基因表达。

结果

雌性小鼠从正常黏膜到发育异常，H3K9ac和H3K14ac表达增加，随后在OSCC中表达降低。4NQO/EtOH组雄性小鼠的H3K9ac和H3K14ac表达较低。与OSCC相比，发育异常病变中H3K27ac较高，尤其是在雌性中。相比之下，4NQO/EtOH组雌性小鼠的H3K9ac和H3K14ac表达高于雄性。接受PPG/EtOH和4NQO/HO处理的雌性小鼠的KAT2A表达低于雄性。