The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA 90095, USA.
UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095, USA.
Int J Mol Sci. 2022 Aug 29;23(17):9779. doi: 10.3390/ijms23179779.
Alcohol consumption is associated with an increased risk of several cancers, including oral/oropharyngeal squamous cell carcinoma (OSCC). Alcohol also enhances the progression and aggressiveness of existing cancers; however, its underlying molecular mechanism remains elusive. Especially, the local carcinogenic effects of alcohol on OSCC in closest contact with ingestion of alcohol are poorly understood. We demonstrated that chronic ethanol exposure to OSCC increased cancer stem cell (CSC) populations and their stemness features, including self-renewal capacity, expression of stem cell markers, ALDH activity, and migration ability. The ethanol exposure also led to a significant increase in aerobic glycolysis. Moreover, increased aerobic glycolytic activity was required to support the stemness phenotype of ethanol-exposed OSCC, suggesting a molecular coupling between cancer stemness and metabolic reprogramming. We further demonstrated that chronic ethanol exposure activated NFAT (nuclear factor of activated T cells) signaling in OSCC. Functional studies revealed that pharmacological and genetic inhibition of NFAT suppressed CSC phenotype and aerobic glycolysis in ethanol-exposed OSCC. Collectively, chronic ethanol exposure promotes cancer stemness and aerobic glycolysis via activation of NFAT signaling. Our study provides a novel insight into the roles of cancer stemness and metabolic reprogramming in the molecular mechanism of alcohol-mediated carcinogenesis.
饮酒与多种癌症（包括口腔/口咽鳞状细胞癌[OSCC]）的风险增加有关。酒精还会促进现有癌症的进展和侵袭性；然而，其潜在的分子机制仍不清楚。特别是，与摄入酒精最接近的 OSCC 的局部致癌作用，人们对此知之甚少。我们证明了慢性乙醇暴露于 OSCC 增加了癌症干细胞（CSC）群体及其干性特征，包括自我更新能力、干细胞标志物的表达、ALDH 活性和迁移能力。乙醇暴露还导致有氧糖酵解显著增加。此外，增加有氧糖酵解活性是支持乙醇暴露的 OSCC 干性表型所必需的，这表明癌症干性和代谢重编程之间存在分子偶联。我们进一步证明，慢性乙醇暴露激活了 OSCC 中的 NFAT（激活 T 细胞的核因子）信号。功能研究表明，NFAT 的药理学和遗传抑制抑制了乙醇暴露的 OSCC 中的 CSC 表型和有氧糖酵解。总的来说，慢性乙醇暴露通过激活 NFAT 信号促进癌症干性和有氧糖酵解。我们的研究为癌症干性和代谢重编程在酒精介导的致癌作用的分子机制中的作用提供了新的见解。
