Vitamin D promotes the cisplatin sensitivity of oral squamous cell carcinoma by inhibiting LCN2-modulated NE-κB pathway activation through RPS3
Vitamin D promotes the cisplatin sensitivity of oral squamous cell carcinoma by inhibiting LCN2-modulated NE-κB pathway activation through RPS3
复制标题
维生素 D 通过 RPS3 抑制 LCN2 调节的 NF-κB 通路激活，从而促进口腔鳞状细胞癌对顺铂的敏感性。
DOI：
10.1038/s41419-019-2177-x
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发表时间：
2019-12-09
影响因子：
9
通讯作者：
Huang, Zhiquan
中科院分区：
文献类型：
--
作者：
Huang, Zixian;Zhang, Yin;Huang, Zhiquan
化疗耐药性是癌症进展和癌症患者死亡的主要原因。开发一种安全的策略来提高化疗敏感性是生物医学科学的一个挑战。最近的研究表明，维生素D补充剂可以降低许多癌症的风险。然而，维生素D在化疗中的作用仍然未知。我们发现维生素D使口腔癌细胞对顺铂敏感，并部分逆转顺铂耐药性。使用RNA-seq，我们发现脂质运载蛋白2（LCN 2）是一种重要的介导物。顺铂通过降低启动子甲基化增强LCN 2的表达，而维生素D增强甲基化，从而抑制LCN 2的表达。在体外和体内，LCN 2的过表达增加了细胞存活率和顺铂耐药性。LCN 2高表达与口腔鳞状细胞癌（OSCC）患者的分化程度、淋巴结转移和T分期呈正相关，并预示预后不良。LCN 2也与化疗后复发相关。此外，我们发现LCN 2通过与核糖体蛋白S3（RPS3）结合促进NE-κ B的活化，并增强RPS3与p65之间的相互作用。我们的研究表明，维生素D可以增强顺铂化疗，并建议在化疗期间补充维生素D，但需要更多的后续临床研究。
Chemoresistance is a major cause of cancer progression and the mortality of cancer patients. Developing a safe strategy for enhancing chemosensitivity is a challenge for biomedical science. Recent studies have suggested that vitamin D supplementation may decrease the risk of many cancers. However, the role of vitamin D in chemotherapy remains unknown. We found that vitamin D sensitised oral cancer cells to cisplatin and partially reversed cisplatin resistance. Using RNA-seq, we discovered that lipocalin 2 (LCN2) is an important mediator. Cisplatin enhanced the expression of LCN2 by decreasing methylation at the promoter, whereas vitamin D enhanced methylation and thereby inhibited the expression of LCN2. Overexpression of LCN2 increased cell survival and cisplatin resistance both in vitro and in vivo. High LCN2 expression was positively associated with differentiation, lymph node metastasis, and T staging and predicted a poor prognosis in oral squamous cell carcinoma (OSCC) patients. LCN2 was also associated with post-chemotherapy recurrence. Moreover, we found that LCN2 promoted the activation of NE-kappa B by binding to ribosomal protein S3 (RPS3) and enhanced the interaction between RPS3 and p65. Our study reveals that vitamin D can enhance cisplatin chemotherapy and suggests that vitamin D should be supplied during chemotherapy; however, more follow-up clinical studies are needed.