Silencing JARID1B suppresses oncogenicity, sternness and increases radiation sensitivity in human oral carcinoma
Silencing JARID1B suppresses oncogenicity, sternness and increases radiation sensitivity in human oral carcinoma
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DOI：
10.1016/j.canlet.2015.07.003
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发表时间：
2015-11-01
期刊：
影响因子：
9.7
通讯作者：
Yeh, Chi-Tai
中科院分区：
文献类型：
--
作者：
Lin, Chun-Shu;Lin, Ying-Chin;Yeh, Chi-Tai
目的：口腔鳞状细胞癌(OSCC)是导致人类死亡的主要原因之一，放射治疗是其主要治疗手段之一，但其治疗效果往往受到放射抵抗的限制。JARID1B是一种表观遗传因子，据报道在各种癌症类型中具有致癌潜力。材料与方法：采用创伤愈合实验、基质侵袭实验、磺胺类药物B实验和类球体形成实验，研究JARID1B对放射治疗反应中信号转导通路的影响。我们评估了81例口腔鳞癌患者中JARID1B的表达与预后的相关性。结果：使用了人口腔鳞癌细胞系，包括SAS、HSO、Cal27、TW2.6和SCC4细胞。与载体或野生型细胞相比，shJARID1B细胞显著抑制迁移和侵袭能力。沉默shJARID1B显著抑制口腔癌干细胞活性，增强放射治疗对口腔鳞癌的抑瘤活性。放射治疗联合shJARID1B基因敲除降低了恶性口腔鳞癌细胞中NQO1、Keap1、NRF2、FOXO1、FOX03、KLF4、OCT4、CD133和Nanog的mRNA水平。在shJARID1B细胞中，口腔鳞状细胞癌球体形成能力明显降低。结论：沉默shJARID1B可抑制口腔鳞癌的迁移和侵袭，降低肿瘤干细胞活性，增强肿瘤抑制放射治疗作用。在放疗前下调JARID1B基因是治疗口腔鳞癌的一种潜在有效的治疗策略。(C)2015爱思唯尔爱尔兰有限公司。保留所有权利。
Purpose: Oral squamous cell carcinoma (OSCC) is a major cause of human mortality globally and radiotherapy is one of the main treatment modalities, however its therapeutic effect is often limited by radioresistance. JARID1B is an epigenetic factor with reported oncogenic potential in various cancer types. We investigated the effect of JARID1B inhibition on migration and invasion of human OSCC cell lines, as well as on clinical patients' outcome.Materials and Methods: Wound healing, matrigel invasion, Sulforhodamine B, and spheroid formation assays were used to characterize the signaling pathways of shJARID1B in response to radiation treatment. We evaluated the prognostic relevance of Jarid1b expression in a cohort of 81 OSCC patients.Results: Human OSCC cell lines, including SAS, HSO, Cal27, TW2.6 and SCC4 cells, were used. shJARID1B cells significantly inhibited migration and invasion ability compared to their vector or wild type counterparts. Silencing shJARID1B significantly inhibited oral cancer stem cell activity and potentiated the tumor-inhibitory activity of radiation therapy in OSCC. Radiotherapy coupled with shJARID1B knockdown reduced mRNA levels of NQO1, KEAP1, NRF2, FOXO1, FOXO3, KLF4, OCT4, CD133, and Nanog in malignant OSCC cells. OSCC spheroid formation ability was markedly reduced in the shJARID1B cells. JARID1B overexpression is a dependent prognostic factor in OSCC patients.Conclusions: Silencing shJARID1B inhibits migration and invasion of human OSCC, reduces cancer stem cell activities and potentiates tumor-inhibiting radiotherapeutic effects. JARID1B knockdown prior to radiotherapy is a potential effective therapeutic strategy for the treatment of OSCC. (C) 2015 Elsevier Ireland Ltd. All rights reserved.