The alcohol metabolite acetaldehyde is a potent human carcinogen linked to esophageal squamous cell carcinoma (ESCC) initiation and development. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme that detoxifies acetaldehyde in the mitochondria. Acetaldehyde accumulation causes genotoxic stress in cells expressing the dysfunctional ALDH2E487K dominant negative mutant protein linked to ALDH2*2, the single nucleotide polymorphism highly prevalent amongst East Asians. Heterozygous ALDH2*2 increases the risk for the development of ESCC and other alcohol-related cancers. Despite its prevalence and link to malignant transformation, how ALDH2 dysfunction influences ESCC pathobiology is incompletely understood. Herein, we characterize how ESCC and preneoplastic cells respond to alcohol exposure using cell lines, three dimensional organoids, and xenograft models. We find that alcohol exposure and ALDH2*2 cooperate to increase putative ESCC cancer stem cells with high CD44 expression (CD44H cells) linked to tumor initiation, repopulation, and therapy resistance. Concurrently, ALHD2*2 augmented alcohol-induced reactive oxygen species and DNA damage to promote apoptosis in the non-CD44H cell population. Pharmacological activation of ALDH2 by Alda-1 inhibits this phenotype, suggesting that acetaldehyde is the primary driver of these changes. Additionally, we find that Aldh2 dysfunction affects the response to cisplatin, a chemotherapeutic commonly used for the treatment of ESCC. Aldh2 dysfunction facilitated enrichment of CD44H cells following cisplatin-induced oxidative stress and cell death in murine organoids, highlighting a potential mechanism driving cisplatin resistance. Together, these data provide evidence that ALDH2 dysfunction accelerates ESCC pathogenesis through enrichment of CD44H cells in response to genotoxic stressors such as environmental carcinogens and chemotherapeutic agents.

中文翻译：

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ALDH2 功能障碍和酒精在癌症干细胞富集过程中协同作用。

酒精代谢物乙醛是一种强效人类致癌物，与食管鳞状细胞癌 (ESCC) 的发生和发展有关。乙醛脱氢酶 2 (ALDH2) 是线粒体中乙醛解毒的主要酶。乙醛积累会导致细胞表达功能失调的 ALDH2E487K 显性失活突变蛋白，该蛋白与 ALDH2*2 相关，ALDH2*2 是东亚人中非常普遍的单核苷酸多态性。杂合 ALDH2*2 会增加患 ESCC 和其他与酒精相关的癌症的风险。尽管 ALDH2 功能障碍普遍存在且与恶性转化有关，但其如何影响 ESCC 病理学尚不完全清楚。在此，我们使用细胞系、三维类器官和异种移植模型描述了食管鳞癌和肿瘤前期细胞对酒精暴露的反应。我们发现，酒精暴露和 ALDH2*2 协同作用，增加了假定的具有高 CD44 表达的 ESCC 癌症干细胞（CD44H 细胞），这些细胞与肿瘤发生、增殖和治疗耐药性相关。同时，ALHD2*2 增强了酒精诱导的活性氧和 DNA 损伤，从而促进非 CD44H 细胞群的凋亡。Alda-1 对 ALDH2 的药理学激活会抑制这种表型，表明乙醛是这些变化的主要驱动因素。此外，我们发现 Aldh2 功能障碍会影响对顺铂（一种常用于治疗 ESCC 的化疗药物）的反应。Aldh2 功能障碍促进顺铂诱导的小鼠类器官氧化应激和细胞死亡后 CD44H 细胞的富集，凸显了驱动顺铂耐药的潜在机制。总之，这些数据提供了证据，表明 ALDH2 功能障碍通过富集 CD44H 细胞来响应环境致癌物和化疗药物等遗传毒性应激源，从而加速 ESCC 发病机制。