Chen Ping-Tsung, Hsieh Ching-Chuan, Wu Chun-Te, Yen Tzu-Chen, Lin Paul-Yang, Chen Wen-Cheng, Chen Miao-Fen
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan. Department of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan. General Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.
Mol Cancer Ther. 2015 Jun;14(6):1365-75. doi: 10.1158/1535-7163.MCT-14-0952. Epub 2015 Mar 30.
The aim of this study was to highlight the role of 1α,25-dihydroxyvitamin D3 (calcitriol) in esophageal squamous cell carcinoma (SCC). The human esophageal SCC cell lines CE81T and TE2 were selected for cellular and animal experiments to investigate the changes in tumor behavior after calcitriol supplementation and the underlying mechanisms. Moreover, we evaluated the relationship between calcitriol supplementation, myeloid-derived suppressor cell (MDSC) recruitment, IL6 levels, and tumor progression by a 4-nitroquinoline 1-oxide (4-NQO)-induced esophageal tumor animal model. In this study, we demonstrated that calcitriol supplementation inhibited aggressive tumor behavior both in vitro and in vivo. The underlying changes included increased cell death, a lower degree of epithelial-mesenchymal transition, and inhibited IL6 signaling. In the 4-NQO-induced esophageal tumor animal model, increased IL6 and MDSC recruitment were linked with invasive esophageal tumors. Supplementation with calcitriol attenuated the level of IL6, the induction of MDSCs, and the incidence of 4-NQO-induced invasive tumors. Moreover, the IL6-induced changes in C57 mice, including augmented MDSC recruitment, increased levels of ROS and p-Stat3 in MDSCs, and higher suppressive function of MDSCs in T-cell proliferation, which were abrogated by calcitriol supplementation. On the basis of our results, we concluded that calcitriol abrogated the IL6-induced aggressive tumor behavior and MDSC recruitment to inhibit esophageal tumor promotion. Therefore, we suggest that supplementation with vitamin D3 may be a promising strategy for the prevention and treatment of esophageal SCC.
本研究的目的是强调1α,25 - 二羟基维生素D3（骨化三醇）在食管鳞状细胞癌（SCC）中的作用。选择人食管SCC细胞系CE81T和TE2进行细胞和动物实验，以研究补充骨化三醇后肿瘤行为的变化及其潜在机制。此外，我们通过4 - 硝基喹啉1 - 氧化物（4 - NQO）诱导的食管肿瘤动物模型，评估了补充骨化三醇、髓源性抑制细胞（MDSC）募集、白细胞介素6（IL6）水平与肿瘤进展之间的关系。在本研究中，我们证明补充骨化三醇在体外和体内均能抑制侵袭性肿瘤行为。潜在的变化包括细胞死亡增加、上皮 - 间质转化程度降低以及IL6信号传导受抑制。在4 - NQO诱导的食管肿瘤动物模型中，IL6增加和MDSC募集与侵袭性食管肿瘤有关。补充骨化三醇可减轻IL6水平、MDSC的诱导以及4 - NQO诱导的侵袭性肿瘤的发生率。此外，IL6诱导的C57小鼠的变化，包括MDSC募集增加、MDSC中活性氧（ROS）和磷酸化信号转导子和转录激活子3（p - Stat3）水平升高以及MDSC对T细胞增殖的更高抑制功能，均被补充骨化三醇所消除。基于我们的研究结果，我们得出结论，骨化三醇消除了IL6诱导的侵袭性肿瘤行为和MDSC募集，从而抑制食管肿瘤的进展。因此，我们建议补充维生素D3可能是预防和治疗食管SCC的一种有前景的策略。
