ALDH2 Repression Promotes Lung Tumor Progression via Accumulated Acetaldehyde and DNA Damage
ALDH2 Repression Promotes Lung Tumor Progression via Accumulated Acetaldehyde and DNA Damage
复制标题
ALDH2 抑制通过积累的乙醛和 DNA 损伤促进肺肿瘤进展
DOI：
10.1016/j.neo.2019.03.008
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发表时间：
2019-06-01
期刊：
影响因子：
4.8
通讯作者：
Deng, Jiong
中科院分区：
文献类型：
--
作者：
Li, Kaimi;Guo, Wenzheng;Deng, Jiong
乙醛脱氢酶2家族（ALDH 2）的主要作用是将乙醛（ACE）解毒为无毒的乙酸。许多证据表明，ALDH 2功能障碍有助于多种人类疾病，包括癌症。然而，ALDH 2在肿瘤进展中的生物学功能和分子机制仍不清楚。在这项研究中，我们发现ALDH 2抑制与肺腺癌的不良预后相关。ALDH 2的过表达抑制肺腺癌细胞的恶性特征，如增殖，干性和迁移，而ALDH 2敲低增加这些功能。从机制上讲，ALDH 2抑制导致ACE的积累，而ACE增强肺腺癌细胞的迁移功能，这与DNA损伤增加有关。重要的是，在体内Aldh 2敲除（KO）小鼠肺组织中鉴定出累积的ACE和增加的DNA损伤。与此概念一致，用ALDH 2激动剂Alda-1处理肺腺癌细胞抑制肺腺癌细胞的增殖、干细胞和迁移特征。因此，激活ALDH 2，例如通过其激动剂，可以提供一种治疗肺癌的新策略。
The major role of aldehyde dehydrogenase 2 family (ALDH2) is to detoxify acetaldehyde (ACE) to non-toxic acetic acid. Many evidences suggest that ALDH2 dysfunction contributes to a variety of human diseases including cancer. However, the biological function and molecular mechanism of ALDH2 in tumor progression remain elusive. In this study, we found that ALDH2 repression was associated with poor prognosis in lung adenocarcinoma. Overexpression of ALDH2 inhibited malignant features of lung adenocarcinoma cells, such as proliferation, stemness and migration, whereas ALDH2 knockdown increased these features. Mechanistically, ALDH2 repression led to accumulation of ACE; whereas ACE enhanced the migration features of lung adenocarcinoma cells, which was associated with increased DNA damage. Importantly, accumulated ACE and increased DNA damage were identified in Aldh2-knockout (KO) mouse lung tissues in vivo. Consistent with this concept, treatment of lung adenocarcinoma cells with ALDH2 agonist Alda-1 suppressed the proliferation, sternness and migration features of lung adenocarcinoma cells. Thus, activating ALDH2, such as via its agonist, may provide a novel strategy for treatment of lung cancer.