Forkhead box D1 promotes EMT and chemoresistance by upregulating lncRNA CYTOR in oral squamous cell carcinoma
Forkhead box D1 promotes EMT and chemoresistance by upregulating lncRNA CYTOR in oral squamous cell carcinoma
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Forkhead box D1 通过上调口腔鳞状细胞癌中的 lncRNA CYTOR 促进 EMT 和化疗耐药
DOI：
10.1016/j.canlet.2020.11.046
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发表时间：
2021-01-23
期刊：
影响因子：
9.7
通讯作者：
Zhang, Quan
中科院分区：
文献类型：
--
作者：
Chen, Shuwei;Yang, Muwen;Zhang, Quan
含顺铂的化疗方案仍然是口腔鳞状细胞癌（OSCC）患者的一线治疗方案；然而，由于化疗耐药和复发，治疗效果往往是短暂的。了解OSCC的化学耐药机制可能会提供新的靶向漏洞。在本研究中，我们发现叉头盒D1 （FOXD1）在OSCC中表达上调，并预测预后不良。此外，在体外和体内，FOXD1的异位表达促进了OSCC的上皮-间质转化（EMT）和化疗耐药，而FOXD1的沉默则抑制了OSCC的耐药。机制上，FOXD1结合长链非编码RNA细胞骨架调节RNA （CYTOR）的启动子并激活其转录。然后CYTOR作为竞争性内源性RNA抑制miR-1252-5p和miR-3148，从而上调脂肪瘤首选伴侣（LPP）的表达。重要的是，CYTOR/LPP轴被证明是foxd1诱导的OSCC EMT和化疗耐药的关键。这些发现揭示了OSCC化疗耐药的新机制，提示FOXD1可能是一个潜在的预后标志物和抗耐药治疗靶点。
Chemotherapy regimens containing cisplatin remain the first-line treatments for patients with oral squamous cell cancer (OSCC); however, the treatment effect is often transient because of chemoresistance and recurrence. Understanding the mechanisms of chemoresistance in OSCC might provide novel targetable vulnerabilities. In the present study, we revealed that Forkhead box D1 (FOXD1) is upregulated in OSCC and predicted poor prognosis. Moreover, ectopic expression of FOXD1 promoted, while silencing of FOXD1 inhibited, the epithelial-mesenchymal transition (EMT) and chemoresistance of OSCC, both in vitro and in vivo. Mechanistically, FOXD1 binds to the promoter of long non-coding RNA Cytoskeleton Regulator RNA (CYTOR) and activates its transcription. CYTOR then acts as a competing endogenous RNA to inhibit miR-1252-5p and miR-3148, thus upregulating lipoma preferred partner (LPP) expression. Importantly, the CYTOR/LPP axis was proven to be essential for FOXD1-induced EMT and chemoresistance in OSCC. These findings reveal a novel mechanism for the chemotherapy resistance of OSCC, suggesting that FOXD1 might be a potential prognostic marker and anti-resistance therapeutic target.