Exosomal-mediated transfer of APCDD1L-AS1 induces 5-fluorouracil resistance in oral squamous cell carcinoma via miR-1224-5p/nuclear receptor binding SET domain protein 2 (NSD2) axis.
Exosomal-mediated transfer of APCDD1L-AS1 induces 5-fluorouracil resistance in oral squamous cell carcinoma via miR-1224-5p/nuclear receptor binding SET domain protein 2 (NSD2) axis.
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外泌体介导的APCDD 1 L-AS 1转移通过miR-1224- 5 p/核受体结合SET结构域蛋白2（NSD 2）轴诱导口腔鳞状细胞癌的5-氟尿嘧啶耐药
DOI：
10.1080/21655979.2021.1979442
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发表时间：
2021-12
期刊：
影响因子：
4.9
通讯作者：
Wu D
中科院分区：
文献类型：
--
作者：
Li S;Shi Z;Fu S;Li Q;Li B;Sang L;Wu D
口腔鳞状细胞癌（OSCC）是一种严重威胁人类健康的疾病。已报道LncRNA APCDD 1 L-AS 1参与肿瘤发生和获得性化学抗性的发展。然而，APCDD 1 L-AS 1在口腔鳞癌5-氟尿嘧啶（5-FU）耐药调控中的作用仍然不清楚。本研究以口腔鳞癌细胞系（HSC-3和HN-4）建立了5-FU耐药细胞模型。RT-qPCR和Western blotting分别检测基因表达和蛋白水平。CCK-8法、集落形成法和流式细胞仪检测5-FU耐药细胞的IC 50值、细胞活力和细胞凋亡。应用双荧光素酶报告基因分析和RIP分析方法鉴定miR-1224- 5 p与APCDD 1 L-AS 1或NSD 2之间的关系。APCDD 1 L-AS 1在对5-FU耐药的口腔鳞癌组织和细胞中高表达，并与口腔鳞癌患者的预后不良有关。APCDD 1 L-AS 1基因敲减可通过降低IC 50值、抑制细胞活力和加速细胞凋亡来削弱5-FU耐药OSCC细胞的5-FU耐药性。此外，胞外APCDD 1 L-AS 1可通过外泌体掺入转移至敏感细胞，从而传递OSCC细胞对5-FU的耐药性。此外，miR-1224- 5 p是APCDD 1 L-AS 1的分子靶点，在5-FU耐药细胞中直接靶向NSD 2。miR-1224- 5 p在5-FU耐药组织中表现出低得多的水平，并且在5-FU耐药OSCC细胞中表现出增加的5-FU敏感性。此外，NSD 2上调中和了在HSC-3/5-FU和HN-4/5-FU细胞中阻断APCDD 1 L-AS 1对5-FU抗性的影响。综上所述，我们的研究表明，外泌体APCDD 1 L-AS 1通过miR-1224- 5 p/NSD 2轴赋予HSC-3/5-FU和HN-4/5-FU细胞对5-FU的抗性，从而为OSCC化学抗性提供了新的靶点。
Oral squamous cell carcinoma (OSCC) poses a threat to public health worldwide. LncRNA APCDD1L-AS1 has been reported to participate in tumorigenesis and development of acquired chemoresistance. However, the role of APCDD1L-AS1 in 5-fluorouracil (5-FU) resistance regulation within OSCC is still obscure. In this study, 5-FU-resistant cell models were established with OSCC cell lines (HSC-3 and HN-4). Gene expressions and protein levels were detected by RT-qPCR and Western blotting, respectively. CCK-8, colony forming, and flow cytometry were utilized to measure IC50 value, cell viability, and cell apoptosis of 5-FU-resistant OSCC cells. Dual-luciferase reporter assay and RIP assay were applied to identify the associations between miR-1224-5p and APCDD1L-AS1 or NSD2. Herein, high APCDD1L-AS1 expression was shown in OSCC tissues and cells resistant to 5-FU and related to the worse prognosis of OSCC patients. APCDD1L-AS1 knockdown impaired 5-FU resistance in 5-FU-resistant OSCC cells by reducing IC50 value, suppressing cell viability, and accelerating cell apoptosis. Besides, extracellular APCDD1L-AS1 could be transferred to sensitive cells via exosome incorporation, thereby transmitting 5-FU resistance in OSCC cells. Besides, miR-1224-5p was a molecular target of APCDD1L-AS1 and directly targeted NSD2 in 5-FU-resistant cells. MiR-1224-5p exhibited a much lower level in 5-FU-resistant tissues and increased 5-FU sensitivity in 5-FU-resistant OSCC cells. Moreover, NSD2 upregulation neutralized the influence of blocking APCDD1L-AS1 in HSC-3/5-FU and HN-4/5-FU cells on 5-FU resistance. To sum up, our study demonstrated that exosomal APCDD1L-AS1 conferred resistance to 5-FU in HSC-3/5-FU and HN-4/5-FU cells via the miR-1224-5p/NSD2 axis, thus providing a novel target for OSCC chemoresistance.
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