Bernabé-Rubio Miguel, Watt Fiona M
Centre for Gene Therapy and Regenerative Medicine, School of Basic and Medical Biosciences, King's College London, London SE1 9RT, United Kingdom.
Directors' Unit, European Molecular Biology Laboratory Heidelberg, Heidelberg 69117, Germany.
Proc Natl Acad Sci U S A. 2024 Dec 10;121(50):e2406944121. doi: 10.1073/pnas.2406944121. Epub 2024 Dec 3.
Oral squamous cell carcinoma (OSCC) is a subtype of head and neck cancer that arises in the multilayered epithelia of the mouth and lips. Although inactivating mutations in are frequently found in human OSCC their role in the disease is unknown. To investigate this, we deleted in the oral epithelium of adult mice. Loss of Caspase-8 resulted in defects in the tongue epithelial barrier and triggered a neutrophil-rich immune infiltrate distinct from that observed on epidermal deletion. Oral deletion led to activation of autophagy. Inhibition of autophagy partially rescued epithelial integrity in mice, while induction of autophagy in wild type mice resulted in oral barrier defects and excessive neutrophil infiltration. On treatment with the carcinogen 4-nitroquinoline-1-oxide mice showed increased susceptibility to developing oral tumors. Depletion of neutrophils reduced tumor incidence, which correlated with a reduction in reactive oxygen species and decreased epithelial DNA damage. Our findings establish a functional link between epithelial integrity, autophagy, and the tumor immune microenvironment, placing Caspase-8 at the center of these processes.
口腔鳞状细胞癌（OSCC）是头颈部癌症的一种亚型，起源于口腔和嘴唇的复层上皮。尽管在人类OSCC中经常发现[相关基因]的失活突变，但其在该疾病中的作用尚不清楚。为了对此进行研究，我们在成年小鼠的口腔上皮中删除了[相关基因]。半胱天冬酶-8的缺失导致舌上皮屏障缺陷，并引发了富含中性粒细胞的免疫浸润，这与在表皮[相关基因]缺失时观察到的情况不同。口腔[相关基因]缺失导致自噬激活。抑制自噬可部分挽救[相关基因]缺失小鼠的上皮完整性，而在野生型小鼠中诱导自噬则导致口腔屏障缺陷和中性粒细胞过度浸润。在用致癌物4-硝基喹啉-1-氧化物处理后，[相关基因]缺失小鼠对发生口腔肿瘤的易感性增加。中性粒细胞耗竭降低了肿瘤发生率，这与活性氧的减少和上皮DNA损伤的减少相关。我们的研究结果建立了上皮完整性、自噬和肿瘤免疫微环境之间的功能联系，将半胱天冬酶-8置于这些过程的中心。
