当前位置: X-MOL 学术Oncogenesis › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Inhibition of Bruton’s tyrosine kinase as a therapeutic strategy for chemoresistant oral squamous cell carcinoma and potential suppression of cancer stemness
Oncogenesis ( IF 6.2 ) Pub Date : 2021-02-27 , DOI: 10.1038/s41389-021-00308-z
Shao-Cheng Liu , Yang-Che Wu , Chih-Ming Huang , Ming-Shou Hsieh , Ting-Yi Huang , Chin-Sheng Huang , Tung-Nien Hsu , Mao-Suan Huang , Wei-Hwa Lee , Chi-Tai Yeh , Chun-Shu Lin

Locally advanced oral squamous cell carcinoma (OSCC) requires multimodal therapy, including surgery and concurrent chemoradiotherapy (CCRT). CCRT-resistant and recurrent cancer has a poor prognosis. We investigated the effects of Bruton’s tyrosine kinase (BTK) on CCRT-resistant OSCC tissues. The effect of ibrutinib, a first-in-class BTK inhibitor, was tested on stem cell-like OSCC tumorspheres. A tissue array was constructed using tissue samples from 70 patients with OSCC. Human OSCC cell lines, SAS, TW2.6 and HSC-3, were examined. Wound healing, Matrigel invasion, and tumorsphere formation assays, as well as immunofluorescence analysis and flow cytometry, were used to investigate the effects of BTK knockdown (shBTK), ibrutinib, cisplatin, and ibrutinib/cisplatin combination on OSCC cells. We demonstrated that BTK was aberrantly highly expressed in the clinical CCRT-resistant OSCC tissue array, which resulted in poor overall survival in our local Tri-Service General Hospital and freely accessible TCGA OSCC cohorts. shBTK significantly downregulated the stemness markers Nanog, CD133, T cell immunoglobulin-3 (TIM-3), and Krüppel-like factor 4 (KLF4) in SAS tumorspheres and attenuated OSCC cell migration and colony formation. Ibrutinib reduced the number of aldehyde dehydrogenase (ALDH)-rich OSCC cells and reduced tumorsphere formation, migration, and invasion in a dose-dependent manner. Compared with ibrutinib or cisplatin monotherapy, the ibrutinib/cisplatin combination significantly reduced the formation of ALDH + OSCC tumorspheres and enhanced apoptosis. These results demonstrate that ibrutinib effectively inhibits the CSCs-like phenotype of OSCC cells through dysregulation of BTK/CD133 signaling. The ibrutinib/cisplatin combination may be considered for future clinical use.



中文翻译:

抑制布鲁顿酪氨酸激酶作为化疗耐药口腔鳞状细胞癌的治疗策略和潜在抑制癌症干性

局部晚期口腔鳞状细胞癌 (OSCC) 需要多模式治疗,包括手术和同步放化疗 (CCRT)。CCRT 耐药和复发性癌症预后较差。我们研究了 Bruton 酪氨酸激酶 (BTK) 对 CCRT 耐药 OSCC 组织的影响。依鲁替尼是一流的 BTK 抑制剂,其作用在干细胞样 OSCC 肿瘤球上进行了测试。使用来自 70 名 OSCC 患者的组织样本构建了组织阵列。检测了人 OSCC 细胞系 SAS、TW2.6 和 HSC-3。伤口愈合、Matrigel 侵袭和肿瘤球形成测定,以及免疫荧光分析和流式细胞术,用于研究 BTK 敲低 (shBTK)、依鲁替尼、顺铂和依鲁替尼/顺铂组合对 OSCC 细胞的影响。我们证明了 BTK 在临床 CCRT 抗性 OSCC 组织阵列中异常高表达,这导致我们当地的三军综合医院和可免费获得的 TCGA OSCC 队列的总体生存率较差。shBTK 显着下调 SAS 肿瘤球中的干细胞标记物 Nanog、CD1​​33、T 细胞免疫球蛋白-3 (TIM-3) 和 Krüppel 样因子 4 (KLF4),并减弱 OSCC 细胞迁移和集落形成。Ibrutinib 以剂量依赖的方式减少了富含醛脱氢酶 (ALDH) 的 OSCC 细胞的数量,并减少了肿瘤球的形成、迁移和侵袭。与依鲁替尼或顺铂单药疗法相比,依鲁替尼/顺铂组合显着减少了 ALDH + OSCC 肿瘤球的形成并增强了细胞凋亡。这些结果表明,依鲁替尼通过 BTK/CD133 信号传导失调有效抑制 OSCC 细胞的 CSCs 样表型。伊布替尼/顺铂组合可考虑用于未来的临床使用。

更新日期:2021-02-28
down
wechat
bug