ADAR1 通过促进致癌 miRNA 的成熟促进口腔癌细胞的上皮-间充质转化和干细胞样细胞表型。
ADAR1 promotes the epithelial-to-mesenchymal transition and stem-like cell phenotype of oral cancer by facilitating oncogenic microRNA maturation.
机构信息
Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, No. 136, Hanzhong Road, Nanjing, 210029, Jiangsu Province, China.
Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China.
出版信息
J Exp Clin Cancer Res. 2019 Jul 17;38(1):315. doi: 10.1186/s13046-019-1300-2.
BACKGROUND
Adenosine deaminases acting on RNA (ADARs) are involved in adenosine-to-inosine (A-to-I) editing and implicated in tumorigenesis and prognosis. Emerging evidence has indicated that ADAR1, an ADAR family member, participates in the regulation of various cancers; however, its biological function in oral squamous cell carcinoma (OSCC) remains unclear. This study aimed to determine the role of ADAR1 in OSCC progression.
METHODS
ADAR1 expression in both normal tissues and carcinoma tissues and in OSCC cell lines was examined by real-time PCR and western blotting. Gain-of-function and loss-of-function approaches were used to examine the effect of ADAR1 on the migration, invasion, epithelial-mesenchymal transition (EMT) and stemness of OSCC. Furthermore, the relationship between ADAR1 and Dicer was determined by co-immunoprecipitation, and the expression of OSCC-associated oncogenic miRNAs was evaluated by real-time PCR. For in vivo experiments, a xenograft model where OSCC cells stably expressing ADAR1 were implanted was used to investigate the effect of ADAR1 on tumor growth and progression, and the expression of ADAR1, PCNA, SOX2 and POU5F1 was further detected by immunohistochemistry. The impact of ADAR1 expression on the survival status of OSCC patients was determined by survival analysis.
RESULTS
ADAR1 was overexpressed in OSCC and significantly associated with poor patient survival. There was a positive correlation between ADAR1 and the migration, invasion, EMT and stemness of OSCC. Mechanistically, ADAR1 was physically associated with Dicer, and six OSCC-associated oncogenic miRNAs were increased in OSCC cells with ADAR1 overexpression. In the mouse xenograft model of OSCC, ADAR1 overexpression promoted tumor growth and progression. Moreover, ADAR1 was highly expressed in OSCC patients with low survival rates.
CONCLUSIONS
Our findings demonstrated that ADAR1 may play a significant role in OSCC progression via combining with Dicer to regulate oncogenic miRNA maturation and further affect cell migration and invasion.
背景
作用于 RNA 的腺苷脱氨酶（ADARs）参与腺苷向肌苷（A-to-I）的编辑，并与肿瘤发生和预后有关。新出现的证据表明，ADAR 家族成员 ADAR1 参与了多种癌症的调控；然而，其在口腔鳞状细胞癌（OSCC）中的生物学功能尚不清楚。本研究旨在确定 ADAR1 在 OSCC 进展中的作用。
方法
通过实时 PCR 和 Western blot 检测 ADAR1 在正常组织和癌组织以及 OSCC 细胞系中的表达。采用功能获得和功能丧失方法研究 ADAR1 对 OSCC 迁移、侵袭、上皮-间充质转化（EMT）和干性的影响。此外，通过免疫共沉淀确定 ADAR1 与 Dicer 的关系，并通过实时 PCR 评估与 OSCC 相关的致癌 miRNA 的表达。进行体内实验时，使用植入稳定表达 ADAR1 的 OSCC 细胞的异种移植模型来研究 ADAR1 对肿瘤生长和进展的影响，并通过免疫组织化学进一步检测 ADAR1、PCNA、SOX2 和 POU5F1 的表达。通过生存分析确定 ADAR1 表达对 OSCC 患者生存状况的影响。
结果
ADAR1 在 OSCC 中过表达，与患者生存状况差显著相关。ADAR1 与 OSCC 的迁移、侵袭、EMT 和干性呈正相关。机制上，ADAR1 与 Dicer 发生物理结合，并且 ADAR1 过表达的 OSCC 细胞中六种与 OSCC 相关的致癌 miRNA 增加。在 OSCC 的小鼠异种移植模型中，ADAR1 过表达促进了肿瘤的生长和进展。此外，ADAR1 在 OSCC 患者中高表达，且这些患者的生存率较低。
结论
我们的研究结果表明，ADAR1 可能通过与 Dicer 结合来调节致癌 miRNA 的成熟，从而进一步影响细胞迁移和侵袭，在 OSCC 进展中发挥重要作用。
Zotero 插件