Inhibition of Bruton’s tyrosine kinase as a therapeutic strategy for chemoresistant oral squamous cell carcinoma and potential suppression of cancer stemness
Abstract 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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-02-01
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| Series: | Oncogenesis |
| Online Access: | https://doi.org/10.1038/s41389-021-00308-z |
| _version_ | 1830345417616785408 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Shao-Cheng Liu |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-19T22:42:38Z |
| format | Article |
| id | doaj.art-4f72df9b96cb4851b97f483a721756ee |
| institution | Directory Open Access Journal |
| issn | 2157-9024 |
| language | English |
| last_indexed | 2024-12-19T22:42:38Z |
| publishDate | 2021-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Oncogenesis |
| spelling | doaj.art-4f72df9b96cb4851b97f483a721756ee2022-12-21T20:03:01ZengNature Publishing GroupOncogenesis2157-90242021-02-0110211810.1038/s41389-021-00308-zInhibition of Bruton’s tyrosine kinase as a therapeutic strategy for chemoresistant oral squamous cell carcinoma and potential suppression of cancer stemnessShao-Cheng Liu0Yang-Che Wu1Chih-Ming Huang2Ming-Shou Hsieh3Ting-Yi Huang4Chin-Sheng Huang5Tung-Nien Hsu6Mao-Suan Huang7Wei-Hwa Lee8Chi-Tai Yeh9Chun-Shu Lin10Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical CenterSchool of Dentistry, College of Oral Medicine, Taipei Medical UniversityDepartment of Otolaryngology, Taitung Mackay Memorial HospitalSchool of Dentistry, College of Oral Medicine, Taipei Medical UniversityDepartment of Hematology and Oncology, Cancer Center, Taipei Medical University—Shuang Ho HospitalSchool of Dentistry, College of Oral Medicine, Taipei Medical UniversitySchool of Dentistry, College of Oral Medicine, Taipei Medical UniversitySchool of Dentistry, College of Oral Medicine, Taipei Medical UniversityDepartment of Medical Research & Education, Taipei Medical University—Shuang Ho HospitalDepartment of Medical Research & Education, Taipei Medical University—Shuang Ho HospitalDepartment of Radiation Oncology, Tri-Service General Hospital, National Defense Medical CenterAbstract 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.https://doi.org/10.1038/s41389-021-00308-z |
| spellingShingle | 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 Inhibition of Bruton’s tyrosine kinase as a therapeutic strategy for chemoresistant oral squamous cell carcinoma and potential suppression of cancer stemness Oncogenesis |
| title | Inhibition of Bruton’s tyrosine kinase as a therapeutic strategy for chemoresistant oral squamous cell carcinoma and potential suppression of cancer stemness |
| title_full | Inhibition of Bruton’s tyrosine kinase as a therapeutic strategy for chemoresistant oral squamous cell carcinoma and potential suppression of cancer stemness |
| title_fullStr | Inhibition of Bruton’s tyrosine kinase as a therapeutic strategy for chemoresistant oral squamous cell carcinoma and potential suppression of cancer stemness |
| title_full_unstemmed | Inhibition of Bruton’s tyrosine kinase as a therapeutic strategy for chemoresistant oral squamous cell carcinoma and potential suppression of cancer stemness |
| title_short | Inhibition of Bruton’s tyrosine kinase as a therapeutic strategy for chemoresistant oral squamous cell carcinoma and potential suppression of cancer stemness |
| title_sort | inhibition of bruton s tyrosine kinase as a therapeutic strategy for chemoresistant oral squamous cell carcinoma and potential suppression of cancer stemness |
| url | https://doi.org/10.1038/s41389-021-00308-z |
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