Department of Otolaryngology & Head and Neck Surgery, Chang Gung Memorial Hospital at Chiayi, Taiwan.
Radiation Oncology, Chang Gung Memorial Hospital at Chiayi, Taiwan; Chang Gung University College of Medicine and Chang Gung Institute of Technology, Taiwan.
Oral Oncol. 2017 Oct;73:88-96. doi: 10.1016/j.oraloncology.2017.08.007. Epub 2017 Aug 30.
Aldehyde dehydrogenase 1 (ALDH1) is associated with tumorigenesis, and shown to identify cancer stem cells (CSC)-like cells. We aimed to investigate the significance of ALDH1 in oral squamous cell carcinoma (OSCC) and its correlation with DNMT3b and immune evasion in the present study.
We retrospectively analyzed the clinical outcomes of OSCC patients and examined its correlation with the levels of ALDH1 in tumors and circulating myeloid-derived suppressor cells (MDSCs) in the peripheral blood. Furthermore, the relationships between the DNMT3b, ALDH1 expression, and immune response were examined via clinical specimens and cellular and animal experiments. We also investigated the therapeutic potential of DNA hypomethylating agents in OSCC.
Our data revealed that the levels of ALDH1 expression were linked to treatment resistance, CSC-like properties, higher circulating MDSC and poor prognosis for OSCC. The radiation resistance noted in ALDH1-positive tumors was associated with augmented radiation-induced increases in the expression of programmed death ligand (PD-L1) and the activation of MDSCs. Furthermore, there was a positive link between ALDH1 and DNMT3b expression shown by clinical specimens and cellular experiments. DNA hypomethylating agents attenuated the radioresistance of ALDH1-positive cancer cells associated with the decreased ALDH1 and the increased DNA damages. In addition, the activation of MDSCs and the expression of PD-L1 were significantly attenuated by epigenetic therapy.
Our findings suggested that ALDH1 played an important role in treatment response and the tumor-promoting microenvironment in OSCC. Moreover, epigenetic therapy could be a promising strategy for the treatment of OSCC.
醛脱氢酶 1（ALDH1）与肿瘤发生有关，并被证明可以鉴定癌症干细胞（CSC）样细胞。本研究旨在探讨 ALDH1 在口腔鳞状细胞癌（OSCC）中的意义及其与 DNMT3b 和免疫逃逸的相关性。
我们回顾性分析了 OSCC 患者的临床结果，并检查了肿瘤中 ALDH1 水平及其在外周血循环髓系来源抑制细胞（MDSCs）中的相关性。此外，通过临床标本和细胞及动物实验研究了 DNMT3b、ALDH1 表达与免疫反应之间的关系。我们还研究了 DNA 去甲基化剂在 OSCC 中的治疗潜力。
我们的数据表明，ALDH1 表达水平与治疗耐药性、CSC 样特性、更高的循环 MDSC 和 OSCC 预后不良有关。ALDH1 阳性肿瘤的放射抵抗性与辐射诱导程序性死亡配体（PD-L1）表达增加和 MDSC 激活有关。此外，临床标本和细胞实验均显示 ALDH1 与 DNMT3b 表达之间存在正相关。DNA 去甲基化剂减弱了与 ALDH1 减少和 DNA 损伤增加相关的 ALDH1 阳性癌细胞的放射抗性。此外，MDSC 的激活和 PD-L1 的表达通过表观遗传治疗显著减弱。
我们的研究结果表明，ALDH1 在 OSCC 的治疗反应和肿瘤促进微环境中发挥重要作用。此外，表观遗传治疗可能是治疗 OSCC 的一种有前途的策略。
