DNA damage‐inducible transcript 4 is an innate guardian for human squamous cell carcinoma and an molecular vector for anti‐carcinoma effect of 1,25(OH)2D3
DNA damage‐inducible transcript 4 is an innate guardian for human squamous cell carcinoma and an molecular vector for anti‐carcinoma effect of 1,25(OH)2D3
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DOI：
10.1111/exd.13815
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发表时间：
2018-12
影响因子：
3.6
通讯作者：
Xiaojiao Zhang;Fuling Luo;Jing Li;J. Wan;Li Zhang;Hong-zhong Li;Aijun Chen;Jin Chen;T. Cai;Xian He;T. Lisse;Hengguang Zhao
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文献类型：
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作者：
Xiaojiao Zhang;Fuling Luo;Jing Li;J. Wan;Li Zhang;Hong-zhong Li;Aijun Chen;Jin Chen;T. Cai;Xian He;T. Lisse;Hengguang Zhao
皮肤鳞状细胞癌（SCC）是全球最常见的非黑色素瘤皮肤癌之一。其确切的致瘤机制尚未完全确定，目前临床上可采用的治疗策略也不太令人满意。在这项研究中，我们打算研究DNA损伤诱导转录本4（DDIT 4）在人类SCC中的作用。首先，我们发现DDIT 4在人SCC组织和培养的A431细胞系中被显著抑制，并且减少的DDIT 4加速角质形成细胞增殖，但通过影响下游S6激酶1，4 E-BP 1，Beclin 1和LC 3 II/I阻碍通过mTORC 1途径的自噬通量。而1，25（OH）2D 3通过增强DDIT 4表达、激活自噬和抑制mTORC 1发挥抗增殖、激活自噬的作用。此外，通过ChIP-qPCR验证了直接维生素D受体（VDR）-DDIT 4转录复合物的形成，这显示了1，25（OH）2D 3如何促进DDIT 4转录的分子机制。第三，梯度浓度1，25（OH）2D 3处理的荷瘤小鼠模型显示，1，25（OH）2D 3在体内具有明显的抗肿瘤作用，DDIT 4通过mTORC 1作为1，25（OH）2D 3的分子载体。最后，在人类光化性角化病组织中证实了DDIT 4表达升高，并且对小鼠进行慢性长期紫外线（UV）照射可促进表皮内的DDIT 4表达。结论：我们的研究提出了一种新的人SCC肿瘤发生的分子机制和1，25（OH）2D 3对人SCC发挥抗肿瘤作用的药理学机制，以及紫外线照射如何在SCC癌变早期发挥致瘤作用同时发挥保护作用的惊人悖论。
Cutaneous squamous cell carcinoma (SCC) is one of the most common non‐melanoma skin cancers worldwide. While its exact tumorigenesis mechanisms is far from well‐established and less satisfied therapeutic strategy can be clinically used nowadays. In this study, we intended to investigate the role of DNA damage‐inducible transcript 4 (DDIT4) in human SCC. Firstly, we identified DDIT4 is significantly suppressed in human SCC tissue and cultured A431 cell line, and reduced DDIT4 accelerates keratinocytes proliferation but impedes the autophagy flux through mTORC1 pathway by affecting the downstream S6 Kinase1, 4E‐BP1, Beclin1 and LC3 II/I. While 1,25(OH)2D3 enhanced DDIT4 expression and activated autophagy and inhibit mTORC1 to take the effect of anti‐proliferation and activating autophagy. Further, formation of direct vitamin D receptor (VDR)‐DDIT4 transcription complex was verified by ChIP‐qPCR, which showed the molecular mechanism of how 1,25(OH)2D3 promotes DDIT4 transcription. Thirdly, xenograft tumor‐bearing mice model treated by gradient concentrations of 1,25(OH)2D3 revealed the obvious anti‐carcinoma effect of 1,25(OH)2D3 in vivo and DDIT4 acted the molecular vector of 1,25(OH)2D3 through mTORC1. Lastly, elevated DDIT4 expression was verified in human actinic keratoses tissue, and chronic long‐term ultraviolet (UV) irradiation on mouse disclosed UV could promote DDIT4 expression inside epidermis. Conclusively, our research suggested a novel molecular mechanism about the human SCC tumorigenesis and the pharmacological mechanism about how 1,25(OH)2D3 take its anti‐carcinoma role on human SCC, as well as a striking paradoxes that how UV irradiation plays the tumorigenesis effect but synchronously take a protective role in the early stage of SCC carcinogenesis.